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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 963-970 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.7431 Indium-111–Pentetreotide Scintigraphy and Somatostatin Receptor Subtype 2 Expression: New Prognostic Factors for Malignant Well-Differentiated Endocrine Tumors
From the Departments of Medical Oncology, Pathology, and Nuclear Medicine, Claudius Regaud Institute; Department of Epidemiology, School of Medicine, Toulouse-Purpan; Department of Gastroenterology and School of Medicine, Toulouse-Rangueil; Centre Hospitalier Universitaire Rangueil, Toulouse, France; and Department of Pharmacology, University of Wurzburg, Wurzburg, Germany Corresponding author: Louis Buscail, MD, L’Institut National de la Santé et de la Recherche Médicale 858, I2MR, Centre Hospitalier Universitaire Rangueil, BP 84225-31432 Toulouse Cedex 04, France; e-mail: Louis.Buscail{at}toulouse.inserm.fr
Purpose Well-differentiated metastatic endocrine carcinomas are difficult to manage because of variable disease outcome. New prognostic factors are required. These tumors overexpress somatostatin receptors (sst), implying the use of somatostatin analogs for tumor localization by somatostatin receptor scintigraphy using indium-111–pentetreotide (111In-pentetreotide) and for medical treatment. The aim of the present study was to evaluate the correlation between 111In-pentetreotide scintigraphy, sst receptor expression, and prognosis. Patients and Methods Between 1994 and 2002, 48 consecutive patients with well-differentiated endocrine carcinomas and a negative 111In-pentetreotide scintigraphy were retrospectively paired according to sex, age, and tumor localization with 50 patients with well-differentiated endocrine carcinomas and a positive tracer uptake at 111In-pentetreotide scintigraphy. Overall survival and expression of sst1 to sst5 receptors by immunohistochemistry were assessed. Results The lack of tracer uptake at the 111In-pentetreotide scintigraphy seemed to be a poor prognostic factor (P = .007) for overall survival by Kaplan-Meier test and in multivariate analysis; age and absence of clinical secretory syndrome also seemed to be poor prognostic factors. The tracer uptake (positive 111In-pentetreotide scintigraphy) correlated with the tumor expression of somatostatin receptor sst2 (P < .001) but not with that of sst1, sst3, sst4, or sst5. In a bivariate analysis, lack of sst2 expression also significantly correlated with poor prognosis. Conclusion We demonstrate the prognostic value of 111In-pentetreotide scintigraphy in well-differentiated malignant endocrine tumors. In these tumors, sst2 somatostatin receptor expression correlates with both tracer uptake and a better prognosis.
Endocrine tumors are rare neoplasms that exhibit major differences in clinical and biologic behavior. They express somatostatin receptors (sst), which is the molecular basis for their detection by somatostatin receptor scintigraphy (using indium-111–pentetreotide [111In-pentetreotide]; OctreoScan scintigraphy; Mallinckrodt Medical, Petten, the Netherlands) and for therapeutic use of stable somatostatin analogs.1-6 Indeed, somatostatin inhibits hormone secretion, cell proliferation, and angiogenesis via specific receptors belonging to the family of G protein–coupled receptors.7,8 Somatostatin analog therapy may stabilize the volume of endocrine tumors in 13% to 40% of patients.7-9 Beside therapeutic implications, it has been postulated that the presence of somatostatin receptors may also have a prognostic value. Indeed, survival is significantly better in children with somatostatin receptor–positive neuroblastoma.10,11 To date, five receptor subtypes (sst1 to sst5) have been identified. Although all receptors bind natural somatostatin with high affinity, only sst2, sst5, and sst3 bind the analogs clinically used with high to moderate affinity.12,13 We demonstrated that sst2 and sst5 mediated the antiproliferative effect of somatostatin analogs when expressed in fibroblastic or pancreatic cancer cells.8,13 Several studies described a correlation between expression of sst2, sst3, or sst5 receptors and positive 111In-pentetreotide scintigraphy in various endocrine tumors. However, the frequency and expression pattern of the individual receptor subtypes varied between the different tumor types.7,8,14-17 According to the recent WHO classification, endocrine tumors are separated into benign endocrine tumors, endocrine tumors with uncertain behavior, and endocrine carcinomas.18 The latter are also separated into two classes, well-differentiated and nondifferentiated or poorly differentiated endocrine carcinomas. Nondifferentiated endocrine carcinomas have a poor prognosis, with a 6-month median survival time. Conversely, patients with well-differentiated carcinomas are known to have a relatively good prognosis, with some metastatic tumor patients achieving a 5-year survival rate of 20% to 40%.19 However, these patients represent a heterogeneous group with a wide heterogeneity in prognosis, which makes the therapeutic management difficult. The only possible curative treatment is the complete resection of all tumor sites. This is a rather uncommon situation, and metastatic disease often has to be managed. However, many therapeutic options could be used, ranging from abstention and survey in nonprogressive tumors to long-term analog treatment for secreting tumors (mostly carcinoids) or to more aggressive options such as chemotherapy, internal radiotherapy using high-energy radiolabeled somatostatin analogs, hepatic chemoembolization, debulking surgery, or liver transplantation for progressive tumors. The therapeutic management could be widely improved by a better evaluation of the spontaneous progression profile of the disease. Various items are recognized to have a prognostic interest, including age, sex, primary tumor site, and determination of the Ki67 proliferative index, but they are not sufficient to isolate homogeneous patient groups.20-24 There is a need for new tools to better appreciate the prognosis to define more homogeneous patient groups. The aim of this study was to evaluate, in the subgroup of patients with malignant well-differentiated endocrine tumors, the prognostic value of tracer uptake at 111In-pentetreotide scintigraphy and the correlation between tracer uptake, prognosis, and tumor expression of the five somatostatin receptors using immunohistochemistry.
