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The role of radiolabeled somatostatin analogs in adrenal imaging
Nuclear Medicine & Biology, Vol. 23, pp. 677-680, CopyrIght 0 1996 Elsevier Science Inc.
ISSN 0969-8051/96/$15.00 + 0.00 PII SO969-805 1(96)00065-O
1996
ELSEVIER
The Role of Radiolabeled Somatostatin Analogs in Adrenal Imaging Simone Maurea, ’ Second0 Lastoria, ’ Corradina Caraci,, 2 Michek k&in, 3 Paola Varrella,3 Wanda Acampa,3 Pietro Muto’ and Marco Salwatore’ lMEDICINA
NUCLEARE,
ISTITUTO
3CATTEDRA
NAZIONALE DI MEDICINA
DE1 TUMORI, NUCLEARE,
‘CENTRO UNIVERSITA
PER LA FEDERICO
MEDICINA
NUCLEARE
II, NAPOLI,
DEL CNR,
AND
ITALY
ABSTRACT.
We investigated the role of radiolabeled somatostatin analogs (SAs) in adrenal imaging. We evaluated 15 patients (6 men and 9 women, mean age 47 + 17 years) with imaging-detected adrenal tumors. Patient population was divided into two groups on the basis of the nature of adrenal lesions. Group 1 consisted of patients with benign adrenal lesions (n = 10). Group 2 consisted of patients with malignant adrenal lesions (n = 5). Pathology examinations were obtained in 13 cases: 7 pheochromocytomas, 2 adenomas, 2 cysts, 1 carcinoma, and 1 fibro-histiocytoma. One patient had a proven diagnosis of non-small-cell lung cancer associated with the presence of a right adrenal mass. The last patient had a clinical diagnosis of Werner syndrome associated with the presence of a large left adrenal mass. All patients underwent scintigraphic studies using radiolabeled SAs, of which indium-111 (In-111) pentetreotide was used in 11 cases and technetium-99m (Tce99m)Jabeled peptides (P-587 or P-829) were used in the remaining four cases. No significant labeled SAs uptake was observed in the majority (8 of 10, 80%) of the benign adrenal lesions (Group 1); however, increased uptake was found in two benign pheochromocytomas. Conversely, significant labeled SAs uptake was observed in the majority (4 of 5, 80%) of th e malignant adrenal lesions (Group 2); however, the last lesion (carcinoma) did not show abnormal uptake. Results of this study show that the majority of benign adrenal tumors do not concentrate radiolabeled SAs; conversely, the majority of malignant adrenal lesions show significant SAs uptake, suggesting the presence of somatostatin receptors. This finding may allow the use of somatostatin as a treatment agent in malignant adrenal tumors. Thus, the main role of labeled SAs in adrenal imaging consists of lesion characterization rather than tumor detection and localization. NUCL MED BIOL 23;6:677-680, 1996.
KEY WORDS. Adrenal
tumors, Receptor
imaging, Scintigraphy,
Somatostatin
analogs, Indium-1
11, Techne-
tium-99m
INTRODUCTION In the diagnostic evaluation of adrenal neoplastic diseases, clinically relevant information needs to be provided for patient management (4). Various imaging techniques are currently available for detecting and localizing adrenal tumors (4). While abdominal ultrasound (US) shows considerable limits in this setting, computed tomography (CT) and magnetic resonance (MR) scans represent the best techniques for this purpose (4). However, one of the crucial points in adrenal imaging is noninvasive tumor characterization in order to avoid adrenal biopsy (2). MR imaging has been proposed to characterize adrenal masses (5, 8); however, significant overlapping findings have been recently reported in lesions of different histologic nature (13, 18). In this regard, several radiopharmaceuticals with specific biological features may be used in nuclear medicine for adrenal tumor characterization. They include labeled norcholesterol for adenomas (6, 15), meta-iodobenzylguanidine (12, 14, 16), and/or hydroxyephedrine (19) for medullary chromaffin tissue lesions (pheochromocytoma and neuroblastoma), and deoxy-glucose (l), for malignant tumors (carcinomas and metastases).
Address reprint requests to: Simone 7. 80132 Nap&, Italy. Accepted 18 March 1996.
Maurea,
MD, Via Raffaele De Cesare no
Recently, molecular engineering had led to peptides of different forms and sizes for tumor imaging (3, 11). In particular, subtypes of peptides with significant potential as clinically accepted radionuelide imaging agents are receptor peptide derivatives. Among these, radiolabeled somatostatin analogs have been proposed in the evaluation of different tumors that show somatostatin receptors (7, 9, 10). Furthermore, somatostatin may be used as a treatment agent in neoplastic diseases (9); however, the presence of somatostatin receptors on tumor cells is requested for this form of treatment. Therefore, the identification of somatostatin receptors on tumor lesions using radiolabeled somatostatin analogs may also predict the use of somatostatin therapy in such patients. In this study, we investigated the role of radiolabeled somatostatin analogs in adrenal imaging, reporting our experience in patients with adrenal tumors.
