Somatostatin receptor scintigraphy useful in stage I–II Hodgkin's disease: more extended disease identified

Authors


P. J. Lugtenberg MD, Department of Haematology, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: lugtenburg@haed.azr.nl

Abstract

Somatostatin receptor (SS-R) scintigraphy successfully  shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.

Limited stage and disseminated Hodgkin's disease (HD) have different outcomes and require different treatment. Patients with limited disease (stages I and II) may be cured using regional radiotherapy. However, in approximately 30% of cases, relapses occur (Gospodarowicz et al, 1992). These patients usually relapse in previously non-irradiated sites (Tubiana et al, 1984, 1989). Therefore, in patients with limited disease, prognostic factors are now used to identify patients at high risk of relapse if treated with local (radio)therapy alone (Tubiana et al, 1989; Mauch, 1994). Advanced disease (stages III and IV) is treated with systemic chemotherapy (Engert et al, 1999). HD is nowadays curable in most patients (Advani & Horning, 1999; Engert et al, 1999).

Diagnostic radiology is one of the cornerstones for assessing the extent of the disease. Imaging studies that are commonly used include conventional frontal and lateral chest radiographs, computerized tomography (CT) scanning, ultrasonography and magnetic resonance imaging (MRI). CT or MRI have definite shortcomings. For instance, they do not distinguish inactive disease or scar tissue from viable tumour tissue. Diagnosis of possible nodal tumour involvement is typically based on detection of lymph nodes > 1·0 cm in short-axis measurements. However, smaller nodes of less than 1·0 cm may also harbour malignant lymphoma, while larger lymph nodes may be benign. In HD, about 10% of involved nodes are normal in size and will therefore not be detected using CT (Reznec & Richards, 1987). There is an apparent need for further improvement of current methods as well as for the development of new imaging techniques. Nuclear medicine studies may offer valuable complementary information.

Somatostatin (SS) is a peptide hormone existing in two different forms, containing 14 or 28 amino acids (Reichlin, 1983a,b). SS binds to specific SS receptors (SS-Rs). Five distinct subtypes of human SS-R have been cloned (SSTR 1–5), all with high-affinity binding characteristics for SS-14 and SS-28 (Patel et al, 1994). A wide variety of human malignancies express SS-Rs (Krenning et al, 1993). We previously demonstrated the presence of SS-Rs in lymph nodes with HD using in vitro SS-R autoradiography (Reubi et al, 1992; van den Anker-Lugtenburg et al, 1996). The presence of SS-Rs on malignant cells of lymphoid origin allows in vivo visualization of sites of HD. The 111Indium-labelled SS analogue DTPA-D-Phe1-octreotide (pentetreotide, OctreoScan) has been conveniently used to visualize SS-R-bearing tumours (Krenning et al, 1993). We have previously reported on the clinical value of SS-R scintigraphy in an initial study of 56 patients with HD (van den Anker-Lugtenburg et al, 1996). Several other groups have investigated the clinical significance of SS-R scintigraphy in the staging of HD (Bares et al, 1993; Van Hagen et al, 1993; Bong et al, 1994; Goldsmith et al, 1995; Lipp et al, 1995; Sarda et al, 1995; Ivancevic et al, 1997), but these studies were based upon relatively small (less than 15) numbers of patients. Here we report the results of a prospectively designed study using SS-R scintigraphy for the staging of Hodgkin's disease in 126 newly diagnosed patients, in which the value of SS-R scintigraphy was compared with the conventional work-up.

Patients and Methods

Patients One hundred and twenty-six consecutive, newly diagnosed and previously untreated patients with histologically proven Hodgkin's disease were enrolled in a prospective study. The stage of the disease according to the Ann Arbor classification (Carbone et al, 1971) was established using conventional methods which always included a physical examination, chest radiography and CT scanning of chest, abdomen and pelvis, and sometimes also ultrasonography of the neck and/or abdomen or a lymphangiography. The diagnosis of bone marrow involvement was always verified following cytological and histopathologicalal examination of a marrow aspirate and biopsy. CT scanning was performed with contiguous 10 mm axial sections after oral and intravenous administration of contrast material. All patients had given informed consent to the study, which had been approved by the ethics committee of the University Hospital Rotterdam.

