ANTICANCER RESEARCH 29: 4697-4702 (2009)

Patients with Clinical/Radiological Hyperplasia

of Mammary Glands Show Pathological
Persistence of Temperature of Skin Points
HENG LI1, XUEYONG SHEN1, JIAN YING1, LING ZHAO1, MINGZI JIN1, SHENGFANG THU1,
CHENPING SUN2, FEJA VOORHORST3, HÅVARD SOILAND4, TONE LENDE4 and JAN P. BAAK4,5,6

1Acupunctureand Tuina College, Shanghai University of Traditional Chinese Medicine, Shanghai;

2Surgery
Department, Longhua Hospital, Shanghai 200030, P.R. China;
3Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
4Department of Pathology, Stavanger University Hospital, Stavanger;
5The Gade Institute, University of Bergen, Bergen, Norway;
6Free University, Amsterdam, the Netherlands

Abstract. Background: Hyperplasia of mammary glands
(HMG) is a frequent disease, with increased cancer risk for
women aged 20-55 years. The aim of this study was to
explore a non-invasive method to identify which patients with
breast complaints need additional mammography for HMG
diagnosis. Patients and Methods: Skin digital infrared
thermal imaging (DITI) in 74 patients with HMG and 63
controls was carried out. Results: In the controls, the
temperature of points close to the breasts and ovaries
decreased with age. In women older than 39 years, HMG
patients showed persistently high temperatures but in the
lower extremities there were no differences. With a threshold
for thoracic skin point KI21 of 33.2ºC, sensitivity and
specificity in distinguishing controls from HMGs were 96%
and 52% (p=0.0001) respectively, as validated in a test set,
similar to recent DITI results for breast cancer detection.
Conclusion: Infrared temperature imaging of specific skin
points is a rapid, non-invasive method to identify patients
requiring mammography to confirm HMG.
Breast cancer is the most frequent malignancy among
women in the Western world and the incidence has sharply
increased over the past four decades (1, 2). In contrast, the
incidence in China, more specifically Shanghai, has
traditionally been very low (5/100,000), but since 1995 there
Correspondence to: Professor X. Shen, Acupuncture and Tuina
College, Shanghai University of Traditional Chinese Medicine,
1200 Cailun Road, Shanghai 201203, P.R. China. Tel: +86
2151322175, Fax: +86 2151322174, e-mail: snowysh@hotmail.com
Key Words: Breast, hyperplasia, dysplasia, infrared temperature,
skin.
has been a sharp (eight fold) increase in the incidence from
5 (1985-1995) to 40/100,000 (in 2005) (3-5).
Many women between 20-55 years of age with complaints
such as uni- or bilateral breast hypersensitivity or pain,
worsening around or during menstruation, are understandably
concerned and may seek medical attention. In most cases,
clinical examination does not show anything specific.
However, in a certain percentage of patients, physical
evaluation reveals that one or both breasts have single or
multiple small nodular changes, the borders of which are not
well defined, have no cohesion with the surrounding tissue and
are therefore easily movable. If in addition, molybden target
X-ray mammography shows no signs of cancer but high-
density mammographic parenchymal patterns, as measured by
the proportion of breast area composed of epithelial and
stromal tissue are detected (6), the combination of these
clinical-palpatory and radiological findings is called
hyperplasia of the mammary glands (7) (see Table I).
As Figure 1 shows, HMG is not the same as mammary
dysplasia, a histopathological condition which develops through
a gradual process from normal breast tissue to hyperplasia,
atypical hyperplasia, to carcinoma in situ (CIS), and invasive
carcinoma (8). Mammary dysplasia is a precancerous lesion and
in some dysplasias, invasive cancer can be found in the follow-
up. The risk of breast cancer in HMG is however, much lower,
although is still higher when compared to healthy women (7).
This means that performing mammography (which can be an
unpleasant procedure) is overtreatment in those women with
HMG who may not actually develop breast cancer. Therefore, it
could be of great benefit to develop a method to identify those
patients with breast complaints which are not HMG, as such
women do not require mammography. Such a method should
be rapid, easily applicable, inexpensive, sensitive and if
possible, non-invasive and harmless.

