in vivo determination of a modified heat capacity of small hepatocellular carcinomas prior to...

Int. J. Hyperthermia, March 2012; 28(2): 122–131

RESEARCH ARTICLE

In vivo determination of a modified heat capacity of small hepatocellularcarcinomas prior to radiofrequency ablation: Correlation with adjacentvasculature and tumour recurrence

ROBERT G. SHEIMAN1, CHARLES MULLAN2, & MUNEEB AHMED1

1Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue,

Boston, Massachusetts, USA, and 2Department of Radiology Altnagelvin Hospital, Londonderry, Northern Ireland, UK

(Received 5 August 2011; Revised 14 November 2011; Accepted 15 November 2011)

AbstractPurpose: To calculate a modified heat capacity (mHC) of small hepatocellular carcinomas (HCCs) in vivo during radiofrequency ablation (RFA) and to determine if mHC correlates with tumour vascularity, adjacent vessels or local recurrence.Patients and methods: This study was IRB approved and informed consent was obtained from all patients. Before formal RFA,ambient HCC temperature and temperature 1 min after heating at constant wattage were measured in 29 patients. Fromtemperature change and wattage, individual mHCs (joules required to increase tumour temperature by 1� Celsius) werecalculated. Pre-RFA, three-phase computerised tomography (CT) scans were reviewed blindly for hepatic arteries, hepaticveins and portal veins abutting or within 3 mm of tumour edge from which twelve vascular parameters were quantified.Tumour enhancement (homogeneous or heterogeneous on arterial phase) was also assessed. Multiple regression was used tocorrelate mHC with vascular parameters and tumour enhancement. Cox proportional hazard model was used to examine therelationship of mHC to local recurrence.Results: There was significant correlation of mHC with lesion enhancement (P¼ 0.0018), length of hepatic arteries(P< 0.0001) and total hepatic vein volume in contact with tumour (P¼ 0.016). No correlation was found with any non-abutting vessel or portal vein parameter. The chance of local recurrence increased with increasing mHC.Conclusion: Because the modified heat capacity of small HCCs in our study population correlated with HCC enhancement,abutting hepatic arteries, the volume of abutting hepatic veins and local recurrence, it may be an indicator of the heat sinkeffect (HSE) and supports the HSE as a risk factor for local recurrence.

Keywords: radiofrequency ablation, heatsink effect, hepatocellular carcinoma, recurrence

Introduction

Radio frequency ablation (RFA) has become well

established in the treatment of unresectable hepato-

cellular carcinoma (HCC) and in bridging patients

with HCC prior to transplantation. The current

intrinsic limitations of RFA are well known and

include tissue impedance which inhibits energy

deposition into tumour [1], a relatively small zone

of active heating [2], and tumour size. Additionally,

vessels adjacent to tumour can conduct heat and are

believed to limit the ability of RFA to cause complete

tumour ablation [3] and to achieve an adequate

ablative margin [4]. This heat sink effect (HSE) as

formally defined by Goldberg et al. [5] is tissue

cooling by adjacent vessels above 1 mm in diameter

causing a thermal lesion whose shape results from

deflection away from these vessels.

Attempts to quantify the HSE during hepatic RFA

have been made by multiple authors. Patterson et al.

[6] found the number of central blood vessels on

histological examination predicted minimum abla-

tion diameter and volume of RFA lesions created in

normal domestic swine liver in vivo. In their work,

Correspondence: Robert G. Sheiman, MD, Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215,

USA. Tel: (617) 754-2673. Fax: (617) 754-2545. E-mail: [email protected]

ISSN 0265–6736 print/ISSN 1464–5157 online � 2012 Informa UK Ltd.

DOI: 10.3109/02656736.2011.642457

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however, the separate effects of different vessel types

(hepatic artery, portal and hepatic veins) were not

discerned. Lu et al. [7] also performed RFA on

normal pig liver and on histology, found invagination

of normal liver between an RFA lesion and corre-

sponding vessels when vessel diameter exceeded

3 mm. The heat sink effect in HCC however, may

not be well-represented from applying RFA to

normal liver in these animal models. Such models

neglect the relative hypervascularity of HCC com-

pared with adjacent liver [8], and the often altered

surrounding hepatic parenchyma resulting from

underlying liver disease. Additionally, a histological

approach to quantification of the HSE is not readily

applicable in the clinical setting as no tissue is usually

available for histological analysis immediately after

RFA of HCC.