On the basis of clinical prognostic factors, two subgroups of patients with supradiaphragmatic HD were identified consisting of patients with a favourable and an unfavourable prognosis [according to criteria of the European Organization for Research and Treatment of Cancer (EORTC) lymphoma collaborative group (Tubiana et al, 1989)]. Patients were classified as unfavourable if they were either aged ≥ 50 years or had an erythrocyte sedimentation rate (ESR) ≥ 30 mm (with B symptoms: weight loss, fever, night sweats), an ESR ≥ 50 mm (with absence of B symptoms), four or more different nodal areas involved or a mediastinum/thorax ratio ≥ 0·35. All other patients were considered favourable.

SS-R scintigraphy The maximum interval between conventional staging procedures and SS-R scintigraphy was 3 weeks. All examinations were completed before initiation of therapy.

Patients were injected intravenously with 220 MBq 111Indium-labelled pentetreotide (OctreoScan, Mallinckrodt Medical BV, Petten, The Netherlands). Planar total body scintigraphy was performed 24 h after injection with a large-field-of-view gamma camera (Counterbalance 3700 and ROTA II; Siemens Gammasonics, Erlangen, Germany) equipped with a medium-energy collimator. Repeat scintigrams were performed 48 h after injection when accumulation of radioactivity in the abdomen was observed on the 24-h scintigrams. Laxatives were given to reduce the presence of intestinal radioactivity caused by some hepatobiliary clearance of 111In-pentetreotide. Head and neck images were obtained anteriorly and laterally from both sides. The remainder of the body was imaged with separate anterior and posterior images of the thorax, upper abdomen (including liver/spleen and kidneys), lower abdomen and extremities. The thorax was imaged with arms elevated. Preset counts were 300·000 for the head and neck and 500·000 for the chest and abdomen or a maximum of 15 min. In all patients, Single Photon Emission Computed Tomography (SPECT) images of the upper abdomen were made 24 h after injection using a triple-head camera (3000XP, Picker, Cleveland, OH, USA). Reconstruction of the SPECT data was carried out by filtered back projection. A detailed description of the scanning protocol used at the University Hospital Rotterdam is given in several reviews (Krenning et al, 1992, 1993, 1994, 1995). In normal individuals, a physiological accumulation of radioactivity is seen at 24 h after injection of [111In]-pentetreotide in the pituitary and thyroid gland, the liver, spleen, kidneys, the intestines, the urinary bladder and the gall bladder. Accumulation of radioactivity at other sites is considered to be abnormal and indicates the presence of pathologicalal SS-R-positive tissue. In organs with physiological uptake of [111In]-pentetreotide (e.g. liver and spleen), unhomogeneous or focal uptake patterns were considered to be indicative of lymphoma. Two experienced nuclear medicine physicians evaluated the scans at the same time; they did not know the identity of the patients or the results of the conventional staging procedures. If initial interpretations were different (this occurred in less than 5% of cases), a blind discussion was held until consensus was reached.

Assessment of the true state of a lesion or a region CT scans and other radiological test were evaluated by experienced radiologists without knowledge of SS-R scintigraphy data. Lymph nodes of more than 15 mm in diameter were considered unequivocally abnormal on CT scanning or ultrasonography and were interpreted to represent Hodgkin's disease (Lister et al, 1989). Lymph nodes of less than 10 mm were considered benign. Lymph nodes with a diameter between 10 mm and 15 mm were considered equivocal. CT and ultrasound criteria for involvement in normal-sized spleen or liver included unexplained infiltrates or focal abnormalities of decreased attenuation. The spleen was considered enlarged on the CT scan, ultrasonography or SS-R scan if the longitudinal diameter was greater than 130 mm (Hess et al, 1993; Munker et al, 1995).

