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Departments of Endocrinology and Metabolism (J.M., N.U., H.L.), Pharmacology and Toxicology (St.S., V.H.), Obstetrics and Gynecology (So.S.), and Nuclear Medicine (J.M., R.S.), Otto-von-Guericke-University, D-39120 Magdeburg, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Hendrik Lehnert Department of Endocrinology and Metabolism University Hospital of Magdeburg Leipziger Strasse 44, D-39120 Magdeburg, Germany. E-mail: hendrik.lehnert{at}medizin.uni-magdeburg.de.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Somatostatin receptors are expressed in many tissues, and multiple subtypes often coexist in the same cell. Five receptor subtypes (sst1–5) have been identified (3). The somatostatin receptor subtypes are encoded by five genes localized on separate chromosomes, belong to the family of seven transmembrane domain G protein-coupled receptors and exhibit high binding affinity to the natural ligands SS-14 and SS-28. The somatostatin receptors are functionally coupled to inhibition of adenylate cyclase and play a role in modulation of MAPK and activation of phosphotyrosine phosphatase (4). Because of the short half-life of natural somatostatin peptides, different somatostatin analogs have been developed such as octreotide (SMS 201–995), lanreotide (BIM 23014), and vapreotide. However, these somatostatin analogs are not able to bind with high affinity to all five somatostatin receptor subtypes (3). Octreotide treatment is helpful in stabilization of neuroendocrine tumor progression by inhibition of specific growth factors like IGF-I and angiogenesis (5). Beyond these effects, octreotide inhibits the proliferation of human T lymphocytes in vitro (6). Somatostatin receptors are classical targets for diagnosis, long-term treatment with nonradioactive analogs and for radiotherapy, e.g. with 90Y-DOTA-D-Phe-Tyr-octreotide, of endocrine tumors (7, 8).
Pheochromocytomas are neoplasms arising from chromaffin tissue of the adrenal medulla or other paraganglionic sites generally associated with catecholamine overproduction. The annual incidence of pheochromocytomas appears to approximate 2/105. The diagnosis of malignant pheochromocytoma depends on local tumor invasion and presence of tumor tissue in nonchromaffin cell sites, such as in lymph nodes, bone, liver, or lung. Extraadrenal locations, early manifestation and large tumor size are major features suggestive of malignancy (9). Among other classical imaging techniques such as ultrasound, magnetic resonance imaging, computer tomography, and 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 111In-octreotide imaging appears much more helpful in detecting malignant than benign pheochromocytomas. We and others (10, 11, 12) have clearly shown that both 123I-MIBG and 111In-octreotide imaging have a complementary role in detecting tumorous lesions in these conditions. In two studies, seven and six metastatic lesions, respectively, were detected by octreotide scintigraphy when MIBG scans were negative because of dedifferentiation or loss of norepinephrine transporter system (10, 11, 12). Van der Harst et al. (12) showed that 111In-octreotide-scan was superior to MIBG scan in visualization of metastases. In six malignant cases, metastases were negative with 123I-MIBG scintigraphy, but in three cases they were detected by 111In-octreotide imaging.
Nevertheless, octreoscan should be reserved for patients in whom conventional imaging cannot detect the tumor or 123I-MIBG scintigraphy is negative because the allover sensitivity of this method is less than 30% (13).
18F-Fluorodopamine is a positron-emitting analog of dopamine and a good substrate for both the plasma membrane and the intracellular vesicular transporters in catecholamine-synthesizing cells. It is a tool to localize pheochromocytomas in most cases, and it can be used if conventional imaging cannot detect the primary or recurrent tumor. Using 6-18F-Fluorodopamine positron emission tomography, Pacak et al. (13) have demonstrated this technique to yield a high sensitivity in detecting pheochromocytoma or metastatic lesions.
