Akciğer kanserli hastalarda primer tümör tanısı ve evrelemede Tc-99m glutatyon sintigrafisinin rolü: ön sonuçlar

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Introduction
Glutathione (GSH, γ--glutamylcysteinylglycine) is
a tripeptide which has an important metabolic role
in detoxification reactions, protecting cells against
damage from endogenous and exogenous free radicals, oxidants and other electrophilic substances such
as chemotherapeutics and also from radiation (1-4).
Some studies have shown that there is an increased
demand for GSH in cell injury and cancer cells (5-7).
GSH can be easily labeled with Tc-99m pertechnetate and labeling efficiency is very high (8,9). Tc-
99m GSH scintigraphy has potential to image the in
vivo GSH metabolism of tumor cells. Up to date, its
labeled form has been studied as a potential radiopharmaceutical for several tumors including head and
neck tumors (8) and malignant melanoma (10).
Increased GSH levels and GSH peroxidase activity
have been reported in small (SCLC) and non-small
cell lung carcinomas (NSCLC) (11-18), and there has
been heightened cellular extraction of GSH from circulation (19,20). Moreover, tumor-bearing lung is
capable of extracting higher amounts of GSH from
the pulmonary circulation compared to normal lung
(21). The aim of this preliminary study was to investigate the potential role of Tc-99m GSH scintigraphy,
as a functional imaging method, in the evaluation of
patients with newly diagnosed lung cancer.
Material and Methods
Patients: Twenty five patients (23 male, 2 female,
aged 37-69, mean 60.5 years) with newly biopsyproven primary lung cancer were included in this
study (Table I). All patients were evaluated by means
of computerized tomography (CT), ultrasonography
(US) and bone scintigraphy for the detection of primary tumor extention, before the onset of specific
treatment. Patients with metastatic lung disease or
lung cancer with other known lung pathologies were
excluded from the study. Approval of the local ethics
* Department of Nuclear Medicine, Gulhane Military Medical Faculty
** Department of Pulmonary Medicine, Gulhane Military Medical Faculty
Reprint request: Dr. A. Özgür Karaçalıoğlu, Department of Nuclear Medicine,
Gulhane Military Medical Faculty, Etlik-06018, Ankara
E-mail: aokaracali@yahoo.com
Date submitted: December 11, 2009 • Date accepted: December 16, 2009236 • December 2009 • Gulhane Med J Karaçalıoğlu et al.
committee was obtained and the study was fully explained to each patient by obtaining their informed
consent prior to the study.
Tc-99m GSH scintigraphy: The reduced form of GSH
(Sigma Chem. Co., U.S.A) was labeled with Tc-99m
pertechnetate and labeling efficiency was controlled
as described previously (8,9). Briefly, 20 mg GSH was
dissolved in 2 ml water and after pH neutralization,
45-50 mCi (1665-1850 MBq) Tc-99m pertechnetate
was added to the solution to label GSH. A sample of
Tc-99m GSH was spotted on one end of ITLC-SG strip
(1x10cm) (Gelman Instrument Co., USA) and the
strip was dipped into a vial containing methyl ethyl
ketone (MEK) or saline as solvents. Free pertechnetate migrated with MEK and free pertechnetate and
Tc-99m GSH migrated with saline in ITLC-SG strips.
The chromatography strip was cut into two pieces
and they were counted in a dose calibrator (Veenstra
inst VDC-202, NL). The labeling efficiency of Tc-99m
GSH was determined (%migrated in saline-% migrated in MEK). Radiochemical purity of Tc-99m GSH
assessed by ITLC-SG was around ≥95%.
Whole body (WB) imaging was performed at the 1st
and 3rd hours after the injection of 555 MBq (15 mCi)
of Tc-99m GSH by using large field of view gamma
camera equipped with a low energy, all purpose collimator (Millennium, GE Medical Systems, Milwaukee,
WI). Single photon emission computed tomography
(SPECT) imaging of the thorax was also performed to
evaluate the lymph node involvement in the mediastinum at first hour. The SPECT acquisition protocol
was 64 projection images over a range of 360
o
, sampling times of 28 seconds and 64x64 matrices. Image
reconstruction was done using filtered back projection with a ramp filter.
Data analysis: Two experienced physicians blinded
to patient’s clinical findings evaluated Tc-99m GSH
WB and SPECT images. Only intense abnormal accumulation clearly separated from normal structures
was considered as positive finding for malignant tumor focus. For semiquantitative analysis, a tumor-tobackground (T/Bg) ratio was calculated by drawing
equal-sized regions of interests (ROI) around the tumor and an area of normal lung tissue in the contra
lateral site on early and late WB scans.
Statistical analysis: Wilcoxon’s Matched-Pairs
Signed-Ranks test and Kruskal Wallis test were used
to evaluate any difference between early and late T/Bg
ratios and any difference in T/Bg ratios of the subgroups, respectively. Statistical analysis was performed
by using the SPSS 10.0 Statistical Package Program
for Windows (SPSS Inc., Chicago, Illinois, USA).
Differences were considered significant at p<0.05.
Results
Increased tracer uptake in primary lesion sites in 23
and 22 of 25 patients in the study group were demonstrated by SPECT and WB Tc-99m GSH imaging,
respectively (Table I). The T/Bg ratios in early and late
images ranged from 1.29 to 2.35 (mean 1.74) and 1.41
to 4.03 (mean 2.01), respectively. A representative
case with lung adenocarcinoma is shown in Figure 1.