Patients Between 1994 and 2002, 48 consecutive patients (27 males, 21 females; mean age, 57 ± 13 years) with proven well-differentiated endocrine carcinoma had a negative examination at 111In-pentetreotide scintigraphy examination (no tracer uptake: negative group). This group was retrospectively paired according to sex, age, primary localization, and tumor differentiation with patients investigated in our institution during the same period and who had positive examination at 111In-pentetreotide scintigraphy (positive group). For an optimal pairing combining all criteria, this group comprised 50 patients (22 males, 28 females; mean age, 56 ± 15 years). At inclusion, all of the 98 tumor specimens were re-examined to confirm the characteristics of well-differentiated carcinoma according to the WHO classification. They comprised 54 primary tumors (pancreatic, n = 15; intestinal, n = 17; pulmonary, n = 16; gastric, n = 3; and gynecologic, n = 3) and 44 metastases (from 17 unknown, 12 pancreatic, five ileal, seven pulmonary, one gastric, and one ovarian primary tumors). Other documented characteristics included WHO status, secondary tumor localization, clinical syndrome, presence of MENI, level of chromogranin A, treatments, and follow-up until death (if applicable).
Methods
Immunohistochemistry Tissue specimens were fixed in formaldehyde and embedded in paraffin wax. Four-micrometer sections were cut and floated onto positively charged slides. Sections were dewaxed three times in xylene and rehydrated in a graded series of ethanol (from 100% to 50%). Slides were microwaved in 10 mmol/L citrate buffer, pH 6.0, for 15 minutes at 750 W. Specimens were then allowed to cool to room temperature and washed three times in triethanolamine-buffered saline. The slides were processed using a Techmate Horizon (Dako, Carpinteria, CA) slide processor. The primary antibodies consisted of affinity purified polyclonal rabbit antisera specifically directed against sst1 (4819), sst2 (6291 or 9304), sst3 (4823), sst4 (4801), and sst5 (51). Specificity of antisera was verified by Western blotting as previously described.15,16,26,27 Antibodies (1 µg/mL) were incubated for 1 hour and revealed using a streptavidin-biotin complex reagent (StrepABComplex/HRP Duet; Dako). Chromogenic substrate was 3,3'-diaminobenzidine. Slides were counterstained with hematoxylin. All tissue sections were treated equally (same duration of fixation, immunohistochemical protocol, and antibody dilution) with automated procedures and in successive runs to assure coherence in all experiences. Tumors were categorized as negative for sst immunoreactivity when no immunostaining was observed, even with a high-power objective, despite unequivocal immunostaining for the neuroendocrine tumor markers. The immunostaining of tumor cells was reported using the following data: the percentage of labeled cells and the intensity of membranous (0: no, +: noncircumferential, ++: circumferential of low intensity, +++: circumferential of strong intensity membrane staining) or cytoplasmic (0: no, +: weak, ++: moderate, +++: strong cytoplasmic staining) staining. Positive control of immunostaining was assessed for each tumor by the highly frequent labeling of pancreatic islet (in case of duodenopancreatic tumor) and/or that of visceral nerves (for other tumors). In case of low-intensity labeling (or weak cytoplasm staining) and in some negative results, immunostaining experiences were conducted again with the same results as initially obtained.