The stable somatostatin analog octreotide has been successfully used for tumor imaging and treatment of human endocrine tumors (2, 5, 8). However, pheochromocytomas often express more than one somatostatin receptor subtype, and it is uncertain by which receptor subtype the functional responses of octreotide are mediated. We therefore determined the precise pattern of sst1, sst2A, sst3, sst4, and sst5 somatostatin receptor protein expression in a series of 52 pheochromocytomas from 35 randomly selected patients. The results of the immunocytochemical somatostatin receptor determination were correlated with the outcome of 111In-octreotide scintigraphy.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Fifty-two pheochromocytoma tumors from 35 randomly selected patients were investigated, including seven paragangliomas from six patients. Informed consent was obtained from all patients. Tumor tissue was removed during the surgical intervention; in each case, surgery was mandatory to remove the pheochromocytoma tumors. Before surgery, there was no specific treatment, except for the necessary preoperative 
-blockade. Pertinent data of patient history are given in Table 1
. Magnetic resonance imaging was not available in all cases, so the diagnoses were made preoperatively by endocrine testing, computed tomography, 123I-MIBG scintigraphy and in some cases by 111In-octreotide scintigraphy (14, 15). The diagnoses were postoperatively confirmed by histological and immunohistochemical examinations. Proof of malignancy was the appearance of metastases in nonchromaffin tissue or local tumor invasion (9). Twenty-seven tumors from 17 patients were malignant; in three of these 17 patients (patient nos. 21, 23, and 25) tissue from the primary tumor, from subsequent metastases and/or recurrent tumors was studied; in three patients (nos. 1, 27, and 29) the tumor material was removed during the same operation. Patient no. 4 (harboring a succinate dehydrogenase subunit B mutation) underwent removal of a paraganglioma (tumor no. 4) 5 yr before appearance of a rib metastasis (tumor no. 5); additionally, a glomus jugulare tumor (tumor no. 20) was detected by octreoscan 3 months later.
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Immunohistochemistry
Seven-micrometer sections were cut and floated onto positively charged slides for immunohistochemical staining. Sections were dewaxed three times in xylene and rehydrated in a graded series of ethanol. After rinsing in TPBS [10 mM Tris, 10 mM phosphate buffer, 137 mM NaCl, 0.05% thimerosalm (pH 7.4)], sections were incubated in methanol containing 0.3% H2O2 for 30 min at room temperature (RT). Sections were transferred into TPBS and subsequently microwaved in 10 mM citric acid (pH 6.0) for 20 min at 600 W. Specimens were then allowed to cool to RT, washed in TPBS and preincubated in TPBS containing 3% normal goat serum for 1 h at RT. Sections were then incubated either with affinity-purified anti-sst1 {4819}, anti-sst2A {6291}, anti-sst3 {4823}, anti-sst4 {4801}, and anti-sst5 {6006} antibodies at a concentration of 1 µg/ml in TPBS containing 1% normal goat serum overnight at 4 C. These polyclonal rabbit antisera were generated against the carboxy-terminal tails of the human somatostatin receptors and have been characterized extensively. The identity of the peptides was CRNGTCTSRITTL, which corresponds to residues 382–391 of the human sst1, ETQRTLLNGDLQTSI, which corresponds to residues 355–369 of the human sst2A, CQERPPSRVA which corresponds to residue 384–393 of the human sst3, CQQEALQPEPGRKRIPLTRTTTF, which corresponds to residues 366–388 of the human sst4, and QEATRPRTAAANGLMQTSKL, which corresponds to residues 345–364 of the human sst5 receptor. In addition, all tumors were stained with the mouse monoclonal anti-SS-14 antibody (Biomeda, Foster City, CA). Staining of primary antibody was detected using biotinylated goat antirabbit IgG or biotinylated goat antimouse IgG followed by an incubation with AB solution [reagents from Vector Laboratories (Burlingame, CA) ABC "Elite" kit]. Tissue was then rinsed and stained with diaminobenzidine (DAB)-glucose oxidase for 15 min. The cell nuclei were lightly counterstained with hematoxylin. Sections were then dehydrated through several concentrations of alcohol, cleared in xylol and coverslipped with DPX (Fluka, Deisenhofen, Germany). For immunohistochemical controls, the primary antibody was either omitted, replaced by preimmune sera, or adsorbed with several concentrations ranging from 1–10 µg/ml of homologous or heterologous peptides for 2 h at RT. A tumor known to stain positively was included in each batch of staining as a positive control.