Although enlarged lymph nodes in the mediastinum
were detected in 13 of 25 patients (52%) by CT imaging, we could not observe any uptake in the mediastinum either on WB or SPECT images. Twelve of 25
patients in the study group had a total of 17 distant
metastatic sites (9 bone, 4 liver and 4 CNS metastases), which were detected with conventional imaging
methods. Six of these metastatic foci (2 bone, 2 liver
and 2 central nervous system) were accurately identified by Tc-99m GSH scintigrapy. On the other hand,
one metastatic focus in paraaortic lymph node and
another one in the left adrenal gland could not be
detected by Tc-99m GSH scintigrapy in two patients.
Table I. Whole body scintigraphic and pathological results of the
study population
No Age Diagnosis Early tumor/
background
Late tumor/
background
1 37 Adenocarcinoma 1.62 1.66
2 56 Adenocarcinoma 2.20 2.41
3 54 Adenocarcinoma 2.30 4.03
4 56 Adenocarcinoma
(Poorly differentiated)
1.29 1.41
5 66 Adenocarcinoma
(Poorly differentiated)
1.60 1.73
6 58 Adenocarcinoma 1.65 1.68
7 48 Adenosquamous carcinoma - -
8 63 Small cell carcinoma 1.62 1.73
9 67 Small cell carcinoma 1.60 1.73
10 66 Small cell carcinoma - -
11 46 Large cell anaplastic carcinoma 1.79 1.88
12 60 Large cell anaplastic carcinoma 1.40 1.44
13 68 Squamous cell carcinoma 1.48 1.74
14 64 Squamous cell carcinoma 2.35 3.64
15 54 Squamous cell carcinoma 1.50 1.80
16 69 Squamous cell carcinoma - -
17 54 Squamous cell carcinoma 1.73 1.89
18 69 Squamous cell carcinoma 2.13 2.24
19 69 Squamous cell carcinoma 1.77 1.94
20 67 Squamous cell carcinoma 1.86 2.01
21 57 Squamous cell carcinoma 1.56 1.94
22 62 Squamous cell carcinoma 1.45 1.73
23 55 Squamous cell carcinoma 1.67 1.75
24 69 Squamous cell carcinoma 1.94 2.22
25 61 Squamous cell carcinoma 1.80 1.82Volume 51 • Issue 4 Tc-99m glutathione scintigraphy in lung cancer • 237
Discussion
According to our results, the efficiency of Tc-99m
GSH to show the primary lung cancer is satisfactory.
Average T/Bg ratios derived from both early and late
images are very close to calculations derived measurements from tumor specimens under in vitro conditions
(21). Tc-99m GSH has been used to image the inflammatory lesions previously (9). Moreover, it has been
shown moderate Tc-99m GSH uptake in primary lung
cancer, as well. So, it is not expected to be helpful in
differential diagnosis of solitary pulmonary nodule.
Tc-99m GSH imaging did not show any pathological uptake in the mediastinum in 13 cases that have
enlarged lymph nodes on their CT scans. Actually,
elevated blood pool activity probably caused by protein binding restricts to assess the lesions located in the
mediastinum, even with SPECT imaging. Moreover,
the detection rate of Tc-99m GSH scintigraphy in
distant metastases demonstrated by conventional
methods in these patients was also low. Although the
decreased uptake mechanism in distant metastases is
not clear, altered GSH metabolism in these metastatic foci may be one of the reasonable explanations.
According to the overall results of this small patient
group, Tc-99m GSH scintigraphy seems not to be
helpful in the staging of lung cancer.
Uptake of the Tc-99m GSH in primary lesions increases in time. A decrease in background activity due
to renal clearance of the radiopharmaceutical or an
increase in tumoral uptake can probably be underlying reasons. Therefore, late imaging as in bone scan
can increase the detection rate of primary lesion and
quality of the scan.
It can be concluded that Tc-99m GSH is not helpful in the clinical management of patients with lung
cancer, but one point should be considered that Tc-
99m GSH scintigraphy can reflect the in vivo GSH
metabolism of a malignant pulmonary lesion. Since,
we can assume that GSH labeled with Tc-99m behaves like GSH in the circulation, it may demonstrate
the GSH metabolism of a malignant lesion. Many reports suggest the elevated cellular GSH as the source
of resistance to chemotherapeutic agents or radiation
therapy in patients with cancer (22-26). On the contrary, depletion of cellular GSH level may cause to
increase cytotoxic effects of anticancer drugs (27-30).
Therefore, functional imaging with Tc-99m GSH may
provide important physiological information about
chemotherapy or radiotherapy resistance by monitoring the GSH levels in vivo.
Although Tc-99m GSH seems to be a nonspecific
tumor imaging agent like Ga-67 citrate, Tl-201 chloride and Tc-99m MIBI, and it is not helpful in staging of lung cancer, it is a promising radiopharmaceutical due to having potential to visualize in vivo
GSH metabolism, which is important in chemo- or
radio-therapy resistance. Further studies are needed
to determine the value of Tc-99m GSH scintigraphy
in the evaluation of both resistance in radiation and
chemotherapy in lung cancer.
Acknowledgement
The authors wish to thank Prof. Meral Ercan for
her excellent guidance in the preparation of the radiopharmaceutical and Tuncay Haciosmanoglu and
Hayati Aksoy for their technical support.