MATERIALS AND METHODS Patient Popdation We studied 15 patients (6 men and 9 women) ranging in age from 24 to 75 years (mean age 47 + 17 years) with unilateral adrenal tumors (8 on left and 7 on right) detected on US, CT, and/or MR imaging scans. Table 1 shows the clinical characteristics of each patient. Laboratory evaluation of cortical and medullary adrenal
678
TABLE
S. Maurea er al.
1. Clinical
Patient 1 2 3 ; 6 7 8 9 10 11 12 13 14 15
Characteristics
of the Patient Population
Age
Sex
Symptoms
31 35 29 75 28 24 33 49 69 62 35 69 58 58 51
F M M F F M F M F F M F M F F
Hypertension Hypertension Hypertension None Hypertension Hypertension Dorsal pain Dorsal pain None None Hypertension None None Bone pain Dorsal pain
Laboratory Catecholamine Catecholamine Catecholamine Normal Catecholamine Catecholamine Normal Normal Normal Normal Catecholamine Anemia Normal Gastrina, PTH, Normal
(+) (+) (+) (+) (+)
(+)
PRL (+)
Site
Size”
Pathology
Left Right Right Left Right Right Left Left Left Right Left Left Right Left Right
2.0 2.5 5.0 5.5 3.5 3.0 5.0 5.0 2.5 2.0 6.0 10.5 4.5 9.5 11.5
Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma cyst cyst Adenoma Adenoma Malignant pheochromocytoma Fibro-histiocytoma Lung cancer + adrenal mass Not available Adrenal carcinoma
a Maximal diameter in centimeters. F = female; (+) indicates increased levels; M = male; PTH = parathormone; PRL = prolactin
function was obtained in all patients. Serum tumor markers were also measured. Adrenal lesions consisted of pheochromocytomas (n = 7), cysts (n = 2), adenomas (n = 2), carcinomas (n = 1) and fibro-histiocytoma (n = 1). In two patients (nos. 13 and 14), pathology examinations of adrenal lesions were not obtained. The first patient (no. 13) had a proven diagnosis of non-small-cell lung cancer associated with a right adrenal mass highly suspicious of metastatic lesion on the basis of CT imaging features. The second patient (no. 14) had a clinical diagnosis of malignant multiendocrine syndrome type 1 (Werner) showing pituitary adenoma on CT scan, and hyperparathyroidism as well as pancreatic and adrenal tumors associated with multiple liver nodular lesions on MR images. In this patient, increased serum levels of prolactin and gastrina were also measured. Finally, multiple skeletal lesions were documented on bone scan. The patient population was divided into two groups on the basis of the benign or malignant nature of adrenal tumors. Group 1 consisted of patients with benign adrenal lesions (n = 10). Group 2 consisted of patients with malignant adrenal lesions (n = 5).
jetted (74-111 MBq). For Tc-99m-labeled somatostatin analogs (P587 or P-829) (Diatide, Londonderry, NH), a dose of 550 to 740 MBq was injected intravenously. Both P-587 and P-829 are new peptides consisting of 10 amino acids. The P-587 labeling occurs after incubation for 15 min at 100°C with Tc-99m glucoheptonate (Glucoscan, DuPont, Billerica, MA). The same labeling procedure at room temperature was utilized for Tc-99m P-829 for 15 min. Quality control using instant thin-layer chromatography was performed, showing that more than 95% of radioactivity was peptide bound. For In-l 11 pentetreotide scans, images were acquired 4 and 24 h after injection. For Tc-99m-labeled somatostatin analog studies, early (within 30 min) and delayed (2 to 4 h) images were acquired after injection. Whole-body anterior and posterior scans were obtained using a large field-of-view gamma camera (Orbiter, Siemens, Erlangen, Germany) equipped with a medium-energy (for In-111 studies) and a low-energy (for Tc-99m scans) collimators. Anterior and posterior abdomen spot views were also obtained. When requested, single photon emission tomography (SPET) acquisition was performed.
Radionuclide
RESULTS
Studies
All patients underwent planar scintigraphic studies using radiolabeled somatostatin analogs: indium-11 1 (In-l 11) pentetreotide in 11 cases and technetium-99m (Tc-99m)-labeled peptides (P-587 or P-829) in the remaining 4 cases. Because the uptake of somatostatin analogs may be suppressed by certain medications (i.e., somatostatin and corticosteroids), such drugs were discontinued 30 days or longer before study acquisition in order to ensure optimal scanning conditions. In five patients studied with In-l 11 pentetreotide (4 pheochromocytomas and 1 carcinoma), planar acquisition was integrated using tomographic imaging (SPECT). In 11 patients, radiolabeled (iodine-131 or iodine-123) metaiodobenzylguanidine (MIBG) studies were also performed, as previously described (14, 17). Finally, in four patients positron emission tomography (PET) with fluorine-18 deoxyglucose was used, as previously described (1).