Findings of SS-R scintigraphy were compared with the sum of conventional staging procedures. The following lymph node regions were evaluated: occipital left/right, upper cervical left/right, medial cervical left/right, supraclavicular left/right, submandibular left/right, preauricular left/right, infraclavicular left/right, axillary left/right, infraclavicular left/right, brachial left/right, mediastinal, lung-hilar left/right, para-aortic (including celiac nodes and nodes from the hepatic and splenic hili), iliac left/right, inguinal left/right, femoral left/right, popliteal left/right, mesenteric and the Waldeyer's ring. In addition, all possible extranodal sites of involvement were also evaluated. This resulted in a total of 70 possibly involved lymph node regions and extranodal sites. In case of discrepant findings between SS-R scintigraphy and conventional staging procedures, we attempted to determine the status of the lesion. Discrepant findings were verified if possible by biopsy or using non-invasive methods, including ultrasonography, magnetic resonance imaging, CT or bone scintigraphy. All patients were followed during and after therapy. For any documented lesion, a final assessment was made of its true state as benign, malignant or indeterminate. This assessment was based on the result of pathologicalal examination (histology and/or cytology if done), supplemented by the clinical course. A lesion was considered benign because of pathologicalal evidence or if the size was less than 10 mm in long-axis measurements and the lesion did not increase in size. A lesion was considered malignant because of pathologicalal evidence or if the size was more than 15 mm in largest diameter or, in retrospect, on the basis of the clinical course (disappearance or change in size of a lesion following therapy). The status of the lesion was considered indeterminate if the nature of the lesion could not be assessed from the data. Regions without lesions on any test were considered to have a true state of absence of disease. Spleen and liver involvement was diagnosed according to the Cotswolds criteria (Lister et al, 1989). The spleen was considered positive for HD if there was unequivocal palpable splenomegaly alone or equivocal palpable splenomegaly with radiological confirmation of either enlargement or multiple focal defects that were not cystic or vascular. Liver involvement was diagnosed if there were multiple focal defects, which were not cystic or vascular, noted with at least two imaging techniques.

Assessment of sensitivity and specificity of a test The sensitivity and specificities of the different tests were calculated separately for each of the regions for which the test was performed. For the calculation of the sensitivity, the lesions with the true state ‘malignant’ were used, while for the calculation of the specificity, the regions without any lesions or only lesions with final assessment ‘benign were used. The sensitivity of a test for a lymph node region or extranodal site was defined as the number of lesions with a positive test result for that region divided by the total number of lesions with final assessment ‘malignant’ in that region. The specificity of a test for a lymph node region or extranodal site was defined as the number of patients with a negative test result divided by the total number of patients tested with true state ‘benign/absent’ in that region.

Results

Patients

The clinical characteristics of the 126 patients enrolled in the study are shown in Table I. Nodular sclerosis and mixed cellularity subtypes were most frequent. A majority (70%) of the patients had limited Hodgkin's disease (stage I or stage II). Table II presents the anatomical distribution of the involved sites of HD. Almost all patients (97%) presented with supradiaphragmatical lesions. These were predominantly located in the neck and/or mediastinum. Lesions below the diaphragm were apparent in 29% of patients and extranodal lesions were rare.

Table I.  Clinical characteristics of 126 patients with Hodgkin's disease.
  • *

    Based on the results of the standard staging procedures.

Age (years)
 Median29
 Range15–75
Sex
 Male75 (59%)
 Female51 (41%)
Histological subtype
 Lymphocyte predominance9 (7%)
 Nodular sclerosis95 (76%)
 Mixed cellularity18 (14%)
 Lymphocyte depleted1 (1%)
 Not classifiable3 (2%)
Ann Arbor clinical stage*
 Stage I29 (23%)
 Stage II59 (47%)
 Stage III25 (20%)
 Stage IV13 (10%)
Table II.  Anatomical distribution of the 483 malignant lesions in 126 patients with Hodgkin's disease, diagnosed on the basis of standard staging procedures and SS-R scintigraphy.
Localization malignant lesion% patients
  1. *Occipital, submandibular and cervical lymph nodes.