Assessment of staining patterns
Immunohistochemical staining pattern were assessed as previously described (16), and all slides have been evaluated by the same investigator. Briefly, the presence or absence of staining and depth of color was noted, as well as the number of cells showing a positive reaction and whether the staining was localized to the plasma membrane.
Western blot analysis
Membranes were prepared from two pheochromocytoma tumor specimens, and glycoproteins were partially purified using wheat germ lectin-agarose (Vector Laboratories) essentially as described previously (17, 18). Briefly, tissue was lysed in homogenization buffer [5 mM EDTA, 3 mM EGTA, 250 mM sucrose, and 10 mM Tris-HCl (pH 7.6) containing 1 mM phenylmethylsulfonyl fluoride, 1 µM pepstatin, 10 µg/ml leupeptin, and 2 µg/ml aprotinin]. The homogenate was spun at 500 x g for 5 min at 4 C to remove unbroken cells and nuclei. Membranes were then pelleted at 20,000 x g for 30 min at 4 C. Membranes were dissolved in lysis buffer [150 mM NaCl, 5 mM EDTA, 3 mM EGTA, and 20 mM HEPES (pH 7.4) containing 4 mg/ml dodecyl-ß-maltoside and proteinase inhibitors as described above] and incubated with 150 µl of wheat germ lectin-agarose beads for 90 min at 4 C. Beads were washed five times in lysis buffer, and adsorbed glycoproteins were eluted with sodium dodecyl sulfate sample buffer for 60 min at 37 C. The protein content was determined using the bicinchoninic acid method according to the instructions of the manufacturer (Pierce, Rockford, IL), and aliquots of each sample containing equal amounts of protein were subjected to 8% SDS-PAGE and immunoblotted onto nitrocellulose. Blots were incubated with affinity-purified anti-sst2A {6291} and anti-sst3 {4823} antibodies at a concentration of 1 µg/ml overnight at 4 C. Blots were developed using peroxidase-conjugated secondary antibodies and enhanced chemiluminescence. For adsorption controls, antisera were preincubated with 10 µg/ml of their cognate peptide for 2 h at room temperature.
Statistical evaluation
Data were analyzed by the use of statistical program package SAS (SAS Institute, Cary, NC). Only one tumor of each patient was involved. Data were grouped into categories and analyzed for correlation either with 
2 or Fisher test. Significant correlation was confirmed at P < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, Fig. 1). We established unequivocal staining patterns when almost the whole tumor or cell clusters were stained. Except for three tumors (two patients), 94% showed a positive staining for somatostatin receptors. Twenty-five tumors (48%) expressed two or more somatostatin receptors. The vast majority of tumors (90%) was positively stained for sst3. Sst1 immunostaining was detected in four tumors (8%), sst2A in 13 tumors (25%), sst4 in five tumors (10%), and sst5 immunostaining was detected in eight tumors (15%) (Table 1). Somatostatin receptor staining pattern was analyzed for correlation of each subtype with malignant or benign, familial or sporadic occurrence and adrenal or extraadrenal localization. This analysis involved only one tumor of each patient. Except for a significantly higher expression of sst2A in extraadrenal pheochromocytomas (P < 0.021), no other significant differences were noted.
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). Thus, increasing loss of cell differentiation in malignant tumors may lead to a reduction of endogenous somatostatin. Whereas immunoreactive sst1, sst4, and sst5 receptors were in most cases distributed throughout the cytoplasm of the tumor cells, immunostaining for sst2A was, except for a few tumors, predominantly confined to the plasma membrane. In contrast, we observed striking differences among sst3-positive tumors with regard to the subcellular distribution of immunoreactive sst3 receptors. Sst3 immunoreactivity was predominantly associated with the plasma membrane only in a subset of cases (n = 8), whereas in most cases immunoreactive sst3 receptors were distributed throughout the cytosol (n = 29). We found an equal distribution of membranous and cytoplasmic sst3 receptors in ten cases.