Somutostatin
Analog
Scintigraphy
For In-l 11 pentetreotide studies, In-l 1 l-DTPA-Phe-I-octreotide (Mallinckrodt, Petten, The Netherlands) was intravenously
in-
No significant labeled somatostatin analog uptake was observed in the majority (8/10, 80%) of the benign adrenal lesions (4 pheochromocytomas, 2 cysts and 2 adenomas); however, increased uptake was found in two benign pheochromocytoma. Conversely, significant labeled somatostatin analog uptake was observed in the majority (4/5, 80%) of the malignant adrenal lesions (1 malignant pheochromocytoma, 1 fibro-histiocytoma, and 2 indeterminate); however, the last malignant lesion (carcinoma) did not show abnormal uptake. In particular, the two indeterminate adrenal lesions deserve some comments. The first patient (no. 13) had a proven diagnosis of non-small-cell lung cancer associated with a right adrenal mass highly suspicious of metastatic lesion on the basis of CT imaging. In this case, significant abnormal P-587 uptake was observed both in the primary lung tumor and in the right adrenal mass; in particular, the intensity of P-587 uptake in the two lesions was comparable, suggesting that the two tumor sites were related. The second patient (no. 14) had a clinical diagnosis of malignant multiendocrine syndrome type I (Werner) associated with a large
Radiolabeled
Somatostatin
in Adrenal
679
Imaging
adrenal mass, multiple liver and bone lesions, as well as a right round lung mass. All these lesions significantly accumulated fluorine-18 deoxyglucose uptake on PET whole-body imaging. Cornparable P-829 images were obtained showing abnormal uptake in the same anatomic sites where increased fluorine-18 deoxyglucose uptake was observed. The comparative evaluation of planar and SPECI somatostatin radionuclide images, performed in five patients, showed similar results. Particularly, in four cases the findings of planar and SPECT scans were comparable. However, in a patient with proven malig nant left pheochromocytoma, SPECT clearly detected a round lesion located anteriorly to the left kidney. In this patient, the lesion was not visualized on anterior and posterior planar images; only the acquisition of a planar left anterior oblique view was able to better identify and separate the left adrenal lesion from the omolateral kidney.
DISCUSSION The diagnostic evaluation of patients with clinically suspected adrenal tumors consists mainly of lesion detection and precise anatomic localization (4). Although US is a noninvasive and multiplanar feasible imaging technique to evaluate adrenals, this method reveals several limits for this purpose. For instance, the presence of bowel gas may interfere with the detection of adrenal masses measuring less than 3 cm; adjacent anatomic structures may also mimic adrenal pseudotumors. Both CT and MR cross-sectional imaging studies represent the modalities of choice to detect and precisely localize adrenal tumors showing high spatial resolution. However, adrenal tumor characterization using imaging techniques has been recently requested for correct diagnosis and treatment planning (2). Although CT and MR scans are able to provide accurate anatomic details in adrenal imaging, these methods show considerable limitations for adrenal tissue characterization (4, 13, 18). Nuclear medicine imaging using different radiopharmaceuticals may provide unique functional information in order to characterize adrenal tumors metabolically (1 I). Radiolabeled nor-cholesterol may be used to characterize adrenal lesions as adenomas (6), labeled meta-iodobenzylguanidine (14) and/or carbon-l 1 hydroxyephedrine (19) as pheochromocytoma, and fluorine-18 2-fluoro-2deoxyglucose (FDG) (1) as malignant tumors (carcinomas and metastases). However, FDG uptake has also been observed in pheochromocytoma (20). Recently, radiolabeled somatostatin analogs have been proposed in the evaluation of various tumors that show somatostatin receptors (7, 9, 10). Identification of somatostatin receptors on adrenal tumors using radiolabeled somatostatin analogs might be useful to provide additional criteria to characterize these lesions. Furthermore, the antiproliferative effects of somatostatin on malignant tumor cells (9) might be used to treat malignant adrenal masses when conventional therapeutic regimens are ineffective. In particular, the antiproliferative effects of somatostatin on neoplastic cells consist of growth inhibition through its receptors, inhibition of hormones and growth factor release, inhibition of tumor angiogenesis as well as modulation of immunological activity. Previous experience demonstrated a high diagnostic sensitivity of In111 pentetreotide in the evaluation of 34 patients with pheochromocytoma (88%) and of 22 with neuroblastoma (77%) (7). Finally, the degree of somatostatin expression has been suggested to be a prognostic indicator in neuroblastoma (11). However, no data regarding somatostatin analog imaging in different adrenal tu-
mors, other than pheochromocytoma or neuroblastoma, are currently available. In the present study, we report our experience about the use of radiolabeled somatostatin analogs in patients with adrenal tumors. We divided our patient population into two groups on the basis of the benign or malignant nature of the adrenal lesions. Our preliminary results demonstrate that the large majority of benign adrenal lesions do not show the presence of somatostatin receptors. However, two benign pheochromocytomas showed significant somatostatin analog uptake; this finding is not surprising since the presence of somatostatin receptors can occur in such lesions (7). Conversely, the majority of malignant adrenal tumors showed significant somatostatin analog uptake, suggesting the presence of somatostatin receptors. Only one lesion consisting of a large adrenal carcinoma did not show In-l 11 pentetreotide uptake; the reason for this result remains uncertain as immunostaining for somatostatin was not obtained in this case. The presence of somatostatin receptors in malignant adrenal lesions may suggest the possibility to use somatostatin therapy in such patients when conventional therapeutic regimens are ineffective. In this regard, one of the malignant adrenal tumors (no. 11) was represented by an invasive pheochromocytoma showing no significant uptake of MIBG. In this patient, the presence of somatostatin receptors, as demonstrated by significant In-l 11 pentetreotide lesion uptake, suggests somatostatin therapy as an alternative to highdose MIBG radiotherapy. Similar findings have been reported in a recent comparative study between radiolabeled octreotide and MIBG in patients with malignant pheochromocytomas (21). Therefore, somatostatin analog imaging may have important clinical implications in patients with adrenal tumors for lesion characterization, for treatment planning, and for prognostic information, rather than tumor detection and localization. In this study, the comparative evaluation of planar and SPECT somatostatin radionuclide images showed concordant results in the majority of adrenal lesions (4/5, 80%). However, in the last patient with a left malignant pheochromocytoma that was located anteriorly to the omolateral kidney, SPECT imaging clearly improved the detection of the adrenal mass compared to planar study. Therefore, radionuclide adrenal tomography may be helpful in this setting and it should be recommended in particular cases.