Supraclavicular lymph nodes75%
Mediastinal lymph nodes71%
Cervical lymph nodes*42%
Lung hilar lymph nodes25%
Axillary lymph nodes24%
Infraclavicular lymph nodes21%
Para-aortic lymph nodes19%
Spleen11%
Inguinal lymph nodes8%
Iliac lymph nodes6%
Lungs5%
Bones2%
Mesenteric lymph nodes1%
Waldeyer's ring1%

Sensitivity and specificity of SS-R scintigraphy

All 126 patients were positive on SS-R scintigraphy. In these patients, 483 malignant lesions, i.e. lesions with involvement of HD, were documented using physical examination in combination with SS-R scintigraphy, other imaging techniques, histopathology and subsequent follow-up. Of these, 423 lesions were above the diaphragm, 54 lesions were below the diaphragm and an additional six lesions were recorded. The majority of the lesions were nodal (n = 457). Only 26 were extranodal. Table III gives the sensitivity of SS-R scintigraphy for the detection of Hodgkin's disease in each of the lymph node regions and extranodal sites. SS-R scintigraphy showed a very high sensitivity (95%-100%) for the detection of Hodgkin's disease in the neck, mediastinum, lung hila and axillae (Fig 1). Of the six malignant intrapulmonal lesions, five were visualized using SS-R scintigraphy. The smallest lesion above the diaphragm detected using SS-R scintigraphy had a diameter of 5 mm and was located in the supraclavicular region. Below the diaphragm the sensitivity of SS-R scintigraphy ranged from 38–100% (Fig 2). The scintigraphic sensitivity for para-aortic lesions was low, i.e. 50%. In four patients, the para-aortic lesions were visualized only on SPECT but were not shown on the planar images. There was no apparent relationship between the size of the pathologicalal lymph node and the probability of a positive para-aortic SS-R scan. The smallest malignant lesion under the diaphragm detected by SS-R scintigraphy was an inguinal lymph node with a diameter of 15 mm. In six patients there was pathologicalal evidence of bone marrow infiltration with HD. In only one of these patients did the SS-R scan reveal marrow positivity.

Table III.  Sensitivity of various diagnostic approaches for the detection of Hodgkin's disease in the different lymph node regions and extranodal sites.

Localization of malignant lesion
Number
of lesions
Physical
examination

X-thorax

CT scan

LAG

Ultrasonography
SS-R
scan
  • *

    Occipital, submandibular and cervical lymph nodes.

  • LAG, bipedal lymphangiography; ( ), indicates the frequency in which the test was performed, only given if different from the number of malignant lesions.

Supraclavicular lymph nodes11686% (115) 80% (15) 96% (45)100%
Cervical lymph nodes*9186% 92% (12) 97% (31)97%
Mediastinal lymph nodes90 61% (82)96%  100%
Lung hilar lymph nodes45 54% (39)91%  96%
Axillary lymph nodes3858% 77% (35)  95%
Infraclavicular lymph nodes36  78%  100%
Lungs6 50%83%  83%
Para-aortic lymph nodes24  88%75% (4)100% (7)50%
Spleen1450% 93% 100% (9)93%
Iliac lymph nodes8  88%100% (1) 38%
Inguinal lymph nodes771% 71%  100%
Total483     94%
Figure 1.

SS-R scintigraphy in a 63-year-old woman with a 2-month history of cervical lymph node enlargement that biopsy revealed to be Hodgkin's disease. Planar anterior image of the neck and upper thorax at 24 h after injection of [111In]-pentetreotide. There is marked uptake of [111In]-pentetreotide in lymph nodes in the right cervical and supraclavicular region (arrows). Physiological accumulation of radioactivity is seen in the thyroid (T), liver (L) and spleen (S).

Figure 2.

Visualization of abdominal Hodgkin's disease in a 39-year-old man using SS-R scintigraphy. Planar anterior image of the lower abdominal region scanned at 24 h. The SS-R scan reveals positive para-aortic (upper arrows) and right inguinal lymph nodes (lower arrow). There is physiological accumulation of radioactivity in the kidneys (K).

The sensitivity of SS-R scintigraphy for the detection of supradiaphragmatic lesions was 98% and for lesions below the diaphragm 67%. For nodal lesions the sensitivity was 94% and for extranodal lesions 88%. The sensitivity for all lesions combined was 94%.

In four lesions, SS-R scintigraphy gave a false-positive result. In two patients, non-specific accumulation of radioactivity was seen in the pleural region, probably as a result of old aspecific lesions. In the third patient, a large haematoma in the anterior iliac spine after a bone marrow biopsy caused aspecific accumulation of radioactivity at that site. The fourth patient with a false-positive SS-R scan showed uptake in the shoulder, owing to a bursitis. Thus, the specificity of SS-R scintigraphy is high.

