* From the Lung Unit (Drs. Buccheri and Ferrigno), and the Service of Nuclear Medicine (Drs. Biggi and Francini) of the A. Carle and S. Croce Hospitals ("Azienda Ospedaliera S. Croce e Carle"), I-12100 Cuneo, Italy.

KEY WORDS: Lung cancer, staging assessment, treatment response evaluation, computed tomography, ^99mTc-tetrofosmin scintigraphy.

Reprint requests and communications regarding the manuscript: Gianfranco Buccheri, MD, Via Repubblica 10/c, I-12018 Roccavione (CN), Italy, Tel.: +39.0171.441733 or +39.0171.441777, Fax: +39.0171.611597 or +39.0171.441764, Email: buccheri@culcasg.org

The Authors have no financial interest in the subject discussed in this paper. They all have sufficiently participated in the work and in the manuscript preparation. The local committee on human research approved this study.

 ABSTRACT

Study Objectives – ^99mTc-tetrofosmin has recently emerged as a new radiopharmaceutical for cancer visualization. In this study, we investigate its ability to assess lung cancer dissemination and progression.

Design – Prospective study. A ^99mTc-tetrofosmin scan was incorporated into the pretreatment and posttreatment diagnostic workup of lung cancer in the years 1998 and 1999.

Setting – Second referral institution for a province of 500,000 inhabitants.

Patients – Sixty-one patients, strongly suspected of lung cancer, were photoscanned; 21 of them were re-scanned after completion of their front line treatment. Eleven patients were eventually operated upon, and 3 others underwent mediastinoscopy.

Interventions – Both planar and SPECT thoracic views were obtained. Images for the whole body were also acquired.

Results – All 57 patients whose lung cancer was pathologically confirmed showed accumulation of the radiotracer (100% sensitivity). However, three of the 4 non-malignant lesions were also ^99mTc-tetrofosmin positive. ^99mTc-tetrofosmin scan was highly sensitive for the detection of the T0-T2 disease (97% sensitivity), and highly specific for the N0-N1 disease (83% specificity). In the 16 pathologically staged mediastina, sensitivity, specificity and accuracy rates were 73%, 100%, and 81%, respectively. ^99mTc-tetrofosmin scan correctly detected most skeleton (9 of 10) and brain (5 of 7) metastases. The treatment response evaluation made with ^99mTc-tetrofosmin corresponded to the clinical estimate in almost half of the sample.

Conclusions – This study shows that ^99mTc-tetrofosmin scan is a relatively accurate method for lung cancer evaluation. Our preliminary data excludes, however, that noninvasive diagnostic efficiency might be dramatically increased by a scintigraphy with ^99mTc-tetrofosmin. More studies are needed for a better understanding of the real value of this technique.

LIST OF ABBREVIATION:

SPECT: single photo emission computed tomography

PET: positron emission tomography

CT: computed tomography

ATS: American Thoracic Society

ECOG PS: Eastern Cooperative Oncology Group performance status

In lung cancer, like in any other human cancer, the techniques of Nuclear Medicine are based on different radiopharmaceuticals, capable of exploiting specific characteristics of the malignant cells ¹. Radiopharmaceuticals may recognize diverse cell densities, growth rates, metabolic pathways, and antigenic or surface receptor expressions ¹. It is generally admitted that both ^57mCo-bleomycin and ^67mGa scintigraphy are tumor sensitive and moderately accurate, but their use has been forsaken by more innovative and encouraging approaches ². A list of the newer radiopharmaceuticals being tested include non-specific radio-tracers (^201mTl and ^99mTc-MIBI), substances useful in particular clinical applications (the somatostatin analogues ^123mI-tyr3 and the ^111mIn octreotide for neuronendocrine tumors), radiolabeled monoclonal antibodies, and the recently introduced positron emission tomography (PET scan) ^{2; 3}. With the possible exception of PET scan, the results obtained so far, albeit stimulating and in same case attractive, remain preliminary ⁴.

Tetrofosmin is a lipophilic, cationic diphosphine, initially developed for myocardial imaging ⁵. Like other myocardial perfusion agents ², ^99mTc-tetrofosmin accumulates in lung cancer ^6-11, but there is virtually no information concerning important clinical applications, such as lung cancer staging and treatment response evaluation.

With the current study, we aimed to compensate that lack of information. In particular, we were interested in ^99mTc-tetrofosmin scan ability to detect primary and metastatic cancer deposits and to recognize their changes in response to treatment.