CONCLUSION Finally, the results of this study suggest that the main role of radiolabeled somatostatin analogs in adrenal imaging consists of tumor characterization. The presence of somatostatin receptors in malig nant adrenal lesions, as demonstrated by somatostatin analog uptake, may allow the use of somatostatin as a treatment agent particularly when conventional therapeutic regimens are ineffective in such patients. Furthermore, the presence of somatostatin receptors in malignant adrenal tumors might reflect a high grade of differentiation, suggesting good prognosis. However, because our experience includes a small number of patients, additional studies are recommended to confirm our preliminary observations. The authors thank Ciro Mainolfi, MD, and Hui Wang, MD (Medicina Nucleare, lstituto Nation& dci Tumori, Napoli, Italy) for their ualuable help in performing PET studies. We also thank Maria Rosaria G&et-Fojaja, MD (Cnttedru di Medicine Nucleare, Universiti Fedenco II, Napoli, Italy), for her valuable help in perfoming MZBG studies. Also, thanks to the Associnzione It&ma per la Ricerca sul Cancro (AIRC) for financial support for this study, corresponding to the
680
project entitled “Morpho-functional information and fusion imaging in brain tumors, adrenal tumors and lymphomns,” senior investigator Marco Salvatore, MD. Finally, the authors thank Diatide Inc., Londonderry, NH, for providing Tc-99m-labeled peptides (P587 and P829).
References 1. Boland G. W., Goldberg M. A., Lee M. J., Mayo-Smith W. W., Dixon J., McNicholas M. M. and Mueller P. R. (1995) Indeterminate adrenal mass in patients with cancer: Evaluation at PET with 2-[F-181.fluoro2-deoxy-D-glucose. Radiology 194, 131-134. 2. Falke T. H. M. and Sandier M. P. (1994) Classification of silent adrenal masses: Time to get practical. J. Nucl. Med. 35, 1152-l 154. 3. Fischman A. J., Babich J. W. and Strauss H. W. (1993) A ticket to ride: Peptide radiopharmaceuticals. .J. Nucl. Med. 34, 2253-2262. 4. Francis I. R., Gross M. D., Shapiro B., Korobkin M. and Quint L. E. (1992) Integrated imaging of adrenal disease. Radiology 184, 1-13. 5. Glazer G. M., Woolsey E. J., Borrello J., Francis IR, Aisen AM, Bookstein F, Amendola MA, Gross MD, Bree RL, Martel W (1986) Adrenal tissue characterization using MR imaging. Radiology 158, 73-79. 6. Gross M. D., Shapiro B., Francis 1. R., Glazer GM, Bree RL, Arcomano MA, Schteingart DE, Mcleod MK, Sansfield ]A, Thompson NW. (1994) Scintigraphic evaluation of clinically silent adrenal masses. J. Nucl. Med. 35, 1145-1152. 7. Hoefnagel C. A. (1994) Metaiodobenzylguanidine and somatostatin in oncology: Role in the management of neural crest tumors. Eur. J. Nucl. Med. 21, 561-581. 8. Kier R. and McCarthy S. (1989) MR characterization of adrenal masses: Field strength and pulse sequence considerations. Radiology 171, 671674. 9. Krenning E. P., Kwekkeboom D. J., Bakker W. H., Breeman WAP, Kooij PPM, Oei HY, van Hagen M, Postema PTE, de long M, Reubi JC, Visser TJ, Reijs AEM, Hofland LJ, Koper JW, Lamberts SWJ. (1993) Somatostatin receptor scintigraphy with In-111-DTPA-Phe and l-123Tyr-octreotide: The Rotterdam experience with more than 1000 patients. Eur. J. Nucl. Med. 20, 716-731. 10. Lamberts S. W. J., Krenning E. P. and Reubi J. C. (1991) The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr. Rev. 19, 450-482. 11. Lamki L. M. (1995) Tissue characterization in nuclear oncology: Its time has come. J. Nucl. Med. 36, 207-210.