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 ANTICANCER RESEARCH 29: 4697-4702 (2009)

Table I. The diagnosis of hyperplasia of the mammary glands (HMG) is based on a combination of clinical and radiological criteria. HMG is not
the same as mammary dysplasia, which is a histopathological diagnosis.

# Type Criterion

1 Main clinical complaints
2 Clinical-physical examination
3 Age distribution
4 Molybden target X-ray mammography
5 Exclusion criteria
Uni- or bilateral breast hypersensitivity or pain, often worse around or during menstruation.
a) One or both breasts have nodular changes.
b) The borders of these nodules are not well defined.
c) The nodules have no cohesion with the surrounding tissue.
d) Therefore, the nodules are easily movable.
The disease is most common between age 20 and 55.
a) No signs for cancer, but,
b) there are high-density mammographic parenchymal patterns, as measured
by the proportion of breast area composed of epithelial and stromal tissue*.
Exclude patients
a) before menarche,
b) currently using hormone treatment,
c) stopped hormone treatment less than 6 months previously, and
d) males.

*Byrne et al. (6).

Digital infrared thermal imaging (DITI) was introduced
into medicine in the late 1950s. Early studies suggested that
the method could be useful for breast cancer detection,
amongst others. But the early instrumentation was not
sensitive enough to detect the subtle changes in temperature
needed for accurate detection and monitoring of breast
disease. However, in recent years the sensitivity and
resolution of infrared instruments has greatly improved. One
recent study on breast biopsies which were recommended
based on prior mammogram or ultrasound indicated that
DITI is a valuable adjunct to mammography and ultrasound,
especially in women with dense breast parenchyma (9).
In agreement with these findings, we recently found that
the infrared radiation temperature of certain skin points is
significantly different in patients with HMG when compared
with healthy women of the same age group (20-55 years). In
order to increase the sensitivity of DITI for identifying
HMG, it remains to be assessed whether these findings are
age dependent (10). If so, DITI could be used in specific age
groups as a simple outpatient clinic system, identifying those
patients with clinical HMG signs who do and those do not
require additional mammography. We have therefore
analyzed 74 patients with clinically radiologically confirmed
HMGand 63 healthy control women of the same age. The
2008 World Health Organization (WHO) system was used to
select the different skin points for measurement (11).
Patients and Methods
Diagnostic criteria, patients and healthy controls. The 2002
diagnostic criteria for HMG (7) were used. Seventy-four patients
with HMG were diagnosed at the Longhua Hospital, Shanghai,
China. During the same period, healthy women in the same age
groups as the patient group were selected from the employee file of
the Shanghai University of Traditional Chinese Medicine.
Participation was strictly voluntary (the study resources did not
allow us to provide a volunteer for all 74 patients). Each of the 63
volunteers was given a thorough physical examination by a medical
specialist in breast disease and additional standard breast
examinations were performed as indicated by the 2002 criteria (7).
None of the volunteers had any signs of breast, endocrine of
hormonal abnormalities, neither at examination nor in her history.
The diagnosis in all cases was confirmed by B-mode ultrasonic
examination or molybdenum target X-ray.
Determination method. The ThermaCAM™ P30 infrared thermal
imaging system manufactured by the FLIR System Company in
Sweden was selected to determine room temperature of 22(±2)˚C,
and relative humidity of 40(±10)%, in a dark room with two 36-watt
fluorescent lamps. There was no obvious air flow, no loud noises
and no electromagnetism in the room. Before determination, the
participants were requested to enter the laboratory, untie their bra,
and sit for 30 min to adapt to the surroundings. After that they were
asked to sit up erectly, and expose the body parts to be assessed.
The examiner adjusted the lens to capture the selected locations
from a fixed position 1 m away. Figure 2 shows the examples of the
measurement results. In the control group, there was no difference
between the control points on the left and right trunk (p=0.56) nor
the left and right feet (p=0.20). As there was no correlation between
the points on the trunk and the feet, points on the trunk and feet
were always used for control purposes.
WHO 2008 skin points. The infrared radiation temperature image
on 10 skin points was recorded. The location of points is based on
the location of points stipulated by the 2008 Standard Skin Points
according to the World Health Organization (11). Figure 3 shows
where these points are located on the body surface.
Statistical methods. The statistical management was performed
with the SPSS15 software package (SPSS inc, Chigago, Il, USA).
Normality of the distributions was tested and no differences were
found. The infrared radiation temperature comparison on body