Sensitivity of different imaging techniques

Table III gives the estimated sensitivities of each of the imaging techniques used in this study, expressed per distinct lymph node region and extranodal site. In comparison with conventional imaging modalities, SS-R scintigraphy has a high sensitivity for the detection of lymph nodes in the neck, axilla and groin. SS-R scintigraphy is also superior for the visualization of mediastinal localizations of HD. However, in the intra-abdominal region, the SS-R scintigraphy is inferior to the CT scan and ultrasonograpy.

Comparison of SS-R scintigraphy with conventional staging procedures

In Table IV, an overview is given of a comparison between the results of SS-R scintigraphy and the conventional staging procedures in the 126 patients. In 43% (n = 54) of the patients, SS-R scintigraphy disclosed activity suggestive of HD that had not been revealed following conventional staging procedures. In 24 of these 54 patients, the enhanced diagnostic yield of SS-R scintigraphy could be confirmed by additional investigations, i.e. by repeated palpation (n = 3), subsequent additional radiodiagnosis (n = 14), cytopathology (n = 2) and/or the clinical course (n = 5). We were unable to verify 30 discrepant SS-R scintigraphy and conventional staging findings because of ethical considerations, lack of patient consent or lack of therapeutic consequences. In 14 patients (11%), lesions apparent by conventional staging were missed on SS-R scintigraphy. In eight patients, the result of SS-R scintigraphy was mixed, i.e. in the same individual additional lesions were disclosed by SS-R scintigraphy, but other lesions were missed. In 40% of patients, the results of SS-R scintigraphy and conventional staging procedures were concordant.

Table IV.  Comparison of the results of SS-R scintigraphy with the conventional staging procedures in 126 patients with Hodgkin's disease.
 Patients
ResultNumber%
SS-R scan detects new lesions5443%
SS-R scan misses lesions1411%
SS-R scan detects new lesions,
 but also misses lesions,
 in the same patient
86%
Agreement between SS-R scan and
 conventional staging procedures
5040%

Table V shows the estimated clinical stages based on the sum of the conventional staging procedures compared with the clinical stages based on the results of SS-R scintigraphy only. The additional lesions revealed using SS-R scintigraphy upgraded the clinical stage in 28 patients. As a result, the treatment plan would have changed in 18 patients (14%). However, in those nine patients (7%) in whom SS-R scintigraphy had failed to recognize certain apparent localizations of HD, the clinical stage, if based on SS-R scintigraphy only, would have been underestimated.

Table V.  Comparison of the clinical stage based on the results of the SS-R scan with the clinical stage based on conventional work-up.
Stage based
on SS-R
Stage based on conventional
staging procedures
 
scan onlyIIIIIIIVTotal
  1. Numbers in bold indicate a change in clinical stage with potential consequences for the treatment choice.

I1701220
II8454158
III31118133
IV132915
Total29592513126

Analysis of SS-R scintigraphy in favourable and unfavourable subjects of stage I and II patients

Stages I and II patients with HD are commonly stratified by risk (according to selected clinical favourable or unfavourable prognostic factors) to adjust and select more or less intensive therapy. We considered in more detail the consequences of the results of the SS-R scan in these prognostically distinct subsets among all 88 patients with stage I and stage II HD. Three different subgroups were identified: favourable supradiaphragmatic HD (37 patients), unfavourable supradiaphragmatic HD (46 patients) and infradiaphragmatic HD (five patients). Table VI shows the localization of the additional new lesions found using SS-R scintigraphy for each of the three prognostic subgroups of stages I and II patients.

Table VI.  Additional lesions demonstrated with SS-R scintigraphy in 88 stages I and II HD patients subdivided according to risk.
 Number of patients (%) with additional lesions 
 Nodal 

Patient prognosis category
Above
diaphragm
Below
diaphragm
Above and
below diaphragm

Extranodal*
  • *

    If the SS-R scan detected additional nodal lesions as well as extranodal sites in the same patient, the patient was scored as extranodal.