S. Maurea et al.
12. Lastoria S., Maurea S., Caracb C., Vergara E, Maurelli L, Indolfi P, Casale F, di Tullio MT, Salvatore M. (1993) Iodine-131 metaiodobenzylguanidine scintigraphy for localizing tumor lesions in children with neuroblastoma: Comparison with computed tomography and ultrasound imaging. Eur. J. Nucl. Med. 20, 1161-1167. 13. Lee M. J., Mayo-Smith W. W., Hahn P. F., Goldberg MA, Boland GW, Saini S, Papamcolauou N. (1994) State-of-the-art MR Imaging of the adrenal gland. Radiographics 14, 1015-1029. 14. Maurea S., Cuocolo A., Reynolds J. C., Tumeh SS, Begley MG, Linehan MW, Norton ]A, McClellan MW, Keiser HR, Neumann RD. (1993) lodme-131 metaiodobenzylguanidme scintigraphy in preoperatlve and postoperative evaluation of paragangliomas: Comparison with CT and MRI. J. Nucl. Med. 34, 173-179. 15. Maurea S., Lastoria S., Klain M., Celentano L, Varrella I’, Rossi R, Acampa W, Bazzicalupo L, Salvatore M. (1994a) Combined use of cortical and medullary adrenal scintigraphy to characterize adrenal masses.J. Nucl. Biol. Med. 38, 269-270 (Abstract). 16. Maurea S., Lastoria S., Carach C., lndolfi P, Casale F, di Tullio MT, Salvatore M. (199413) 131-Iodine MIBG imaging for monitoring response to chemotherapy in advanced neuroblastoma: Comparison with laboratory analysis. J. Nucl. Med. 35, 1429-1435. 17. Maurea S., Lastoria S., Cuocolo A., Celentano L. and Salvatore M. (1995) The diagnosis of nonfunctioning pheochromocytoma: The role of 1-123 metaiodobenzylguanidine imaging. Clin. Nucl. Med. 20, 22-24. 18. Reinig J. W., Stutley J. E., Leonhardt C. M., Spicer K. M., Margolis M. and Caldwell C. B. (1994) Differentiation of adrenal masses with MR imaging: Comparison of techniques. Radiology 192, 41-46. 19. Shulkin B. L., Wieland D. M., Schwaiger M., Thompson NW, Francis IR, Haka MS, Rosenspire KC, Shapiro B, Sisson JC, Kuhl DE. (1992) PET scanning with hydroxyephedrine: An approach to the localization of pheochromocytoma. J. Nucl. Med. 33, 1125-1131. 20. Shulkin B. L., Koeppe R. A., Francis I. R., Deeb G. M., Lloyd R. V. and Thompson N. W. (1993) Pheochromocytomas that do not accumulate metaiodobenzylguanidine: Localization with PET and administration of FDG. Radiolog-, 186, 711-715. 21. Tenenbaum F., Lumbroso J., Schlumberger M., Mure A, Plouin PF, Caillou 8, Parmentier C. (1995) Comparison of radiolabeled octreotide and meta-iodobenzylguanidine (MIBG) scintigraphy in malignant pheochromocytoma. J. Nucl. Med. 36, l-6.
ISSN 0969-8051/96/$15.00 + 0.00 PII SO969-805 1(96)00065-O
1996
ELSEVIER
The Role of Radiolabeled Somatostatin Analogs in Adrenal Imaging Simone Maurea, ’ Second0 Lastoria, ’ Corradina Caraci,, 2 Michek k&in, 3 Paola Varrella,3 Wanda Acampa,3 Pietro Muto’ and Marco Salwatore’ lMEDICINA
NUCLEARE,
ISTITUTO
3CATTEDRA
NAZIONALE DI MEDICINA
DE1 TUMORI, NUCLEARE,
‘CENTRO UNIVERSITA
PER LA FEDERICO
MEDICINA
NUCLEARE
II, NAPOLI,
DEL CNR,
AND
ITALY
ABSTRACT.
We investigated the role of radiolabeled somatostatin analogs (SAs) in adrenal imaging. We evaluated 15 patients (6 men and 9 women, mean age 47 + 17 years) with imaging-detected adrenal tumors. Patient population was divided into two groups on the basis of the nature of adrenal lesions. Group 1 consisted of patients with benign adrenal lesions (n = 10). Group 2 consisted of patients with malignant adrenal lesions (n = 5). Pathology examinations were obtained in 13 cases: 7 pheochromocytomas, 2 adenomas, 2 cysts, 1 carcinoma, and 1 fibro-histiocytoma. One patient had a proven diagnosis of non-small-cell lung cancer associated with the presence of a right adrenal mass. The last patient had a clinical diagnosis of Werner syndrome associated with the presence of a large left adrenal mass. All patients underwent scintigraphic studies using radiolabeled SAs, of which indium-111 (In-111) pentetreotide was used in 11 cases and technetium-99m (Tce99m)Jabeled peptides (P-587 or P-829) were used in the remaining four cases. No significant labeled SAs uptake was observed in the majority (8 of 10, 80%) of the benign adrenal lesions (Group 1); however, increased uptake was found in two benign pheochromocytomas. Conversely, significant labeled SAs uptake was observed in the majority (4 of 5, 80%) of th e malignant adrenal lesions (Group 2); however, the last lesion (carcinoma) did not show abnormal uptake. Results of this study show that the majority of benign adrenal tumors do not concentrate radiolabeled SAs; conversely, the majority of malignant adrenal lesions show significant SAs uptake, suggesting the presence of somatostatin receptors. This finding may allow the use of somatostatin as a treatment agent in malignant adrenal tumors. Thus, the main role of labeled SAs in adrenal imaging consists of lesion characterization rather than tumor detection and localization. NUCL MED BIOL 23;6:677-680, 1996.