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 Li et al: DITI in Breast Hyperplasia

Figure 1. Diagram illustrating the relationship between patients with breast

complaints, hyperplasia of the mammary glands and dysplasia. Many
women have breast complaints (blue circle), but only a small proportion
have specific physical palpatory and radiological mammographic changes
which are diagnostic for HMG (green-orange circle) (see text). Some of
these HMG patients also have microscopic dysplasia (dotted black circle)
associated with an increased cancer risk. Patients with HMG also have an
increased cancer risk, although not as high as patients with dysplasia.

Figure 2. Examples of the infrared temperature measurement results of

the trunk（top）and lower extremity (bottom) skin points. Top:. From
left to right, under the needles are right chest control point, CV17 and
left chest left point. Spot (Sp) 1 is the point being measured. Bottom: Figure 3. The localization of the different WHO 2008 skin points
Below the needles are right KI3 and right foot control point (Sp1). analysed.

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 ANTICANCER RESEARCH 29: 4697-4702 (2009)
Figure 4. Scatter plot of age versus the temperature of skin point KI21
(Youmen) on the right side of the body. Correlation analysis showed a
decrease with age in the controls (R=–0.42, p=0.0007). However, in
patients with hyperplasia of the mammary glands (HMG) the temperature
persists at a high level with increasing age (R=–0.04, p=0.74).
surface of points was made by Student’s t- and Mann-Whitney
tests (whenever applicable). Correlation analysis used the Pearson
and Spearman tests. We found practically the same results in the
parametric and non-parametric test, and present the latter. Scatter
plots and box plots were used for graphical analysis of the data.
Receiver operating curve (ROC) analysis was used to discretize
the continuous variables for stepwise multivariate regression
analysis, using the diagnostic groups (healthy controls, HMG
patients) as the classification variable. Random numbers were used
to create a set for learning and testing the results. Moreover, the
results were cross validated, in which each case was classified by
the functions derived from all cases other than that case (leaving
one out method). Sensitivities, specificities, positive and negative
predictive values and overall predictive values were calculated.
Multivariate binary logistic analysis was performed to find the
most optimal combined set of points discriminating HMG patients
and healthy controls.
Results
The age ranged from 20-55 years (mean and standard
deviation: 36.3±8.8 years) for the 74 HMG patients and from
20-50 years (mean and S.D.: 34.5±8.9) for the 63 healthy
controls. The difference in age was not significant (p=0.63).
In the total group of 74+63=137 women, the
temperature of many points on the trunk decreased with
age. However, separate analysis in healthy and HMG
women showed that there is a difference between the two
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Figure 5. Box-plot analysis of separate age groups for the temperature of
point right KI21 (Youmen) of the controls (blue bars) and patients with
hyperplasia of the mammary glands (HMG) (green bars). Note the
difference in skin temperature between HMG cases and controls in
different age groups, which is significant in women over 39 years of age.
groups (Table II). Whereas in the controls the temperature
of nearly all points decreased with age, in HMG patients
the temperature of several points persisted at a high level.
The persistent high temperature of trunk points mainly
concerned HMG patients over the age of 39 years
(p<0.0001, Figures 4 and 5) and was especially evident in
points close to the breasts (WHO skin points KI21 and
LR14), and in the midline of the lower abdomen (point
CV4). On the lower extremities, the skin temperatures
were different from the findings on the trunk as the
temperature was found to decrease with age both in the
healthy controls and HMG, and was therefore basically the
same in the two groups studied.
As the results are clearly most significant for those over
the age of 39, these patients were further investigated. In
order to obtain more reliable results, the analyses were
carried out of the learning set and validated in the tests set.
The temperature at points KI21, LR14 and CV4 gave the
most significant discriminating features. However, KI21 and
LR14 were strongly correlated and binary logistic regression
analysis showed that KI21 and CV4 (p=0.0001 and 0.04
respectively) provide the optimal set of features
discriminating between the HMG patients and healthy
controls. With a threshold of 33.2 ºC for KI21, the optimal
sensitivity (96%), specificity (52%), positive predictive value
(PPV) 68% and negative predictive value (NPV) 93% were
 Li et al: DITI in Breast Hyperplasia