PATIENTS AND METHODS

Patients and Study Design

Sixty new unselected patients, who were evaluated for surgical cure of a highly suspected lung cancer, were set as a minimum target sample for this study. This figure was achieved in less than 2 years (March 27, 1998-August 20, 1999). Eligible patients either had histologically proved lung cancer, or had undergone thoracotomy for a clinical diagnosis of lung cancer. All had been considered operable after a preliminary evaluation based on clinical history and physical examination, blood chemistry and hematological counts, bronchoscopy, functional respiratory tests, chest x-rays and any other examination required by the results of the basic staging work-up. All registered patients underwent ^99mTc-tetrofosmin scan (both planar and single photo-emission computed tomography [SPECT] images), ^99mTc-methilene diphosphonate bone scan, and computed tomography (CT) of the thorax, abdomen, and brain. Other imaging studies, such as bone radiograms and ultrasonographic studies of the abdomen, were performed to support diagnosis or to guide needle aspirations and biopsies. All staging tests were obtained within a 3-week period. Tumor cell type and stage of disease were classified according to internationally adopted criteria ^{12; 13}.

We obtained follow-up clinical reassessments at 3- to 4-week intervals during chemotherapy, and every three to six weeks in case of palliation radiotherapy, or no active anticancer treatment. Patients treated with radical surgery were seen at longer intervals, ranging three to six months. In 21 patients, a complete re-staging evaluation was obtained three months after the first initial evaluation. Such re-staging evaluation included all the examinations performed at diagnosis (including the scintigraphy), along any other test as clinically indicated. At each follow-up re-assessment, the status of disease was classified using the standard criteria of objective response ¹⁴. To account for any meaningful variation in tumor volume, we interposed a category of minor regression between partial response and stable disease. Minor regression was defined as any unequivocal tumor volume shrinkage that did not fulfill the criteria of partial regression.

Patients were informed of the nature, aim, potential risks and benefits of both ^99mTc-tetrofosmin scan and iodine-contrasted CT scan, and gave their consent before entering the study. The local committee on human research approved this study. Anthropometric and clinical characteristics of the 61 registered and assessable patients are summarized in Table 1.

99mTc-tetrofosmin scan: Radio pharmaceutical, Imaging and Interpretation of the Images

Tetrofosmin was obtained commercially (Mioview Kit, Nycomed Sorin Amersham, Milan, Italy). The labeling and quality control procedures were performed according to the manufacturer’s instruction. The radiochemical purity of ^99mTc-tetrofosmin used in this study was consistently higher than 90%.

The subjects received 11.1 MBq/kg of ^99mTc-tetrofosmin. Planar spot images were acquired by a large field of view gamma camera (GE 400 ACT, General Electric, Milwaukee, WI, USA) fitted with a medium-low-energy high resolution parallel-hole collimator. Planar images (5 minutes per images,128*128 matrix) of the chest (anterior and posterior) were acquired 5’, 20’, 60’ and 120’ after injection in order to clinically validate the multidrug resistance hypothesis (data not reported in this article). SPECT views of the thorax were obtained 30’ after injection and SPECT views of the brain were obtained 60’ after injection. In both cases, sixty-four planar images were collected around 360° with a 64*64 word-mode matrix. SPECT images were used for staging purposes and for comparison with CT. The acquisition time for each plane was 20 sec. The 64 planar projections were reconstructed to transverse slices with the use of a Butterworth filter (cut-off frequencies= 0.4 cycles/cm, power factor=20) at a 2-pixel thickness for each transverse (12.8 mm thick) slice. No attenuation correction was used. Transverse sections were reoriented into the sagittal and coronal planes.

SPECT images of the chest or brain were regarded as positive when an abnormal ^99mTc-tetrofosmin uptake that exceeded pulmonary or brain background was documented in at least two sequential planes (either transverse, or sagittal, or coronal). The abnormality was located into a pulmonary, hilar, or mediastinal region according to topographic criteria. Pulmonary uptakes adjacent to the chest wall were read as T3, while accumulations involving the mediastinal space were classified as T4 lesions. Mediastinal lesions were assigned to a definite nodal station according to topographic criteria and the American Thoracic Society (ATS) node-mapping scheme ¹⁵.

The data were visually evaluated by two experienced Nuclear Medicine Physicians (A.B. and A.F.) with knowledge of the CT results and blinded to the pathological findings, according to the above definitions and the 1997 Revision of the International Staging System¹³.