The perceived importance of the HSE is that it

theoretically places a patient at risk for local tumour

recurrence. Kim et al. [9] evaluated the effect of

HCC recurrence when tumour was in contact with

the inferior vena cava or portal or hepatic veins, and

identified local tumour recurrence more frequently

when lesions were in contact with vessels above

3 mm. In this work, the extent of vessel contact with

tumour was determined by contrast enhanced CT

performed within 24 h after RFA. An additional

retrospective clinical study [10] lends credence to the

HSE, again identifying abutting vessels above 3 mm

as a risk factor for recurrence.

A starting point to quantitatively examine vessel

proximity to tumour and thus the heat sink effect, is

to assess a tumour’s overall ability to tolerate heating,

i.e. to determine the amount of energy required to

increase a tumour’s temperature. Heat capacity of

tissue is formally defined as the amount of energy

required to increase the tissue by 1�C per gram of

tissue. A modified definition of heat capacity, the

amount of energy required to increase the temper-

ature of tissue directly adjacent to an RFA electrode,

can be assessed immediately prior to RFA by

employing the RFA electrode’s thermocouple.

Local temperatures obtained within tumour have

been used by other investigators as an indicator for

the extent of overall tumour heating [11]. Thus, this

modified heat capacity (mHC) could potentially be a

general indicator of a tumour’s ability to tolerate

thermal energy which logically depends on a multi-

tude of factors including intrinsic tumour vascularity

and any heat sink effects from adjacent vessels. Thus,

we sought to calculate the mHC of small (<3 cm in

diameter) HCCs in patients undergoing RFA and to

determine whether these values correlate with

tumour vascularity, vessels adjacent to or abutting

tumour as identified on pre-RFA, contrast enhanced

CT scans, and local recurrence after RFA.

Patients and methods

Study population

This study was IRB approved, and informed consent

was obtained from all patients. Patients were iden-

tified by a multidisciplinary team consisting of

transplant surgeons, hepatologists and interventional

radiologists with RFA used primarily on tumours

below 3 cm to bridge to liver transplantation. Study

entrance also required pathological confirmation of

HCC, meeting standard criteria for RFA ablation

[12] and lack of prior ablation (radio frequency,

microwave, and ethanol) or chemoembolisation,

either of which may alter peri-tumoural vascularity.

From October 2008 to October 2010, 29 consecutive

patients with 34 HCCs met these criteria. There were

25 men and four women, median age 58.2 years

(range 29–84). Patient demographics are shown in

Table I. Of the 29 study patients, 25 had docu-

mented cirrhosis (12 Child Class A, 13 Child Class

B). Fifteen had HCV, nine had HBV, one had

alcoholic cirrhosis, one had both HBV and HCV,

and three had non-alcoholic steatohepatitis (NASH).

Radio frequency ablation and calculation of mHC:

Radio frequency ablation was performed using a

single, internally-cooled (Cool-tip�, Valleylab,

Covidien, Boulder, CO) radio frequency electrode

with a 3-cm exposed tip, a 200 W generator

(Covidien) and carried out by one of two interven-

tional radiologists with a minimum of six years of

experience in RFA. To avoid any cluster effects,

when a patient had more than one lesion, only one

lesion was included in our analysis, this chosen by

the interventional radiologist as the first lesion to

undergo ablation and based on ease of accessibility.

Electrode placement through the tumour epicentre

was carried out under CT guidance with adjuvant

grey-scale and colour Doppler ultrasound as needed.

The tapered portion of the electrode’s tip was placed

just beyond the tumour’s edge to standardise the

position of the electrode’s thermocouple within and

just proximal to the distal margin of the tumour.

After desired electrode placement was confirmed by

CT, initial baseline tumour temperature was mea-

sured prior to iced saline infusion. The RFA

electrode was then used for tumour heating with

power maintained constant for each patient for

1 min, after which the generator was turned off and

maximum tumour temperature recorded with the

electrode’s thermocouple. Electrode tip infusion with

cold saline, though used, was stopped at approxi-

mately 40 s (20 s before the generator) to exclude any

effects of the saline on final maximum tumour

temperature. Constant power range varied between

patients but was between 130 and 150 W in all cases.