Given the striking differences in the subcellular distributions of immunoreactive sst3 receptors, sst3 immunoreactivity in human pheochromocytoma was further characterized using Western blot analysis. When glycoproteins were enriched from membrane preparations of two tumor specimens and subjected to Western blot analysis using anti-sst2A and anti-sst3 antibodies, we detected broad bands migrating at a molecular mass of 75,000 for both sst2A and sst3 (Fig. 2). These bands were completely neutralized by preincubation of the antibodies with their immunizing peptides (Fig. 2). Interestingly, whereas immunoreactive sst3 receptors were detected in both tumor samples, sst2A immunoreactivity was only seen in one tumor sample (Fig. 2).
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Seventeen of 20 SS-14 and sst3-positive tumors showed a predominantly intracellular staining of sst3. But only three of four SS-14 and sst2A-positive tumors showed a sst2A-immunostaining partially localized in the cytoplasm.
Seventeen patients received a preoperative octreoscan. Of these, 13 tumors from eleven patients demonstrated positive tracer uptake. Octreotide possesses a preferentially high affinity for sst2A but also binds to sst3 and sst5 with moderate affinity. In six of 13 positive octreoscans expression of sst2A localized to the plasma membrane was found (representative example is depicted in Fig. 3). All positive octreoscans in the absence of sst2A revealed either completely or partially membrane-associated sst3 receptors (representative example is depicted in Fig. 4).
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. Of the 13 tissues with a positive octreoscan, seven cases showed a predominant localization of sst3 to the plasma membrane, in five cases sst3 was localized either only in the cytoplasm (two cases) or more cytoplasmic than membranous (three cases) (Table 2).
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). The remaining three tumors from one patient showed a positive staining for sst2A or a membrane staining for sst3 but were very small lesions (<1 cm) and might therefore not be detectable by octreoscan. The intraindividual analysis includes 30 tumors from 13 patients. A similar intraindividual distribution of somatostatin receptors was demonstrated in eight patients (62%). All of the familial, bilateral pheochromocytomas and even two different locations of a multilocular adrenal pheochromocytoma showed an equal staining pattern. The pheochromocytoma of patient no. 21 was positive for sst3, sst4 and sst5, whereas the recurrent tumors showed a lack of sst4 immunostaining. Possibly cellular dedifferentiation may have led to a loss of sst4 expression. The somatostatin receptor status of patient no. 25 supports this assumption; the liver metastasis was positive for sst3, whereas the recurrent tumor and the im metastasis did not show any immunostaining; but the positive octreoscan of the skin metastasis suggests the expression of somatostatin receptors. The bilateral, sporadic pheochromocytomas of patient no. 29 was removed during the same surgery; the left-sided pheochromocytoma expressed sst1 and sst3; histologically, most of the right sided pheochromocytoma (no. 44) was necrotic, which might explain the absence of immunostaining.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although previous studies determined the expression of sst1 and sst2A receptors, the present study is the first to identify the high incidence of immunoreactive sst3 receptors in human pheochromocytoma. Sst1 was detected in four of 52 (7.7%) tumors and sst2A in 11 of 52 (25%) tumors. Hofland et al. (21) found four of five tumors positive for sst1 and three of five positive for sst2A. Reubi et al. (22) examined endocrine tumor tissue with regard to subcellular distribution of sst2A receptors. Thirteen of 15 paragangliomas, and 16 of 18 paraffin-embedded pheochromocytomas were stained positive for sst2A.
Previous studies explain the subcellular localization of sst2A by somatostatin-dependent internalization (23). Pheochromocytomas with a high level of endogenous somatostatin mRNA show a cytoplasmic sst2A staining, whereas a more plasma membranous staining was observed in tumors lacking somatostatin mRNA (23). Although the agonist-dependent regulation of somatostatin receptors is well known (3, 24), the subcellular distribution of sst2A and sst3 is not completely understood. In sst2A-3-coexpressing pheochromocytomas, we observed that sst3 is often associated with the localization of sst2A in the same manner. Recent studies revealed that a sst2A-3-coexpression lead to a heterodimerization that results in a novel receptor. This receptor exhibits a complete inactivation of sst3 receptor function and a greater resistance against somatostatin-dependent internalization (18). This provides an additional explanation for a sst2A and sst3 expression on the plasma membrane. This coexpression of sst2A and sst3 was found in six of 11 samples.