Regions of interest were localized in the tumor mass and normal lung, both on planar (20’ and 120’ images) and SPECT images. From them, the tumor-to-normal lung ratio was obtained.

 Thoracic CT : technique and reading

All patients included in this report were studied with a CT of the thorax, upper abdomen and brain. Until October 1998, CT scans were performed on a conventional scanner (GE 9800, General Electric, Milwaukee, WI, USA); then, a spiral-CT machine (CT twin flash, Elscint Ltd., Haifa, Israel) was used. Ten millimeter-thick sections of the thorax were obtained at 1-cm intervals, during suspended inspiration, from the lung apices to the upper abdomen. In selected cases, five mm-thick sections at five mm-intervals were acquired through the region of interest. Iodinated intravenous contrast (150 c³ bolus, plus 100 c³ in slow infusion) was injected prior to all studies. Appropriate windows were used for viewing both lungs and soft tissues.

Mediastinal nodes were labeled as abnormal if they were 1 cm or larger (short axis) and/or 1.5 cm or longer (long axis) on the transverse plan images. Enlarged mediastinal lymph nodes were ascribed to a definite nodal station on the basis of the ATS classification ¹⁵. All CT scans were interpreted by two experienced radiologists (D.G., P.V.), with no restriction to the clinical information available at the time of the exam.

Surgical Sampling and Pathologic Examination

In patients who underwent surgery, nodal stations positive to either CT or SPECT were carefully inspected and sampled, even when lymph nodes appeared macroscopically normal. All enlarged, palpable or visible nodes were removed in their integrity. In apparently normal mediastina with negative preoperative studies, a minimum sampling of 3 node stations was required to reject the hypothesis of N2 disease. Mediastinoscopies (and, in one case, left anterior mediastinotomy) were performed when CT or scintigraphy were positive for accessible lymph nodes in otherwise operable patients. Removed lymph nodes were fixed separately in 10% neutral buffered formalin, and labeled according to the ATS criteria ¹⁵.

Statistical Analysis

All ^99mTc-tetrofosmin scans (SPECT results) were designated true positive, false positive, true negative, and false negative for the T and N factor, using either the best clinical estimate, or the pathological reference when available. In pathologically staged patients, also CT scan results were reviewed and labeled as true positive, false positive, true negative, and false negative. Values of sensitivity, specificity, accuracy, and predictive capabilities were calculated according to the formulas given by Galen ¹⁶. Proportions are presented along with their 95% confidence interval ¹⁷.

RESULTS

Characteristics of Patients

Sixty-one patients (11 females and 50 males) were registered onto this study and assessable. Of them, 27 had a lung tumor located peripherally in the lung parenchyma (tumor growth beyond the lobar bronchi or non-visible at bronchoscopy), 30 had a central lesion. The final diagnosis was squamous cell carcinoma (21 patients), small cell cancer (8), adenocarcinoma (18), large cell anaplastic carcinoma (5), undefined cell type or mixed histology lung cancer (5), non-malignant lung lesion (4, including 1 sclerotic bronchiectasis and 3 radiologically atypical pneumonias). All patients, but 2, had an Eastern Cooperative Oncology Group performance status (ECOG PS) ¹⁸ comprised between 0 and 2. At the end of the pre-treatment staging evaluation, 11 patients were operated upon, 3 underwent mediastinoscopy, and 2 had cervical exploration of supraclavicular glands. As a result, 16 patients had a pathologically documented N classification. There were also 12 T pathologic classifications (i.e., the 11 patients operated upon, plus one patient with a pleural effusion containing malignant cells). Table 1 summarizes the demographic, clinical, pathological, and follow-up data of the 61 patients.

Imaging the Primary Tumor

Table 2 summarizes ^99mTc-tetrofosmin scan data, reporting the total number of acquired planar and SPECT images, the tumor/background ratio and the evaluations of disease extent and treatment response. In all, we obtained 85 planar and SPECT views from 64 subjects. However, three patients were photo-scanned only after treatment and lacked a baseline evaluation. For this reason, they were excluded from study. All lung cancer patients showed an accumulation of Tetrofosmin in their lesion. As expected, tumor/background ratio was, on average, higher in SPECT than in planar views, and tended to be lower after treatment. No difference in tumor/background ratio was evident comparing early and late planar images.