Correlation with adjacent vasculature and tumour recurrence 123

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Knowing ablation time of 1 min, constant generator

power and initial and final temperatures as indicated

by the RFA electrode, the number of joules required

to increase the adjacent tumour temperature by 1�C

could be calculated, this value termed the mHC with

dimensions of J/�C. Simply put, wattage is joules per

second, generator time was 60 s and temperature rise

from baseline are all known variables. Multiplying

wattage by 60 gives the total number of joules

delivered to the tumour adjacent to the probe with

the resulting temperature caused by this energy

deposition being known. Following the above, all

patients underwent standard RFA for 12 min using a

pulsed RFA technique [13] as recommended by the

manufacturer. In tumours exceeding 2 cm in diam-

eter, overlapping ablations were routinely performed.

Immediate post-ablation probe thermocouple tem-

perature was measured to ensure tumouricidal tem-

peratures over 60�C. An immediate triple-phase scan

was performed employing the same protocol as for

post-ablation follow-up (see CT protocol below) to

assess for any persistent tumour and determine the

need for electrode repositioning and additional

ablation. Ablation was considered complete when a

coagulation zone encompassed the entire tumour

with an ablation margin of at least 5 mm.

Imaging assessment of peri-tumoural hepatic

vasculature

Pre-RFA contrast enhanced CT images of all

tumours were reviewed by two abdominal radiolo-

gists in consensus with a minimum of five years

experience, uninvolved in the actual ablation proce-

dures and using an image archival system

(Centricity, General Electric, Milwaukee, WI).

Images were assessed blinded to patient information

and knowledge of mHC values and at a minimum of

4 weeks after mHC calculation (one abdominal

radiologist performed the calculations). Our hepatic

multi-detector CT protocol consisted of injection of

100 mL of non-ionic contrast (Optiray 350,

Mallinckrodt, Hazelwood, MO) via an antecubital

vein at 5 mL/s during which bolus tracking was used

Table I. Patient demographics (N¼ 29).

Age/gender HCC diameter (mm) HCV HBV Cirrhosis ETOH NASH mHC

65 m 16.0 Y Y 203.08

64 m 17.6 Y Y Y 630.00

54 m 13.2 Y Y Y 240.00

71 f 23.2 Y Y 223.90

52 m 13.7 Y 327.27

49 m 26.7 Y 315.20

55 m 27.3 Y Y 1128.00

63 m 16.1 Y Y 540.21

52 m 10.1 Y Y 324.00

77 m 27.3 Y Y Y 283.33

57 m 12.5 Y Y 262.22

54 m 15.6 Y Y Y 423.08

42 m 27.2 Y Y Y 161.63

58 m 20.7 Y Y 238.24

62 m 20.3 Y Y 1354.29

57 f 14.8 Y 223.90

59 m 13.1 Y Y 451.43

64 m 17.2 Y Y 266.09

29 m 13.7 Y 197.14

53 m 29.1 Y Y Y 496.36

64 m 22.6 Y Y 96.34

56 m 20.8 Y Y 272.90

67 m 20.7 Y Y 243.43

84 f 13.1 Y Y 670.91

53 m 20.2 Y Y 265.71

64 f 11.5 Y Y Y 236.25

69 m 22.1 Y Y 126.67

46 m 20.8 Y Y 195.79

49 m 11.2 Y Y 327.27

Total 29 16 10 25 6 3

mHC�SD* 349.87� 299.97 398.10�278.50 384.15� 292.03 392.71�242.75 366.34� 279.70

m, male; f, female; Y, yes; mHC, modified heat capacity in J/�C; HBV, HCV, hepatitis type B, C; NASH, non-alcoholic steatohepatitis; SD,standard deviation.*Indicates no significant difference in mHC between HCV, HBV and NASH.

124 R. G. Sheiman et al.

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to acquire an arterial phase CT (triggered at

200 HU). This was followed by a portal venous

phase 45 s later. CT parameters included a pitch of

0.984, table increment of 2.5 mm, 40.00 mm/rota-

tion and at 120 kVp with milliampere-second (mAs)

tailored using autosmart software. All CT imaging

was performed on a 64 detector spiral scanner

(Discovery, General Electric) with maximum pixel

size of 0.5–0.7 mm. Axial and multi-planar refor-

matted images were assessed by consensus for

hepatic and portal veins and hepatic arteries above

1 mm in diameter and within 3 mm of the tumour’s

edge as well as vessels abutting tumour. When

abutting tumour, vessel type (artery, hepatic vein,

or portal vein), diameter and the length (arc) of

contact with tumour were independently measured

three times by each reviewer (total of six) and the

average used. Tumour dimensions were also mea-

sured in a similar fashion and their average

documented.