Favourable patients (n = 37)13 (35%)4 (11%)1 (3%)2 (5%)
Unfavourable patients (n = 46)10 (22%)3 (7%)3 (7%)2 (4%)
Abdominal HD (n = 5)3 (60%)000

In 19% (7 out of 37) of the favourable patients and in 17% (8 out of 46) of the unfavourable patients SS-R scintigraphy disclosed previously unknown lesions below the diaphragm or at extranodal sites, resulting in an upstaging to stage III or stage IV. In three of the five patients with infradiaphragmatic HD, the disease was upstaged to stage III as a consequence of SS-R scintigraphy demonstrating previously undetected lesions above the diaphragm.

Discussion

Studies concerning the value of staging laparotomy have demonstrated that about 30% of patients with stage I and stage II HD have occult splenic or upper abdominal nodal involvement not detected by CT, MRI or lymphangiography (Leibenhaut et al, 1989; Mauch et al, 1990). An indirect estimation of the probability of occult abdominal disease will direct treatment choice in patients with limited stage HD. In patients with supradiaphragmatic HD, clinical prognostic factors are used as surrogate markers for more or less extended disease to select a more or less intensive treatment approach (Pavlovsky et al, 1988; Tubiana et al, 1989). Patients with favourable prognostic factors are usually candidates for radiation therapy with or without dose-reduced chemotherapy. Patients with unfavourable prognostic factors receive more dose-intensive chemotherapy with or without radiation therapy as the initial treatment. However, more sensitive imaging techniques, which would directly demonstrate abdominal involvement of HD more precisely, would allow for better tailoring of treatment.

The expression of SS-Rs on cells in lymph nodes from patients with Hodgkin's disease, as demonstrated several years ago (Reubi et al, 1992; van den Anker-Lugtenburg et al, 1996), has opened possibilities for in vivo visualization of SS-R-positive Hodgkin's localizations. Several groups have shown the feasibility of SS-R scintigraphy for imaging of HD (Bares et al, 1993; Van Hagen et al, 1993; Bong et al, 1994; Goldsmith et al, 1995; Lipp et al, 1995; Sarda et al, 1995; van den Anker-Lugtenburg et al, 1996; Ivancevic et al, 1997). However, the numbers of patients in these studies have remained minimal, varying from two to 11 patients, so that the clinical value of SS-R scintigraphy for staging of HD has never been properly established. Our prior experience in 56 HD patients yielded a high patient-related sensitivity (van den Anker-Lugtenburg et al, 1996). This prospective study was designed to investigate the role of SS-R scintigraphy in the initial staging of 126 patients with untreated HD. The results of the study confirm unambiguously that SS-R scintigraphy has a notably high positivity in patients with HD. In our study, each patient had one or more Hodgkin's localizations that were positive on the SS-R scan, demonstrating that Hodgkin's lymphomas, without exception, express SS-Rs.

The results of our study would support the validity of SS-R scanning as a powerful diagnostic method for staging patients with HD. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In contrast to most other studies, in which new patients and previously treated patients were evaluated together, our study specifically addressed the question of the value of SS-R scintigraphy in newly diagnosed cases (Bares et al, 1993; Bong et al, 1994; Ivancevic et al, 1997).

Compared with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. Malignant lymph nodes as small as 5 mm diameter were visualized. In the intra-abdominal region, the CT scan appeared considerably more sensitive than SS-R scintigraphy. The limited sensitivity for intra-abdominal Hodgkin's lesions is a disadvantage of SS-R scintigraphy. Optimal visualization of the para-aortic and iliac regions is hampered by the physiological accumulation of the labelled pentetreotide in the liver and spleen and its elimination by bile, bowel and kidneys. Apparently, the use of SPECT can overcome this problem at least in part. We have used standard filtered back projection for the reconstruction of the SPECT data (Rusinek, 1995). A drawback of this method is the presence of considerable reconstruction artifacts in the region between the liver, spleen and kidneys. It is conceivable that the use of iterative reconstruction methods will avoid such artifacts. Additionally, the extension of SPECT imaging to the lower abdominal region may further improve the sensitivity. The sensitivity of SS-R scintigraphy in the intra-abdominal region is currently insufficient to recommend its use in all patients. However, in stage I and stage II patients, SS-R scintigraphy has added value in detecting more advanced disease in a significant proportion of the patients, thus directly impacting on treatment decision. Not only patients with unfavourable prognostic factors but also patients with favourable prognostic factors appear to carry more disseminated disease according to in vivo SS-R evaluation. We recognize that lack of histological proof of our imaging interpretations is a significant deficiency of our study. However, invasive diagnostic procedures represent increased risk for the patient and staging laparotomies are now infrequently performed. Because there were only a small fraction of false-positive SS-R scintigraphy findings (four lesions), we think that most of the unresolved SS-R scintigraphy findings are probably true positive.