KEY WORDS. Adrenal
tumors, Receptor
imaging, Scintigraphy,
Somatostatin
analogs, Indium-1
11, Techne-
tium-99m
INTRODUCTION In the diagnostic evaluation of adrenal neoplastic diseases, clinically relevant information needs to be provided for patient management (4). Various imaging techniques are currently available for detecting and localizing adrenal tumors (4). While abdominal ultrasound (US) shows considerable limits in this setting, computed tomography (CT) and magnetic resonance (MR) scans represent the best techniques for this purpose (4). However, one of the crucial points in adrenal imaging is noninvasive tumor characterization in order to avoid adrenal biopsy (2). MR imaging has been proposed to characterize adrenal masses (5, 8); however, significant overlapping findings have been recently reported in lesions of different histologic nature (13, 18). In this regard, several radiopharmaceuticals with specific biological features may be used in nuclear medicine for adrenal tumor characterization. They include labeled norcholesterol for adenomas (6, 15), meta-iodobenzylguanidine (12, 14, 16), and/or hydroxyephedrine (19) for medullary chromaffin tissue lesions (pheochromocytoma and neuroblastoma), and deoxy-glucose (l), for malignant tumors (carcinomas and metastases).
Address reprint requests to: Simone 7. 80132 Nap&, Italy. Accepted 18 March 1996.
Maurea,
MD, Via Raffaele De Cesare no
Recently, molecular engineering had led to peptides of different forms and sizes for tumor imaging (3, 11). In particular, subtypes of peptides with significant potential as clinically accepted radionuelide imaging agents are receptor peptide derivatives. Among these, radiolabeled somatostatin analogs have been proposed in the evaluation of different tumors that show somatostatin receptors (7, 9, 10). Furthermore, somatostatin may be used as a treatment agent in neoplastic diseases (9); however, the presence of somatostatin receptors on tumor cells is requested for this form of treatment. Therefore, the identification of somatostatin receptors on tumor lesions using radiolabeled somatostatin analogs may also predict the use of somatostatin therapy in such patients. In this study, we investigated the role of radiolabeled somatostatin analogs in adrenal imaging, reporting our experience in patients with adrenal tumors.
MATERIALS AND METHODS Patient Popdation We studied 15 patients (6 men and 9 women) ranging in age from 24 to 75 years (mean age 47 + 17 years) with unilateral adrenal tumors (8 on left and 7 on right) detected on US, CT, and/or MR imaging scans. Table 1 shows the clinical characteristics of each patient. Laboratory evaluation of cortical and medullary adrenal
678
TABLE
S. Maurea er al.
1. Clinical
Patient 1 2 3 ; 6 7 8 9 10 11 12 13 14 15
Characteristics
of the Patient Population
Age
Sex
Symptoms
31 35 29 75 28 24 33 49 69 62 35 69 58 58 51
F M M F F M F M F F M F M F F
Hypertension Hypertension Hypertension None Hypertension Hypertension Dorsal pain Dorsal pain None None Hypertension None None Bone pain Dorsal pain
Laboratory Catecholamine Catecholamine Catecholamine Normal Catecholamine Catecholamine Normal Normal Normal Normal Catecholamine Anemia Normal Gastrina, PTH, Normal
(+) (+) (+) (+) (+)
(+)
PRL (+)
Site
Size”
Pathology
Left Right Right Left Right Right Left Left Left Right Left Left Right Left Right
2.0 2.5 5.0 5.5 3.5 3.0 5.0 5.0 2.5 2.0 6.0 10.5 4.5 9.5 11.5
Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma Benign Pheochromocytoma cyst cyst Adenoma Adenoma Malignant pheochromocytoma Fibro-histiocytoma Lung cancer + adrenal mass Not available Adrenal carcinoma
a Maximal diameter in centimeters. F = female; (+) indicates increased levels; M = male; PTH = parathormone; PRL = prolactin
function was obtained in all patients. Serum tumor markers were also measured. Adrenal lesions consisted of pheochromocytomas (n = 7), cysts (n = 2), adenomas (n = 2), carcinomas (n = 1) and fibro-histiocytoma (n = 1). In two patients (nos. 13 and 14), pathology examinations of adrenal lesions were not obtained. The first patient (no. 13) had a proven diagnosis of non-small-cell lung cancer associated with a right adrenal mass highly suspicious of metastatic lesion on the basis of CT imaging features. The second patient (no. 14) had a clinical diagnosis of malignant multiendocrine syndrome type 1 (Werner) showing pituitary adenoma on CT scan, and hyperparathyroidism as well as pancreatic and adrenal tumors associated with multiple liver nodular lesions on MR images. In this patient, increased serum levels of prolactin and gastrina were also measured. Finally, multiple skeletal lesions were documented on bone scan. The patient population was divided into two groups on the basis of the benign or malignant nature of adrenal tumors. Group 1 consisted of patients with benign adrenal lesions (n = 10). Group 2 consisted of patients with malignant adrenal lesions (n = 5).