99mTc-tetrofosmin scan was incorrectly positive in 3 subjects whose initial diagnosis of lung cancer was excluded at the completion of their diagnostic process. In these patients, the follow-up observation and the demonstration of a partial (or complete) resolution of the radiological densities suggested the final diagnosis of pneumonia. Fig. 1 depicts the increased uptake of ^99mTc-tetrofosmin in a supposed malignant lesion (patient 42) that showed a complete CT clearing after antibiotics. As already said, ^99mTc-tetrofosmin scan was correctly positive in all 57 lung cancer patients (100% sensitivity). The minimum size of tumor that could be detected was 1.2*1 cm.

Staging the Intrathoracic Disease

Table 3 put in correlation ^99mTc-tetrofosmin findings with either the best clinical estimate or the pathological diagnosis. In 54% of the cases, ^99mTc-tetrofosmin estimates corresponded to the best clinical assessment (T factor evaluation), which was underestimated in another 31% of the patients. In the subgroup of 12 patients with a pathological T assessment, a slightly inferior accuracy rate (42%) and an increased error of underestimation (50%) were observed. ^99mTc-tetrofosmin SPECT readings were fairly more accurate in pathologically documented nodal disease (accuracy rate: 69%).

Based on the above data, formulas for the diagnosis of "locally limited disease" (T1-T2 disease) or "regionally limited disease" (N0-N1) could be calculated. Table 4 provides the precise estimates and the 95% confidence intervals of sensitivity, specificity, accuracy, positive and negative predictability for the ^99mTc-tetrofosmin scan diagnosis of "limited disease". Calculations are made using both the clinical and the pathological reference. With limitation to the pathologically documented cases, a comparison with CT scan, assumed to be the gold standard for pre-surgical evaluation, is provided. Such a comparison showed an apparently equivalence of the two techniques (a 9% accuracy advantage of ^99mTc-tetrofosmin scan, in assessing the T factor, was compensated by a 13% disadvantage in the N factor evaluation). Remarkably, ^99mTc-tetrofosmin scan shared with CT a positive predictive value of 100% (diagnosis of N2-disease, Table 4).

Detecting Distant Metastases

Table 5 allows a summary of the ^99mTc-tetrofosmin scan diagnostic capability for the metastatic disease. Before entering into details, it must be remarked that, given the physiologic distribution of Tetrofosmin, only a few sites of possible metastatic spread (i.e., brain, lung and the skeleton) were assessable. Table 5 provides data concerning 27 metastatic patients and another non-metastatic subject, who had an unconfirmed scintigraphic diagnosis of bone metastasis. In particular, the site(s) of metastasis, the method(s) used for their confirmation, and the results of ^99mTc-tetrofosmin scan are listed.

Overall, ^99mTc-tetrofosmin scan was truly positive, for at least one metastatic site, in 17 patients and truly negative in another 29 cases; it was falsely positive in 1 subject and falsely negative in another 9. This means an overall accuracy rate of 82% and a rewarding specificity of 97%. Fig.2 shows the intense brain accumulation of ^99mTc-tetrofosmin in patient 16.

Assessing the Response to Treatment

Twenty-one patients underwent a fully re-staging evaluation, including a repetition of ^99mTc-tetrofosmin scan three months after starting treatment. In three of them, the re-staging evaluation followed an apparently radical tumor resection (two right superior bilobectomies and one left pneumonectomy). In the remaining 18 subjects, the main treatment was chemotherapy with or without thoracic irradiation. Based on the standard assessment, all surgical subjects were judged disease-free (or complete responders). In addition, there were other 2 complete, 9 partial, 4 minor responders, and 3 progressing patients in the chemotherapy group. ^99mTc-tetrofosmin scan response assessment (Fig. 3) was identical in 47% of the sample and reasonably similar in another 38%. It differed markedly in 3 patients, where Tetrofosmin uptake remained unchanged, while radiological findings were consistent with a dramatic reduction or even a disappearance of the cancerous lesion. Fig. 4 gives an example of non-concordant diagnosis of response (i.e., modest ^99mTc-tetrofosmin response, with dramatic CT scan improvement).