The usefulness of SS-R scintigraphy is heavily dependent on optimal equipment and technique. We administered a high dose of 111Indium (always > 200 MBq), which probably enhances the sensitivity of detection. Furthermore, the counting time of images should be sufficiently long in order to avoid lesions with a relatively low uptake of radioactivity being missed. In our experience, SPECT imaging of the upper abdomen is essential. In a considerable number of patients (4 out of 24) with abdominal HD, the para-aortic lesions were not detected on the planar images but were visualized by SPECT. This makes the procedure time-consuming (SPECT, counting time) and expensive (dose, time). However, in our study, the addition of an SS-R scan to the work-up in patients with stages I and II HD proved to be cost-effective. The results of the cost-effective study will be reported in a separate paper.

SS-R scintigraphy by its nature can never compete with conventional imaging in anatomical delineation of the disease sites, but the technique offers complementary information owing to its physiological features. In patients with HD, the presence and abundance of SS-R expression can easily be detected in vivo. At present, peptide receptor-targeted radionucleotide therapy (PRRT) is being developed as a new therapeutic option for cancer patients. A promising effect of therapy with multiple high radiotherapeutical doses of [111In]-pentetreotide was demonstrated in patients with end-stage neuroendocrine tumours (Krenning et al, 1999). In this study, there was a tendency towards better results in patients whose tumours had a higher accumulation of the radioligand. Most neuroendocrine tumours have a high SSTR-2 expression, while lymphomas generally have a medium to low rate of SSTR-2 expression. However, in contrast to the relatively radioresistent neuroendocrine tumours, lymphomas are generally radiosensitive. Thus, despite the low receptor expression, it is possible to expect therapeutic effects of targeted treatment with [111In]-pentetreotide or one of its variants, e.g. [90Y]-DOTATOC (Otte et al, 1999), in patients with HD. Critical organs for PRRT are the kidneys and probably the bone marrow. This imposes a limit to the maximal activity that can be employed safely. Whether PRRT is a promising option for malignant lymphoma remains to be investigated.

Gallium scintigraphy is not routinely used for the initial staging of Hodgkin's disease, owing to the lower sensitivity compared with the CT scan, especially in the abdomen (Front et al, 1990; Hagemeister et al, 1990; Larcos et al, 1994). Traditionally, gallium scintigraphy plays a role in the evaluation of the post-treatment residual mass. Gallium imaging may be helpful to confirm the presence of residual active disease and resistance to treatment (Wylie et al, 1989; Front et al, 1992; Cooper et al, 1993; Zinzani et al, 1999a). However, it tends to underestimate small deposits of disease (Cooper et al, 1993; Salloum et al, 1997). A number of reports have recently demonstrated a potential role for whole-body positron emission tomography with 2-[18F]-fluoro-2-deoxy- d-glucose (FDG-PET) in lymphoma imaging (Bar-Shalom et al, 2000). Published results indicate that FDG-PET may be equal or superior to CT for the detection of nodal as well as extranodal involvement in HD (Bangerter et al, 1998; Stumpe et al, 1998). For post-treatment evaluation, data indicate that FDG-PET has a higher diagnostic and prognostic value than CT (Jerusalem et al, 1999; Zinzani et al, 1999b).We are currently investigating in a prospective study on the role of SS-R scintigraphy in the management of residual masses. Furthermore, it will be of interest to investigate the comparative values of gallium scanning, SS-R scintigraphy and FDG-PET in the diagnostic work-up of patients with Hodgkin's disease.

Acknowledgments

The authors thank Mrs J. J. Sluys-Dallinga and Mrs P. Blom, research nurses, for their excellent data management. This study was supported by a grant from the Dutch National Health Care Council.

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