jetted (74-111 MBq). For Tc-99m-labeled somatostatin analogs (P587 or P-829) (Diatide, Londonderry, NH), a dose of 550 to 740 MBq was injected intravenously. Both P-587 and P-829 are new peptides consisting of 10 amino acids. The P-587 labeling occurs after incubation for 15 min at 100°C with Tc-99m glucoheptonate (Glucoscan, DuPont, Billerica, MA). The same labeling procedure at room temperature was utilized for Tc-99m P-829 for 15 min. Quality control using instant thin-layer chromatography was performed, showing that more than 95% of radioactivity was peptide bound. For In-l 11 pentetreotide scans, images were acquired 4 and 24 h after injection. For Tc-99m-labeled somatostatin analog studies, early (within 30 min) and delayed (2 to 4 h) images were acquired after injection. Whole-body anterior and posterior scans were obtained using a large field-of-view gamma camera (Orbiter, Siemens, Erlangen, Germany) equipped with a medium-energy (for In-111 studies) and a low-energy (for Tc-99m scans) collimators. Anterior and posterior abdomen spot views were also obtained. When requested, single photon emission tomography (SPET) acquisition was performed.
Radionuclide
RESULTS
Studies
All patients underwent planar scintigraphic studies using radiolabeled somatostatin analogs: indium-11 1 (In-l 11) pentetreotide in 11 cases and technetium-99m (Tc-99m)-labeled peptides (P-587 or P-829) in the remaining 4 cases. Because the uptake of somatostatin analogs may be suppressed by certain medications (i.e., somatostatin and corticosteroids), such drugs were discontinued 30 days or longer before study acquisition in order to ensure optimal scanning conditions. In five patients studied with In-l 11 pentetreotide (4 pheochromocytomas and 1 carcinoma), planar acquisition was integrated using tomographic imaging (SPECT). In 11 patients, radiolabeled (iodine-131 or iodine-123) metaiodobenzylguanidine (MIBG) studies were also performed, as previously described (14, 17). Finally, in four patients positron emission tomography (PET) with fluorine-18 deoxyglucose was used, as previously described (1).
Somutostatin
Analog
Scintigraphy
For In-l 11 pentetreotide studies, In-l 1 l-DTPA-Phe-I-octreotide (Mallinckrodt, Petten, The Netherlands) was intravenously
in-
No significant labeled somatostatin analog uptake was observed in the majority (8/10, 80%) of the benign adrenal lesions (4 pheochromocytomas, 2 cysts and 2 adenomas); however, increased uptake was found in two benign pheochromocytoma. Conversely, significant labeled somatostatin analog uptake was observed in the majority (4/5, 80%) of the malignant adrenal lesions (1 malignant pheochromocytoma, 1 fibro-histiocytoma, and 2 indeterminate); however, the last malignant lesion (carcinoma) did not show abnormal uptake. In particular, the two indeterminate adrenal lesions deserve some comments. The first patient (no. 13) had a proven diagnosis of non-small-cell lung cancer associated with a right adrenal mass highly suspicious of metastatic lesion on the basis of CT imaging. In this case, significant abnormal P-587 uptake was observed both in the primary lung tumor and in the right adrenal mass; in particular, the intensity of P-587 uptake in the two lesions was comparable, suggesting that the two tumor sites were related. The second patient (no. 14) had a clinical diagnosis of malignant multiendocrine syndrome type I (Werner) associated with a large
Radiolabeled
Somatostatin
in Adrenal
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Imaging
adrenal mass, multiple liver and bone lesions, as well as a right round lung mass. All these lesions significantly accumulated fluorine-18 deoxyglucose uptake on PET whole-body imaging. Cornparable P-829 images were obtained showing abnormal uptake in the same anatomic sites where increased fluorine-18 deoxyglucose uptake was observed. The comparative evaluation of planar and SPECI somatostatin radionuclide images, performed in five patients, showed similar results. Particularly, in four cases the findings of planar and SPECT scans were comparable. However, in a patient with proven malig nant left pheochromocytoma, SPECT clearly detected a round lesion located anteriorly to the left kidney. In this patient, the lesion was not visualized on anterior and posterior planar images; only the acquisition of a planar left anterior oblique view was able to better identify and separate the left adrenal lesion from the omolateral kidney.