DISCUSSION

In lung cancer, surgery remains the only chance of cure ¹⁹. An accurate non-invasive evaluation of the real extent of disease is the premise for a successful operation ¹⁹. Ideally, the preoperative staging maneuvers should be able to save patients futile surgery, guaranteeing the surgical cure if this is appropriate. Often, the final evaluation of resectability depends on invasive staging procedures, such as mediastinoscopy and anterior mediastinotomy ^{19; 20}. A reliable non-invasive test might be useful in limiting the recourse to these procedures, by selecting subgroups of patients with various probabilities of mediastinal involvement. CT scan is normally used in this context ²¹. A classic meta-analytic review of 42 early studies documented, on average, a CT accuracy rate of 80% ²². Recent estimates suggest more prudent figures, in the 50-60% range in USA and in the 60-70% range in Europe and Japan ^{23; 24}. According to these last data, thoracic CT might be insufficiently accurate for being the ideal preoperative staging test.

Nuclear Medicine continues to introduce novel techniques for cancer imaging. New scintigraphic methods have been introduced for the detection, pretreatment staging work-up and posttreatment response evaluation of bronchial carcinoma ². Unfortunately, no scintigraphic technique has been found sufficiently effective and feasible to replace the routine use of CT ². For example, when we studied ^67mGa scintigraphy and, later, the anti-CEA monoclonal antibody scintigraphy, we obtained results that were often interesting but never really satisfactory ^25-32.

99mTc-tetrofosmin is a new myocardial-imaging agent with high affinity for cancer tissues. The mechanism of tumor uptake for this radiopharmaceutical is not clearly understood. Hypotheses explicative of the phenomenon include a ^99mTc-tetrofosmin binding to the cytosol of tumor cell, its intracytoplasmatic retention due to a reduced activity of the 170 kDa P-glycoprotein, or an increased tumor blood flow or capillary permeability⁵.

Clinical studies that have confirmed the affinity of ^99mTc-tetrofosmin for lung cancer are already numerous. In 1995, Basoglu and co-workers reported a pilot study of 5 patients with bronchial carcinoma, in different phases of treatment, four of which showed a localized tumor uptake of ^99mTc-tetrofosmin ³³. In their mature analysis ⁹, a clear accumulation of the radiotracer was visibly present in 26 of 34 malignant tumors, but also in 3 of the 11 benign lesions. Of the 26 patients with malignant tumors accumulating ^99mTc-tetrofosmin, nine had repeated imaging 6 to 8 weeks after radio-chemotherapy. In five of the nine, the course of the ^99mTc-tetrofosmin uptake in follow-up imaging was in accordance with the radiological size of the tumor, used as the criteria of reference for response. Two of the four remaining subjects showed some degree of inconsistency between changes in ^99mTc-tetrofosmin uptake and radiological size. In another study, Atasever and colleagues imaged 30 patients with ^99mTc-tetrofosmin ⁷. There were 21 cases of primary lung cancer (10 squamous cell, 5 small cell, 4 adenocarcinoma and 2 large cell) and 9 benign lung lesions (4 pneumonia, 3 tuberculosis, 1 infected bronchiectasis and 1 obliterating bronchiectasis). Of the 21 primary malignant lesions 19 showed a ^99mTc-tetrofosmin accumulation. But, also 4 (44%) of the nine benign lesions (3 cases of pneumonia and the one case of active tuberculosis) showed an increased uptake. In 1997, Kao and colleagues studied 49 patients with a single solid lung mass, to determine the capability of ^99mTc-tetrofosmin SPECT to differentiate between malignant and benign lesions ¹¹. In this study, only 61% of the lung tumors were detected by ^99mTc-tetrofosmin SPECT of the chest. In addition, 50% of the benign lesions were falsely visualized. Tetrofosmin uptake was not related to the mass size. The authors concluded that, for differentiating malignant and benign lesions presenting as a single solid lung mass, ^99mTc-tetrofosmin SPECT of the chest is of little or no value ¹¹. In the study by Takekawa et al. ⁶, 46 patients with lung cancer were photo scanned after the intravenous injection of 740 MBq ^99mTc- tetrofosmin and 111 MBq ^201mT1-chloride. The authors reported that ^99mTc-tetrofosmin visualized 89% of the primary lung cancers, 96% of which accumulated ^201mT1. The difference between ^201mTl and ^99mTc-tetrofosmin uptake ratios was significantly greater in squamous cell carcinomas than in small cell carcinomas (P < 0.01) and tended to be greater in squamous cell carcinomas than in adenocarcinomas (P = 0.093), indicating that such a different biological behavior of ^99mTc-tetrofosmin and ^201mT1 might provide useful information regarding the histological type ⁶. In summary, the current literature indicates that ^99mTc-tetrofosmin is accumulated in 60%-90% of all lung cancers (with possible variation due to the cell type) and in a rough 50 % of all benign lesions erroneously considered cancer in a first clinical evaluation. Also our data (100% sensitivity and 25% specificity) underlines the good affinity of ^99mTc-tetrofosmin for both cancerous and non-cancerous lesions of the lung.