Table II. Comparison of the correlations between the temperature of
skin points and age in healthy controls and patients with hyperplasia of
the mammary glands (HMG). Trunk temperature decreases with age in
the healthy controls, whereas in HMG there is persistent high
temperature at these points.
Table III. Cross validation of the classification, in which each case is
classified by the functions derived from all cases other than that case. A
total of 40/52 (77%) of the original grouped cases were correctly
classified, while 39/52 (75%) of cross-validated grouped cases were
correctly classified.

Skin point Statistic Healthy Patients Difference Diagnostic Predicted group Total
(WHO 2008) controls with between group membership
HMG controls
and HMG Controls HMG
patients
Original Controls 18 (72%) 7 (28%) 25 (100%)
Trunk HMG 5 (19%) 22 (81%) 27 (100%)
CV17 Correlation coefficient –0.35 0.06 Yes Cross-validated Controls 17 (68%) 8 (32%) 25 (100%)
P 0.004 0.64 HMG 5 (19%) 22 (81%) 27 (100%)
ST18 Left Correlation coefficient –0.13 0.13 No
P 0.31 0.26 Results of cross validation
ST18 Right Correlation coefficient –0.22 0.01 No
P 0.09 0.96 Sensitivity 81%
LR14 Left Correlation coefficient –0.29 0.13 Yes Specificity 68%
P 0.02 0.29 Positive predictive value 73%
Negative predictive value 77%
LR14 Right Correlation coefficient –0.37 0.08 Yes
Overall correctly classified 75%
P 0.003 0.51
KI21 Left Correlation coefficient –0.33 –0.03 Yes
P 0.009 0.80
KI21 Right Correlation coefficient –0.42 –0.04 Yes Table IV. Comparison of the sensitivity and specificity of dermal infrared
P 0.0007 0.74 skin temperature measurements by digital infrared thermal imaging (DITI),
CV6 Correlation coefficient –0.38 –0.13 Yes for patients of 40-55 years of age with breast cancer and hyperplasia of
P 0.002 0.29 the mammary glands (HMG).
CV4 Correlation coefficient –0.43 –0.21 Yes
P 0.0004 0.08 Breast cancer* HMG