Because HCC enhancement is known to correlate

with perfusion and overall vascularity [14, 15],

tumours were defined as homogeneous in enhance-

ment if they showed uniform enhancement exceed-

ing that of adjacent liver during the arterial phase or

heterogeneous if they had mixed areas of hyper-, iso-

and/or hypodensity relative to adjacent liver during

the arterial phase.

Vascular parameters correlated to mHC

Quantification of adjacent tumour vascularity, and in

theory the heat sink effect, was carried out in the

following manner. For each type of vessel less than or

equal to 3 mm away from and not abutting tumour,

vessel diameters were summated to yield the total

diameter of all hepatic arteries (HATD� 3 mm),

hepatic veins (HVTD� 3 mm) and portal veins

(PVTD� 3 mm). For vessels in contact with

tumour, length (arc) of contact was summated for

each type of vessel to yield total length (arc) of

hepatic artery (HATC), hepatic vein (HVTC) and

portal vein (PVTC) contact with tumour.

Additionally, to normalise vessel contact for lesion

size, the ratio of total length of contact of each type of

vessel was divided by lesion volume to yield contact

per mm3 of tumour, this defined as HATCn, HVTCn

and PVTCn. Tumour volume was determined using

the formula for an ellipse as has been done previously

[16]. Since the heat sink effect should be related to

the volume of blood flow in each adjacent vessel, for

all vessels in contact with tumour, their length of

contact was multiplied by their cross-sectional area

(assuming a circular shape). These values were

summated for each vessel type to approximate

vessel volume by type that was in contact with

tumour.

Post radio frequency ablation follow-up

Follow up multi-detector CT imaging using identical

protocol to that described above, was performed

immediately after ablation and at 1 month, 3 months

and then every 6 months. For patients who did not

undergo liver transplantation over the time of this

study, local disease-free follow-up was considered

the time from RFA to the time of their last CT scan,

and for those with local recurrence, the time from

RFA to the first CT confirming recurrence. Criteria

for CT recurrence consisted of abnormally enhanc-

ing tissue either within or along any portion of the

original ablation zone on arterial phase images. For

those who were transplanted, local diseasefree

follow-up or time to local tumour recurrence was

based on the date and findings at explant pathology.

Statistical analysis

The overall goal was to examine if any of these 12

defined vascular parameters obtained from pre-RFA

CT and presumed to be an indicator of the heat sink

effect, correlated with the mHC. Stepwise multi-

regression analysis was carried out to assess for any

true independent association of any vascular param-

eter with mHC. Tumour enhancement pattern

and tumour volume were also added to our analysis

to look for any relationship with mHC. A non-

parametric t-test was used to assess for any differ-

ences in follow-up time or mHC values between

patients with and without local recurrence and for

differences in mHC between patients with HCV,

HBV, cirrhosis and non-alcoholic steatohepatitis.

These analyses were performed using the SAS

system, version 9.1 (SAS Institute, Cary, NC).

Finally, a Cox proportional hazard model was used

to assess for any relationship between mHC and local

recurrence using Matlab software version R2007a

(Mathworks, Natick, MA).

Results

Vascular parameters correlated to mHC

Mean lesion size (maximum dimension) was

18.6� 5.6 mm (�SD) and lesion volume was

4.21� 3.58 cm3. The mean number of ablations

per lesion was 1.7 (range 1–3) Modified heat capacity

values ranged from 96 to 1354.29 J/�C with a mean of

366.34� 279.70 J/�C. Twelve tumours were in con-

tact with hepatic arteries (Figure 2), 13 with portal

veins and 13 with hepatic veins. These included four

with both hepatic artery and hepatic vein contact,

two with artery and portal vein contact and three with

contact by both portal and hepatic veins. Two

tumours were in contact with all three types of

vessels and four had no contact with any vessel. The


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distribution of vessels in contact with each individual

HCC as related to their mHC values is summarised

in Figure 1. For vessels in contact with tumour,

mean hepatic artery diameter was 1.4 mm� 0.7 mm,

mean hepatic vein diameter was 2.8 mm� 1.5 mm

and mean portal vein diameter was 2.8

mm� 1.1 mm.