Statistical Evaluation
Clinical and Biologic Characteristics of Selected Patients Patients with proven well-differentiated endocrine carcinoma were divided into two groups, a positive group (positive examination at 111In-pentetreotide scintigraphy) and a negative group (negative examination at 111In-pentetreotide scintigraphy). The two groups were comparable regarding age, tumor differentiation, primary localization, WHO status, presence of multiple endocrine neoplasia type 1, and chromogranin A serum level. Significant differences were found regarding frequency of hepatic metastases and, consequently, clinical carcinoid syndrome and somatostatin analog treatment in the positive group (Table 1). The somatostatin analog treatment was indicated because of a clinical carcinoid syndrome, and the decision of this treatment was independent of the results of 111In-pentetreotide scintigraphy. In addition, no significant difference was observed between the two groups in terms of surgery and/or chemotherapy.
Prognostic Value of 111In-Pentetreotide Scintigraphy for Well-Differentiated Endocrine Tumors As shown in Figure 2, patients with well-differentiated endocrine carcinomas and tracer uptake 111In-pentetreotide scintigraphy had significant better overall survival than patients without tracer uptake. The median survival time of patients in the positive group was not reached at 60 months (5-year survival rate, 55%) compared with a median survival time of 22 months in the negative group (5-year survival rate, 30%; log-rank P = .007; Fig 2). We then subdivided the group of negative patients into two subgroups depending of the tracer uptake as low (lower than the liver normal tracer uptake) or absent. In these two subgroups, the median survival time was significantly lower than that observed in the positive group (log-rank P = .006) but was not significantly different between the two subgroups (median survival time: uptake absent, 27 months; low uptake, 19 months). In addition, to avoid bias introduced by antitumor treatments, we examined the survival rate in patients who did not receive somatostatin analog; the survival rate was still significantly higher in the positive group (3-year survival rate, 77%) compared with the negative group (3-year survival rate, 33%; log-rank, P = .0001). Similar results were obtained in the subgroup of patients who did not receive chemotherapy (3-year survival rate, 86% and 30% for positive and negative groups, respectively; log-rank P = .0001).
Endocrine Tumor sst Receptor Expression and Correlation With 111In-Pentetreotide Scintigraphy Status In normal pancreas, the islet cells used as positive controls showed strong immunoreactivity for sst1, sst3, sst4, and sst5 (which was detected in the cytoplasm and partly but weakly on the membrane) and for sst2A immunostaining (which was predominantly localized on the plasma membrane; data not shown). Immunohistochemistry for sst2 and sst5 receptors was performed on 81 primary (n = 48) or metastatic (n = 33) endocrine carcinoma tissues available from the 98 patients (83%), whereas analysis was performed on 80 tumor tissues (primary, n = 48; metastatic, n = 32) for sst1 and sst3 receptors. Finally, immunohistochemistry for sst4 receptor was performed in 60 tumors. The analysis revealed that sst2A and sst5 were more frequently expressed (63% of tumors for both receptors, n = 51) than sst1, sst3, and sst4, which were expressed in 2.5% (n = 2), 28.2% (n = 24), and 38% (n = 22) of tumors, respectively. Immunostaining was at the tumor cell membrane level for sst2 and at the tumor cell cytoplasmic levels for sst1, sst3, sst5, and sst4 (Fig 3 and data not shown).
As detailed in Table 2, only sst2 expression was significantly associated with a positive tumor signal at 111In-pentetreotide scintigraphy. Among the five tumor tissues with a positive 111In-pentetreotide scintigraphy and sst2-negative immunostaining immunocytochemistry, three of the tumors were positive for sst5, the other tumors were negative for sst5, sst1, and sst3, but all were positive for sst4 at the cytoplasm level. In contrast, among the 12 tumor tissues with negative scintigraphy and positive sst2 expression, the mean percentage of positive tumor cells was of 38% (median, 40%).
Correlations With Patient Survival As shown in Table 3, in a multivariate analysis, lack of tracer uptake was a poor prognostic factor, along with two others factors (age up to 50 years and absence of carcinoid syndrome); sex, presence of hepatic metastasis, and primary localization did not reach significance. In bivariate analysis, absence of sst2 receptor tumor tissue expression was also an indicator of poor prognosis. No correlation could be found between expression of sst5, sst1, sst3, and sst4 and patient survival (data not shown).