Sensitivity 97% 96%

Lower extremities
Specificity 44% 52%
ST40 Left Correlation coefficient 0.44 0.30 No
Negative predictive value 82% 93%
P 0.0004 0.01
ST40 Right Correlation coefficient 0.42 0.28 No
*Arora et al. (9). Note the similarity in the figures. The negative predictive
P 0.0006 0.02 value of DITI for detection of HMG makes the technique suitable for
ST42 Left Correlation coefficient 0.09 0.12 No identifying patients with breast complaints who do or do not need additional
P 0.47 0.31 mammography to confirm the diagnosis of HMG.
ST42 Right Correlation coefficient 0.02 0.22 No
P 0.89 0.06
LR3 Left Correlation coefficient 0.05 0.21 No Discussion
P 0.68 0.08
LR3 Right Correlation coefficient 0.07 0.24 Yes The results show that compared with healthy controls,
P 0.58 0.04 patients with HMG have a pathologically persistent high
KI3 Left Correlation coefficient 0.02 0.18 No
temperature on body surface points closely located to the
P 0.90 0.12
KI3 Right Correlation coefficient 0.02 0.18 No breasts (KI21, LR14), particularly in women 39 years of age
P 0.90 0.14 and older. The fact that the results are very similar in the set
for learning and testing, and in the cross-validation analysis,
P, Probability of no significance. indicates that the number of patients is adequate and the
results robust and reliable. Nevertheless, validation in future
independent patients remains important.
obtained (area under the curve 0.82, standard error 0.06, Interestingly, a recent article found that DITI identified
p=0.0001). Using the ‘leaving one out’ method, cross breast cancer with 97% sensitivity, 44% specificity, and 82%
validation analysis again indicated that KI21 and CV4 were negative predictive value (9). In the current study to detect
the only two skin points with additional independent breast hyperplasia, the values are the same or better (97%,
discriminating value. The classification results of the test set 52% and 93%, respectively, see Table IV). This indicates that
and cross validation are nearly identical, with 77% and 75% the accuracy of DITI in detecting different types of breast
correctly classified cases, respectively (Table III). lesions is similar. The high NPV of DITI for detection of

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 ANTICANCER RESEARCH 29: 4697-4702 (2009)
HMG makes the technique suitable to identify patients with
breast complaints who need additional mammography to
confirm the diagnosis of HMG.
The findings may reflect up-regulation of the growth activity
of glandular cells of the breast whereas the abnormally
persistent high temperature at skin point CV4 possibly indicates
persistent overactivity of the ovaries with high oestrogen
secretion. This may result in an oestrogen-dependent
hyperplasia of the mammary glands, as continuous growth
stimulation of the breast cells has been hypothesized as being a
cause of breast cancer. Indeed, long-term hormonal replacement
therapy is related to a significant increase in breast cancer (12).
The question is whether persistent high activity at CV4 is
correlated with persistently high blood oestrogen levels.
Unfortunately, we do not have endocrinological data of our
patients, but such a study would be scientifically interesting and
important. Another possible explanation is that the persistent
activity may be related to the patient being overweight, which
has recently been classified by the World Health Organization
and the International Agency for Research on Cancer as an
important risk factor for breast cancer (13). The increase of
overweight individuals in the Western world, and also in China,
is alarming. It would therefore be important to study whether a
relationship exists between the body mass index and skin point
temperature. Preferably, the proliferation activity of the breast
glandular cells should also be analyzed in such future studies, as
this by definition is an important aetiological factor in breast
carcinogenesis. Proliferation depends in part on the
vascularization of the tumour, which explains that the degree of
vascularisation in certain studies is prognostically important
(14). Indeed, measurement of the vascularisation in breast
cancer by automated digital image processing is strongly
prognostic (15, 16), but requires biopsy material. Dynamic
nuclear magnetic resonance imaging is possibly an alternative
non-invasive method to measure vascularization, but
unfortunately is labour intensive and expensive.
Conclusion
Female patients with HMG 39 years of age and older show a
pathological persistence of high temperature on body surface
points related to the breasts and ovaries. A similar but non
significant trend was observed for those under 39 years old.
Therefore, in women 39-55 years of age and possibly also
younger women with breast complaints, infrared temperature
measurement of specific skin points may be a non-invasive
method to decide which patients need additional mammography
to confirm the diagnosis of HMG.
Acknowledgements
This study was partially supported by the National Basic Research
Program of China (2005CB523306 2009CB522901) and project
2008-08 from the Stichting Bevordering Diagnosatische Morfometrie,
Middelburg, the Netherlands.
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Received June 8, 2009
Revised September 14, 2009
Accepted September 22, 2009