Vascular parameter values and statistical results

are summarised in Table II. Multiple regression

indicated significant correlation of mHC with lesion

enhancement (P< 0.0018), HATC (P< 0.0001),

and HATCn (P¼ 0.0077) but not hepatic artery

volume. Hepatic vein and portal vein arc of contact

(HVTC, PVTC) did not correlate with the modified

heat capacity either alone or when normalised for

tumour size (HVTCn and PVTCn). However, total

hepatic vein volume in contact with tumour

(Figure 3) did correlate with mHC (P¼ 0.016)

while portal vein volume did not (Figure 4).

No patients had hepatic veins within 3 mm of

tumour edge, so the relationship between

HVTD� 3 mm and mHC could not be explored.

Eight had arteries and 12 had portal veins within

3 mm of tumour edge. In these cases mean arterial

diameter was 1.2 mm� 0.1 mm and for portal veins,

3.2 mm� 0.1 mm. No correlation between mHC

and PVTD� 3 mm or HATD� 3 mm was found.

Finally, there was no relationship between mHC and

tumour volume, nor significant differences in mHC

between patients with HCV, HBV, cirrhosis or

NASH.

Post radio frequency ablation follow-up

Patient follow-up is summarised in Table III. Mean

follow-up time was 309 days� 95 days for all 29

patients. Based on CT follow-up in patients who did

not undergo transplantation, seventeen remained

free from local recurrence at a mean follow-up of

310� 89 days while four showed local recurrence at

362� 47days after RFA.

Eight patients underwent transplantation, none

showed local tumour recurrence based on CT,

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

HA

HA+HV

HA+PV

HA+HV+P

VHV

HV+PV PV

NOCONTA

CT

Vessel type

mH

C

Figure 1. Each bar represents a single HCC with the type of abutting vessels and associated mHC value indicated on theX and Y axes respectively. Less energy (lower mHC) was required to heat tumour adjacent to the RFA electrode when therewere no abutting hepatic arteries or veins or only abutting portal veins. mHC values significantly increased with the extent ofcontact with hepatic arteries and hepatic veins. mHC, modified heat capacity in J/�C. HA, hepatic artery; HV, hepatic vein;PV, portal vein.

Figure 2. Coronal arterial phase CT image of a 55-year-old man with HBV cirrhosis. Note artery (black arrows)abutting the inferolateral margin of a heterogeneouslyenhancing HCC (white arrowhead). Patients’ modifiedheat capacity was 1128 J/�C.


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however three had recurrence at 211� 123 days

based on viable tumour at the periphery of the RFA

site seen on explant pathology. The remaining five

patients were free of local recurrence based on

explant pathology at 322� 114 days follow-up.

Overall, recurrence was seen in seven of 29 patients

at a mean follow-up of 297� 112 days, which did not

significantly differ from follow-up in those without

recurrence at a mean of 313� 92 days. The mean

mHC value in those with recurrence was

691.71� 393.2 J/�C which significantly differed

from the mean mHC value of 267� 291.92 J/�C

seen in those with recurrence (P< 0.01). Cox pro-

portional hazard model demonstrated a significant

relationship between mHC and local recurrence

(P¼ 0.017); and indicated the chance of local recur-

rence increased 2.03-fold (95%CI 1.14–3.63) for

every increase in mHC of 100 J/�C. All seven patients

with local recurrence had a mHC above 315 J/�C

compared with only four of 22 without recurrence.

Discussion

The heat sink effect is generally considered a

limitation of the effectiveness of RFA in general

and when compared to other ablation techniques

[17]. Histological confirmation of the HSE has been

performed in animal studies in vivo using normal

lung and hepatic tissue. Lu et al. [7] carried out RFA

on normal swine liver and found viable hepatocytes

juxtaposed between the radio frequency lesion and

vessel wall in 12 of 24 veins greater than 3 mm in

diameter, seven of seven veins greater than 5 mm but

in zero of 96 vessels less than 2 mm in diameter.

These investigators concluded that the HSE should

be expected in hepatic tissue undergoing RFA when

adjacent to vessels above 2–4 mm. Similarly, on

histological assessment, Steinke et al. [18] found an

inverse relationship between the extent of vessel wall

damage caused by RFA (their definition of the HSE)

and vessel diameter in normal sheep lung. They

identified a 3-mm diameter threshold for vessels

above which the HSE was consistently seen.