DISCUSSION The diagnostic evaluation of patients with clinically suspected adrenal tumors consists mainly of lesion detection and precise anatomic localization (4). Although US is a noninvasive and multiplanar feasible imaging technique to evaluate adrenals, this method reveals several limits for this purpose. For instance, the presence of bowel gas may interfere with the detection of adrenal masses measuring less than 3 cm; adjacent anatomic structures may also mimic adrenal pseudotumors. Both CT and MR cross-sectional imaging studies represent the modalities of choice to detect and precisely localize adrenal tumors showing high spatial resolution. However, adrenal tumor characterization using imaging techniques has been recently requested for correct diagnosis and treatment planning (2). Although CT and MR scans are able to provide accurate anatomic details in adrenal imaging, these methods show considerable limitations for adrenal tissue characterization (4, 13, 18). Nuclear medicine imaging using different radiopharmaceuticals may provide unique functional information in order to characterize adrenal tumors metabolically (1 I). Radiolabeled nor-cholesterol may be used to characterize adrenal lesions as adenomas (6), labeled meta-iodobenzylguanidine (14) and/or carbon-l 1 hydroxyephedrine (19) as pheochromocytoma, and fluorine-18 2-fluoro-2deoxyglucose (FDG) (1) as malignant tumors (carcinomas and metastases). However, FDG uptake has also been observed in pheochromocytoma (20). Recently, radiolabeled somatostatin analogs have been proposed in the evaluation of various tumors that show somatostatin receptors (7, 9, 10). Identification of somatostatin receptors on adrenal tumors using radiolabeled somatostatin analogs might be useful to provide additional criteria to characterize these lesions. Furthermore, the antiproliferative effects of somatostatin on malignant tumor cells (9) might be used to treat malignant adrenal masses when conventional therapeutic regimens are ineffective. In particular, the antiproliferative effects of somatostatin on neoplastic cells consist of growth inhibition through its receptors, inhibition of hormones and growth factor release, inhibition of tumor angiogenesis as well as modulation of immunological activity. Previous experience demonstrated a high diagnostic sensitivity of In111 pentetreotide in the evaluation of 34 patients with pheochromocytoma (88%) and of 22 with neuroblastoma (77%) (7). Finally, the degree of somatostatin expression has been suggested to be a prognostic indicator in neuroblastoma (11). However, no data regarding somatostatin analog imaging in different adrenal tu-
mors, other than pheochromocytoma or neuroblastoma, are currently available. In the present study, we report our experience about the use of radiolabeled somatostatin analogs in patients with adrenal tumors. We divided our patient population into two groups on the basis of the benign or malignant nature of the adrenal lesions. Our preliminary results demonstrate that the large majority of benign adrenal lesions do not show the presence of somatostatin receptors. However, two benign pheochromocytomas showed significant somatostatin analog uptake; this finding is not surprising since the presence of somatostatin receptors can occur in such lesions (7). Conversely, the majority of malignant adrenal tumors showed significant somatostatin analog uptake, suggesting the presence of somatostatin receptors. Only one lesion consisting of a large adrenal carcinoma did not show In-l 11 pentetreotide uptake; the reason for this result remains uncertain as immunostaining for somatostatin was not obtained in this case. The presence of somatostatin receptors in malignant adrenal lesions may suggest the possibility to use somatostatin therapy in such patients when conventional therapeutic regimens are ineffective. In this regard, one of the malignant adrenal tumors (no. 11) was represented by an invasive pheochromocytoma showing no significant uptake of MIBG. In this patient, the presence of somatostatin receptors, as demonstrated by significant In-l 11 pentetreotide lesion uptake, suggests somatostatin therapy as an alternative to highdose MIBG radiotherapy. Similar findings have been reported in a recent comparative study between radiolabeled octreotide and MIBG in patients with malignant pheochromocytomas (21). Therefore, somatostatin analog imaging may have important clinical implications in patients with adrenal tumors for lesion characterization, for treatment planning, and for prognostic information, rather than tumor detection and localization. In this study, the comparative evaluation of planar and SPECT somatostatin radionuclide images showed concordant results in the majority of adrenal lesions (4/5, 80%). However, in the last patient with a left malignant pheochromocytoma that was located anteriorly to the omolateral kidney, SPECT imaging clearly improved the detection of the adrenal mass compared to planar study. Therefore, radionuclide adrenal tomography may be helpful in this setting and it should be recommended in particular cases.
CONCLUSION Finally, the results of this study suggest that the main role of radiolabeled somatostatin analogs in adrenal imaging consists of tumor characterization. The presence of somatostatin receptors in malig nant adrenal lesions, as demonstrated by somatostatin analog uptake, may allow the use of somatostatin as a treatment agent particularly when conventional therapeutic regimens are ineffective in such patients. Furthermore, the presence of somatostatin receptors in malignant adrenal tumors might reflect a high grade of differentiation, suggesting good prognosis. However, because our experience includes a small number of patients, additional studies are recommended to confirm our preliminary observations. The authors thank Ciro Mainolfi, MD, and Hui Wang, MD (Medicina Nucleare, lstituto Nation& dci Tumori, Napoli, Italy) for their ualuable help in performing PET studies. We also thank Maria Rosaria G&et-Fojaja, MD (Cnttedru di Medicine Nucleare, Universiti Fedenco II, Napoli, Italy), for her valuable help in perfoming MZBG studies. Also, thanks to the Associnzione It&ma per la Ricerca sul Cancro (AIRC) for financial support for this study, corresponding to the
680
project entitled “Morpho-functional information and fusion imaging in brain tumors, adrenal tumors and lymphomns,” senior investigator Marco Salvatore, MD. Finally, the authors thank Diatide Inc., Londonderry, NH, for providing Tc-99m-labeled peptides (P587 and P829).
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