From our results, we demonstrate that, in a subgroup of patients with well-differentiated endocrine carcinomas, a negative 111In-pentetreotide scintigraphy (primary or metastatic tumor) is correlated with a poor prognosis. Moreover, results of scintigraphy were also correlated with sst2 receptor tumor expression at tumor cell membrane, and finally, the loss of sst2 expression was itself correlated with poor prognosis. These two new prognostic factors could markedly improve the management of well-differentiated endocrine carcinomas in combination with already known factors such as age, sex, presence of hepatic metastases and carcinoid syndrome, and primary localization. 111In-pentetreotide scintigraphy, based on the expression of somatostatin receptors by the endocrine tumors, is generally used to detect metastases of an already known primary endocrine carcinoma. Pending validation of our results after a prospective study, 111In-pentetreotide scintigraphy may find a new role because the fixation of radionuclide could influence the management of well-differentiated endocrine carcinomas, especially in a metastatic situation. An early active treatment could be initiated in negative patients, whereas the positive patients may undergo either observation or an active treatment depending of their progressive status. We found that, in patients from the somatostatin receptor–positive group (who live longer), significantly more patients had liver metastases and carcinoid syndrome. As a consequence, these patients had been treated more often with somatostatin analogs. Because this treatment modality could be a factor that is responsible for the longer survival, we examined the survival rate in patients who did not receive somatostatin analog treatment (as well as chemotherapy). In untreated patients, the survival rate was still significantly higher in the positive group when compared with the negative group. These results confirmed that, in absence of any treatment (that could influence prognosis), the result of 111In-pentetreotide scintigraphy is an independent prognosis factor. The sst2 receptor is known to display high affinity for stable somatostatin analogs including 111In-diethylenetriaminopentaacetic-octreotide (111In-pentetreotide),28,29 and our results confirm correlations obtained at mRNA and protein levels in previous studies.8,14-17,30 However, these studies had included various types of endocrine tumors (malignant or not, differentiated or not), and the five receptor subtypes had been rarely simultaneously studied (especially sst3 and sst5). Recent studies pointed out a specificity of somatostatin expression for a given endocrine tumor (ie, sst3 is predominant in pheochromocytoma).16 We also demonstrated that, in the subgroup of well-differentiated endocrine carcinomas, the in vivo tracer uptake correlated with the tumor expression of somatostatin receptor sst2 but not with that of sst5, sst3, sst1, and sst4 receptors. Statistical analysis revealed that the lack of sst2 expression significantly correlated with poor prognosis, whereas the expression of the other receptors did not. We previously demonstrated that expression of sst2 is lost in exocrine pancreatic carcinoma, and its re-expression by heterologous gene expression induces an antioncogenic effect both in vitro and in vivo.31-34 Even if these effects have not been demonstrated in endocrine carcinoma, the loss of a receptor with antioncogenic properties may indicate a gain of tumor growth/progression of well-differentiated endocrine carcinoma and, as a consequence, a decrease of survival. One limitation of the use of 111In-pentetreotide scintigraphy alone to evaluate prognosis is that small tumors can be missed on scintigraphy because of lack of spatial resolution or if the tumor is located in the vicinity of a physiologic uptake. As described also for immunoscintigraphy, the negativity of 111In-pentetreotide can be explained by a poor density of sst expression.25 We also found that, in case of negative scintigraphy and sst2-positive staining at immunohistochemistry, the percentage of positive tumor cells was lower than that observed in tumors that were both positive for scintigraphy and sst2 immunostaining. Conversely, in case of positive scintigraphy and negative sst2 immunostaining, the expression of sst5 may be responsible for 111In-pentetreotide fixation, as previously observed for insulinoma.26 The fact that sst2 expression is highly correlated with positive 111In-pentetreotide scintigraphy indicates that sst2 immunohistochemistry could be useful in current practice when preoperative diagnosis of endocrine tumor is unknown. After removal of the tumor, sst2 immunohistochemistry could determine whether or not 111In-pentetreotide scintigraphy is relevant for the staging of disease. In conclusion, this is the first study demonstrating the good prognostic value of positive 111In-pentetreotide scintigraphy in well-differentiated malignant endocrine tumors. In these tumors, sst2 somatostatin receptor expression at the protein level correlates with tracer uptake as well as with a better prognosis. 111In-pentetreotide scintigraphy as well as tumor sst2 receptor expression could be included in the clinical discussion for the management of such tumors.
The author(s) indicated no potential conflicts of interest.
Conception and design: Philippe Rochaix, Christiane Susini, Andrée Boneu, Rosine Guimbaud Provision of study materials or patients: Frédéric Courbon, Philippe Rochaix, Stefan Schulz, Rosine Guimbaud, Louis Buscail Collection and assembly of data: Amani Asnacios, Frédéric Courbon, Christiane Susini, Andrée Boneu, Rosine Guimbaud, Louis Buscail Data analysis and interpretation: Amani Asnacios, Philippe Rochaix, Eric Bauvin, Valérie Cances-Lauwers, Louis Buscail Manuscript writing: Christiane Susini, Stefan Schulz, Rosine Guimbaud, Louis Buscail
Supported by grants from Groupe de Recherche de l’Institut Claudius Régaud, Association pour la Recherche Contre le Cancer, and L’Institut National de la Santé et de la Recherche Médicale. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
was used. Differences were considered statistically different at P < .05. 