Although such results seem to confirm the concept

of the HSE, the clinical applicability of results relying

on normal tissue is questionable due to neglecting

the effects of tumour perfusion and altered sur-

rounding tissue composition, both of which are

known to have a major impact on RFA volume

based on tumour and mathematical models [19, 20].

Within the literature there also appears to be

controversy concerning the validity of the HSE as a

true risk factor for local HCC recurrence after RFA.

Kim et al. [9] found that nine of 19 HCCs with

abutting vessels above 3 mm had local recurrence

after RFA compared with only 10 of 53 with abutting

vessels below 3 mm. Although this appeared to be a

significant difference on univariate analysis, it was

not maintained on multivariate analysis.

Additionally, a follow-up study by these same

investigators [21] found only that an ablative

margin <3 mm was associated with local HCC

progression after RFA. The importance of the

ablation margin rather than the HSE was also

identified by others [22, 23] who found no correla-

tion between local HCC recurrence and either

tumour contact with major (major not defined)

vessels or vessels within 5 mm of a tumour margin.

Figure 3. Axial portal venous phase CT image in an84-year-old woman with Nash and an HCC (black arrow)involving segment VIII of the liver. A hepatic vein (whitearrowheads) is seen abutting tumour along its posterolat-eral aspect. Before performing blinded CT assessment, themodified heat capacity was determined to be 670.91 J/�C.

Figure 4. Man, 57 years old, with HCV cirrhosis. SagittalCT image during the portal venous phase shows a portalvein (black arrow) along the posterior aspect of a patho-logically confirmed HCC (white arrow). No other vesselswere noted to be abutting tumour. Modified heat capacitywas found to be 262.22 J/�C, well below the studypopulation mean of 366.34 J/�C.


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Table III. Patient follow-up from time of RFA and corresponding mHC.

Patient

number

Local recurrence

(days)

Recurrence mHc

(joules/centigrade)

No recurrence

(days)

No recurrence mHc

(joules/centigrade)

1 270 203.08

2 437 630.00

3 477 240.00

4 171 223.90

5 425 327.27

6 466 315.20

7 165 1128.00*

8 526 540.21

9 259 324.00

10 470 283.33

11 294 262.22

12 420 423.08

13 234 161.63

14 510 238.24

15 118 1354.29*

16 235 223.90

17 350 451.43*

18 338 266.09

19 407 197.14

20 223 496.36

21 311 96.34

22 275 272.90

23 315 243.43

24 241 670.91

25 335 265.71

26 244 236.25

27 228 126.67

28 299 195.79

29 329 327.27

Average 355 691.71 313 267.37

Standard deviation 155 393.24 91 291.92

* Recurrence based on explant pathology.

Table II. Correlation of vascular parameters and tumour enhancement to mHC.

Parameter Mean�SD Correlation with mHC

Tumour enhancement NA P¼ 0.0018

Homogeneous (n¼ 16) NA P40.05

Heterogeneous (n¼ 13)

HATC 20.7�12.7 mm P< 0.0001

PVTC 13.2�12.8 mm P40.05

HVTC 16.0�12.9 mm P40.05

HATCn 0.0071� 0.0079 m/mm3 P¼ 0.0077

PVTCn 0.0044� 0.0063 m/mm3 P40.05

HVTCn 0.0045� 0.00591 m/mm3 P40.05

Total hepatic artery volume 37.22� 23.80 mm3 P40.05

Total portal vein volume 90.33� 90.68 mm3 P40.05

Total hepatic vein volume 106.80� 120.47 mm3 P¼ 0.016

HATD� 3 mm (n¼ 8) 1.2�0.1 mm P40.05

PVTD�3 mm (n¼ 12) 3.2�0.1 mm P40.05

HVTD� 3 mm (n¼ 0) NA NA

HATC, PVTC, HVTC, arc of contact of hepatic artery, portal vein, hepatic vein in contact with tumour edge;HATCn, PVTCn, HVTCn, above parameters normalized for tumour volume; HATD� 3 mm, PVTD� 3 mm,HVTD� 3 mm, summation of hepatic artery, portal vein, hepatic vein diameters within 3 mm of tumour edge;mHC, modified heat capacity in J/�. P< 0.05 indicates statistical significance.