Immunostaining of sst2A was found to be more expressed at the cell membrane than in the cytoplasm (21). Janson et al. (25) made the same observation in tissue of human carcinoid tumors. Kimura et al. (26) found an expression of sst2 in 15/15 pheochromocytomas (three with metastases). The sst2A seems less influenced by somatostatin-dependent internalization (24). The immunostaining of sst3 was found to be more cytoplasmic than membranous possibly representing internalized receptors.
Perhaps the most intriguing finding of our study is that cell surface expression of functional sst3 somatostatin receptors is sufficient for true-positive octreotide scintigraphy in pheochromocytoma. Specifically, we found six cases with positive octreoscan in the absence of immunoreactive sst2A receptors. In virtually all of these cases immunoreactive sst3 receptors were largely confined to the plasma membrane. More important, the majority of positive octreoscans (12 of 13 cases) was accompanied with expression of sst3. In contrast, in all cases with cytoplasmic sst3 receptors and lack of sst2A receptors octreoscan was negative. Similar findings with regard to sst3 expression have been described for thymomas (27). Although this study was not designed to examine the sensitivity of octreotide scintigraphy, it allowed us to attribute positive nuclide scans to the presence or absence of ssts. As pointed out earlier, we and others (11, 12, 13) have clearly shown that MIBG scintigraphy is superior to octreotide scanning. Nevertheless, in MIBG-negative or in malignant pheochromocytoma octreotide scintigraphy may be positive. In these cases it is important to be performed because of its complementary role.
To test the hypothesis that cytoplasmic receptors may represent sst3 receptors internalized by endogenous somatostatin that are inaccessible for radiolabeled octreotide, we evaluated the relationship between the sst3-immunostaining and SS-14-immunostaining. In 17 of 20 SS-14-positive tumors, immunoreactive sst3 receptors were predominantly intracellular. Three of 20 SS-14-positive tumors revealed regional differences in their subcellular sst3 distribution with part of the tumor showing predominant membranous sst3 receptors and the other part of the tumor with cytoplasmic sst3 receptors. In the absence of SS-14, however, only 50% of tumors displayed membrane-associated receptors whereas the remaining cases revealed intracellular sst3 receptors. Thus, there was no clear correlation between SS-14 expression and the presence of intracellular sst3 receptors. Nevertheless, it cannot be ruled out that endogenous cortistatin, a neuropeptide relative of somatostatin, may contribute to sst3 internalization (28). An alternative explanation for the large proportion of intracellular receptors may be that overexpressed sst3 receptors may require an interacting protein for trafficking from the endoplasmic reticulum to the plasma membrane, which is not present in some pheochromocytomas (29, 30, 31).
Besides this diagnostic feature, the somatostatin induced apoptosis seems to be mediated via sst3 (32), suggesting that radionuclids or peptide analogs with improved sst3 effect may represent a promising modality for the treatment of pheochromocytomas.
Together, we provide evidence for functional sst3 receptors in a subgroup of human pheochromocytomas. Octreotide has preferentially high affinity for sst2A and only moderate affinity for sst3 and sst5 suggesting that these tumors may represent a potential target for treatment with somatostatin receptor agonists with improved sst3 affinity. Given our recent finding that heterodimerization of sst2A and sst3 results in inactivation of sst3 receptor function, it would be expected that sst3 selective agonists are ineffective in cases with coexpression of the two receptors. Cases with selective membrane expression of sst3, however, would be expected to respond to sst3 selective agonists.
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Acknowledgments |
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Footnotes |
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J.M. and N.U. contributed equally to this work.
Abbreviations: DAB, Diaminobenzidine; HEK, human embryonic kidney; MIBG, metaiodobenzylguanidine; RT, room temperature.
Received February 19, 2003.
Accepted August 11, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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