Concerning the main scope of this study, almost no information is available. So far, our investigation is the only organic, sufficiently large, piece of evidence. It has been shown, with no possibility of doubt, that ^99mTc-tetrofosmin scan may be used effectively in both lung cancer staging and tumor response evaluation. However, the exact merit of this technique cannot be assessed on the sole basis of this report. The comparison with CT scan seems to suggest that ^99mTc-tetrofosmin scan might be equivalent to CT in the study of mediastinum. The ability of ^99mTc-tetrofosmin to visualize distant metastases in the brain and the skeleton is also attractive. The fair correlation between the standard assessment of response and the uptake of ^99mTc-tetrofosmin has been already reported ⁹ and our study offers confirming evidence.

Unfortunately, surgical maneuvers still remain essential for a correct staging classification, and the scintigraphy with ^99mTc-tetrofosmin does not change the situation radically. In the lack of better options, we believe that thoracic CT remains the standard test for pretreatment and posttreatment evaluation of lung cancer. More information is needed to correctly catalog ^99mTc-tetrofosmin scan in the diagnostic armamentarium for lung cancer.

 

FIGURE LEGENDS (we apoligize for the lack of the images on this on-line version of the manuscript)

Figure 1. Transaxial, coronal and sagittal images of the thorax (patient 42) generated from SPECT and obtained 30 minutes after injection. Note the intense, inhomogeneous uptake of ^99mTc-tetrofosmin into the right lung and the focal uptake into a mediastinal node. The lesion, initially supposed malignant, was eventually shown to be benign (radiologically atypical pneumonia), on the basis of a strict clinical and radiological follow-up.

Figure 2. Transaxial, coronal and sagittal images of the brain (patient 16) generated from SPECT and obtained 60 minutes after injection. The arrows indicate the focal uptake of ^99mTc-tetrofosmin in a lesion located into the right occipital lobe. Note the "normal" uptake of the tracer into the choroid plexuses.

Figure 3. Percentage of agreement, mild disagreement, and complete disagreement between ^99mTc-tetrofosmin scan estimates and the standard evaluation of treatment response.

Figure 4 (a-b). Pre-treatment (2/15/99) and post-treatment (6/4/99) transaxial, coronal and sagittal SPECT images of the thorax (Figure 4a). The arrows indicate the abnormal uptake of the hilar (bilaterally) and mediastinal nodes. Corresponding CT images are given for comparison (Figure 4b). After chemotherapy (3 cycles with cisplatin and etoposide), the nodal uptake is almost unchanged, while a marked reduction of the mediastinal disease is evident on CT (patient 24).

* In 4 patients the diagnosis of malignancy was excluded either pathologically (1 case of sclerotic pleuricy) or clinically after a minimum followup of 6 months (3 cases of pneumonias).  Abbreviations: ECOG PS= Eastern Cooperative Oncology Group performance status; yr= years; y=yes; n=no; Tumor cell type: E= epidermoid -squamous cell cancer; S= small cell cancer; A= adenocarcinoma; L=large cell anaplastic cancer; U=undetermined or mixed cell type; Tumor endobronchial location: T=trachea; M=main bronchus; L=lobar bronchus; P=segmental or more peripheral bronchus; S=surgical resection; O= other main treatment; U= unknown (2 patients were lost to followup); Objective Response Category: CR=complete remission or post-operative disease free status; PR=partial remission; MR=minor regression;SD=stable disease; PD=progressive disease. 

* Three subjectes had only a posttreatment scintigraphy and were unassessable for this study. Abbreviations: D= performed at diagnosis; F= performed during the follow-up; y=yes; n=no; SPECT= single photo emission computed tomography; Objective Response Category: CR=complete remission or post-operative disease free status; PR=partial remission; MR=minor regression;SD=stable disease; PD=progressive disease.  

* The final diagnosis was based on either clinical or pathological assessment (in brackets the cases with a pathological reference). Abbreviations: SPECT= single photo emission computed tomography (Technectium-99m-Tetrofosmin Scintigraphy).