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On the other hand, Lu et al. [10] performed a

retrospective review of 47 HCCs treated with RFA

and found local recurrence was significantly higher

for lesions adjacent to vessels above 3 mm (8/15)

compared to lesions without abutting vessels (28/32).

Although these authors also did not discern between

vessel types, their findings support the HSE as a risk

factor for local recurrence in clinical practice.

Our results were obtained in vivo from patholog-

ically confirmed, small HCCs (<3 cm) within pre-

dominantly diseased liver, and appear to support the

existence of the HSE during RFA of HCC. The

mHC of an HCC, by definition, is a general indicator

of the ability of tumour adjacent to the electrode to

tolerate heating. Although it does not localise the

points of contact of vessel with tumour or necessarily

uniformly apply to all of the tumour, because the

mHC directly correlated with the volume of abutting

hepatic veins and extent (arc) of hepatic arterial

contact with tumour, it follows that these abutting

vessels affected the ability of RFA to heat the small

HCCs in our study population. We believe that the

mHC could represent an easily obtainable and

clinically realistic parameter which reflects the HSE

experienced by small HCCs during RFA.

As important, on initial assessment the mHC may

allow insight into the risk of local tumour recurrence

after RFA, a finding that further supports the concept

of the HSE. Local recurrence was seen in seven of 11

patients with a mHC above 315 J/�C and in none

below this value. The risk of local recurrence was

found to double for every 100 J/�C increment in

mHC. We point out that this is a cautious conclusion

given that CT is less sensitive for local tumour

evaluation than explant pathology [10] and recur-

rence based on both were combined to achieve

sufficient power for statistical analysis. Because of the

limited number of HCC ablations performed at our

institution and its use for bridging to transplantation,

it is difficult for us to accrue patients who develop

local recurrence based on imaging after RFA. The

potential that the 19 patients without local recur-

rence on follow-up CT could have histological

recurrence does exist. We do note that the mean

mHC of patients with CT-confirmed recurrence was

477.07� 137.2 versus 207.95� 160.83 for those

without recurrence on follow-up CT.

We also found that the mHC of small HCCs

was significantly higher in homogeneously hyper-

enhancing tumours during arterial-phase CT com-

pared to those with heterogeneous enhancement.

With increasing tissue enhancement and thus perfu-

sion [14, 15], there is a decrease in thermal resistance

and increase in heat flow to adjacent vessels [24].

This would help explain why homogeneous tumours

were found to require more thermal energy than

heterogeneous tumours to increase their

temperature, i.e. a higher mHC. These findings are

also supported by mathematical modelling of the

bioheat equation which confirmed that the greater

the tumour vascularity, the greater the thermal sink

and inability to undergo heating by RFA [19].

Heat transfer from tissue to adjacent vessels occurs

predominantly by conduction, governed by Fourier’s

Law [25] and is directly related to the area of contact

and the temperature gradient between the two [26].

Logically, as heat is transferred to blood within a

vessel, the temperature gradient between tissue and

vessel declines and so does heat transfer. The influx

of unheated blood or volumetric blood flow should

therefore directly affect the temperature gradient.

The higher the volumetric blood flow within a vessel,

all else constant, the better the temperature gradient

is maintained and the ability to transfer heat by

conduction (act as a heat sink). Because volumetric

blood flow in a vessel is determined by both cross-

sectional area and blood velocity, for a similar sized

hepatic vein, portal vein and hepatic artery, the

volumetric flow can vary widely due to differences in

blood velocity. This argues that these vessels should

be evaluated separately with respect to their HSE

rather than pooled as done previously, especially for

HCC in a cirrhotic liver. The vascular parameters we

assessed were more robust than in previous studies,

besides making the distinction between vessel type,

we looked at all vessels greater than 1 mm in

diameter, abutting and within 3 mm of tumour

edge. Interpretation included measurements on

extent of tumour contact, extent of contact relative

to tumour size, vessel volume and vessel distance

from tumour edge as a function of vessel type.

Although actual area of vessel contact with tumour is

an important part of heat transfer, this obviously was

not possible to assess with any accuracy on our CT

images.

The modified heat capacity showed no relationship

to the length of abutting hepatic and portal veins or

to the volume of abutting portal veins and arteries. It

did however, correlate with the volume of hepatic

veins in contact with tumour. Because volume was

determined by multiplying vein length of contact

with tumour by vessel cross-sectional area and no

relationship between mHC and contact length was

found, it follows that cross-sectional area, and thus

vein diameter directly impacted on mHC. This is in

comparison to hepatic arteries where the modified

heat capacity was found to correlate with HATC and

HATCn but not hepatic artery volume. Both of these

results may be explained by again considering the

impact of blood volumetric flow on heat transfer. For

the size of hepatic veins dealt with in our study,

volumetric blood flow probably relied more on vessel

size rather than blood velocity, while in the hepatic

arteries velocity was the dominant factor.


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The lack of correlation of mHC with any portal

vein parameter is likely due to our patient population

which consisted of individuals with chronic liver

disease (25/29 with cirrhosis). These patients have

relatively decreased portal flow and compensatory

increased arterial flow [27]. Because of poor portal

flow, these vessels probably act as poor heat sinks in

the true clinical setting and it logically follows that

they should have little to no effect on mHC of HCC

in a cirrhotic liver. Additionally we found no corre-

lation of mHC with hepatic arteries within 3 mm of

but not in contact with HCC. One would think

hepatic arteries close by but non-abutting tumour

could have an effect on mHC given the strong

correlation found with abutting hepatic arteries.

Perhaps, because we had only eight patients with

this scenario and with a mean hepatic artery size of

only 1.2 mm, this relationship was not adequately

tested. Alternatively, the insulatory effect proposed

for cirrhotic tissue [20, 28] which was interposed

between vessel and tumour may explain this finding.

Clearly a larger number of patients with a wider

range of non-abutting arterial diameters are needed

to fully assess this relationship.

There are study limitations that need to be

identified. First, we assumed that vessels abutting

or within 3 mm of tumour would have an effect on

temperature measured by the RFA electrode that was

positioned for tumour ablation rather than at mul-

tiple positions along the tumour’s edge. This

assumption seems valid for our study population,

given that the modified heat capacity had a strong

correlation with abutting arteries and hepatic vein

volume and was unrelated to tumour volume. Thus,

statistically these relationships cannot be random or

due to chance. Additionally, this assumption was

made in all cases so the relative differences among

mHC values and what they reflect should be relevant.

Other published studies concerning overall thermal

clearance within tumours have also relied on only

temperatures obtained from the tumour’s epicentre

[11]. Finally, in clinical practice electrode tempera-

ture is considered the standard surrogate marker for

overall tumour temperature and the tumouricidal

effect of RFA on the entire lesion and not just

tumour adjacent to the electrode. We acknowledge

that all our tumours were small (mean diameter of

18.6 mm) and perhaps in larger tumours, electrode

position relative to tumour’s edge could influence the

results, i.e. in larger lesions determining the mHC

per gram of tissue or true heat capacity may be

necessary to assess the HSE.

We also assumed that tissue heating for 1 min at

constant wattage had no effect on tumour tissue,

intratumoural vessels and adjacent vascularity. This

may not be accurate given that final temperatures

1 min after heating did reach above 50�C in all but

five patients. Above 50�C, tissue necrosis and vessel

thrombosis can occur [29] which would inhibit heat

conductivity within tumour and result in lower

values of heat capacity. However, we argue that

achieving a temperature above 50�C after 1 min of

heating indicates an HCC’s intrinsic inability to

tolerate thermal energy and thus its intrinsic low heat

capacity to start with. In all five patients in whom the

temperature did not exceed 50�C, their HCCs had

abutting arteries which we believe inhibited their

temperature rise. Finally, we also want to again stress

that our results are applicable to HCCs below 3 cm

and predominantly in a cirrhotic liver. They should

not be generalised to larger lesions or other types of

hepatic primary or metastatic malignancies in other-

wise normal liver parenchyma.

In conclusion, the modified heat capacity of small

hepatocellular carcinomas, the ability of tumour

adjacent to the electrode to undergo heating, was

assessed numerically, in vivo, using the thermocou-

ple within an RFA electrode. The mHC values in our

study population were found to correlate with

abutting arteries and the volume of abutting hepatic

veins, and therefore may be a quantitative indicator

of the heat sink effect unique to each small HCC.

Initial observations indicate that the mHC also seems

to substantiate a relationship between the heat sink

effect and potential local recurrence of small HCCs

after RFA.

Declaration of interest: No conflict of interest

exists among any of the authors. The authors alone

are responsible for the content and writing of the

paper.

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in vivo determination of a modified heat capacity of small hepatocellular carcinomas prior to...

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