Neuroendocrine tumors in the brain

Neuroendocrine tumors in the brain

Annals of Oncology 12 (Suppl 2): S131-S134, 2001. © 2001 Kluwer Academic Publishers. Printed in the Netherlands. Review Neuroendocrine tumors in the ...

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Annals of Oncology 12 (Suppl 2): S131-S134, 2001. © 2001 Kluwer Academic Publishers. Printed in the Netherlands.

Review Neuroendocrine tumors in the brain P. Cavalla & D. Schiffer Department of Neuroscience, University of Turin, Turin, Italy

Summary

Introduction

Neuropeptides such as VIP, somatostatin, neuropeptide Y (NPY), neurotensin, GRP (bombesin) and substance P, fulfil an important role in the regulation of normal neuronal development [1]. As for their physiological role, somatostatin, for example, acts in the adult CNS as a neurotransmitter and a neuromodulator; it is a physiological regulator of neocortical, striatal, limbic and hypothalamic neurons, and is involved in motor and sensory function, as well as in cognition, learning and memory [2]. In pathological conditions, neuropeptides have been considered to be involved in the progression and differentiation of malignant tumors of the central (and peripheral) nervous system [3,4]. Somatostatin (SST) and other neuropeptides are expressed in tumors originating from: a) neuronal precursors (meduUoblastoma, cPNET or central Primitive Neuro-Ectodermal Tumor, neurocytoma), b) mature neuron or ganglion cells (gangliocytoma), c) paraganglia (paraganglioma), d) olfactory receptor cells (olfactory neuroblastoma) [5]. The latter four tumors are very rare, representing less

Key words: gliomas, medulloblastomas, meningiomas, PNET, somatostatin, SSTR

than 1% of all brain tumors, and data on their neuroendocrine differentiation are limited (Figure 1). On the contrary, meduUoblastoma and cPNET are much more frequent and, moreover, they express high levels of somatostatin receptors (SSTRs) [4]. Tumors originating from neuronal precursors

MeduUoblastoma is the most common malignant brain tumor in pediatric age. It arises in the cerebellum, and its origin and histopathological classification have been the matter of a still open debate. MeduUoblastoma cells have round-oval nuclei, scanty cytoplasm, high mitotic activity and predominant neuronal differentiation with possible neuroblastic rosettes [5]. According to some authors, this embryonal tumor of the posterior fossa is very similar to the so-called cPNET, which can be found elsewhere in the CNS. Therefore, medulloblastoma is the PNETof the posterior fossa and would derive from precursor cells (subependymal precursor cells) common to supratentorial PNET [6, 7]. Recent molecular genetic studies show that 17p

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Somatostatin and other neuropeptides are expressed in tumors originating from neuronal precursors and paraganglia, namely meduUoblastoma, central Primitive Neuro-Ectodermal Tumors (cPNETs), neurocytoma, gangliocytoma, olfactory neuroblastoma, paraganglioma. In meduUoblastoma, the most common malignant tumor in childhood, there is an extensive expression of somatostatin in addition to somatostatin receptors (SSTR) type 2. Although density of SSTR-2 and intensity of expression of somatostatin genes have no prognostic significance in meduUoblastoma, their presence may bring along important information on oncogenesis and relate meduUoblastoma to cPNETs. Radio-labeled octreotide scintigraphy may be useful in the follow-up of these patients, allowing differentiation between scar and tumoral tissue. Moreover, on the basis of octreotide-induced inhibition of cell proliferation in meduUoblastoma, a trial with octreotide in patients with recurrent or high-risk tumor is warranted. Meningiomas and low-grade astrocytic gliomas, even if not displaying a clear neuroendocrine phenotype, have high levels of SSTR-2. In meningiomas,

SSTRs-scintigraphy is not part of the routine pre-operative assessment; moreover, a therapeutic trial with somatostatinanalogues in patients with recurrent or inoperable meningiomas should be carried-out with great caution, because somatostatin and octreotide slightly increase cell proliferation in cultured meningiomatous cells. Low-grade gliomas (WHO grade 2), and a smaller fraction of anaplastic astrocytomas, express SSTR-2, while glioblastomas usually do not. Unfortunately, radiolabeled-octreotide scintigraphy is not useful in the differential diagnosis of gliomas, because the results are altered by the disruption of the blood brain barrier (BBB); in addition, radionuclide-labeled somatostatin analogues are not useful in the therapy of low-grade gliomas, because the intact BBB prevents them from reaching the target SSTR-2. Recently, a pilot study in gliomas, has proposed the use of a radio-labeled somatostostatin analogue with a loco-regional approach in order to overcome the intact BBB.

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Figure I Neurocytoma: extensive Synaptophysin immunostaining (Mab SY-38, ABC method, DAB revelation), x 400.

Non-neuronal related tumors

loss of heterozygosity (LOH) can be found in 50% medulloblastomas, but not in supratentorial PNETs [5]. These findings would be against the hypothesis of a common origin for all PNETs. However, findings on neuropeptides [7] and on somatostatin receptor distribution would support it. Infact both medulloblastoma and cPNET are characterized by a unique profile for intermediate filaments expression, the extensive expression of synaptophysin (Figure 2) and the variable expression of neuropeptides [7]. Somatostatin and substance P are expressed in 100% medulloblastomas and cPNET, when examined through radio-immunoassay, and VIP and bombesin are also inconstantly found [4]. By RT-PCR and in vitro autoradiography, medulloblastomas and, to a lesser extent, cPNETs express SSTR-2 [8]. Cells of the external granular layer (EGL) of the developing cerebellum also express SSTR-2 at high levels. During cerebellar development, all five layers express SSTR-2 at week 20; later on, there is a much stronger labeling of the EGL compared to other cerebellar layers and this pattern remains stable until the physiologic involution of the EGL at the 8th month. In adult cerebellum, no labeling can be observed [8]. These results are consistent with a crucial role of somatostatin

Even though they do not display a clear neuroendocrine phenotype, two common brain tumors should be mentioned. High levels of SSTRs have been found in meningiomas, which derive from meningothelial cells and represent usually benign tumors of the meninges [5], while detectable SSTRs may also be found in astrocytic gliomas. The latter represent very common neuroepithelial tumors that can be distinguished in: diffuse astrocytoma, WHO grade 2; anaplastic astrocytoma, WHO grade 3 and glioblastoma, WHO grade 4 [5]. The precise function of SSTRs in these tumors is unclear: SSTRs represent a major class of inhibitory receptors, which would also be important in cell proliferation and apoptosis [10]. The possible use of SSTRs for diagnosis and therapy in these neoplasms is being evaluated. Meningiomas Meningiomas express SSTRs in nearly 100% of cases, both in scintigraphy and in cell culture studies. By an in situ hybridization technique, meningiomas have been confirmed to express only intense and homogeneous SSTR-2 [11]. More recently, frequent overexpression of

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Figure 2 Medulloblastoma: Synaptophysin immunostaining (Mab SY-38, ABC method, DAB revelation), x 400.

in the development of human cerebellum and of medulloblastoma. According to Friihwald et al., a precursor cell in the EGL with high SSTR-2 density would be exposed to an arresting signal by somatostatin; this cell, which physiologically should have migrated to deeper layers of cerebellar cortex, may become the target of other growth factors that in turn would lead to the malignant phenotype of medulloblastoma [8]. Somatostatin peptide and SSTRs binding in neuroblastoma are favorable prognostic factors, being related to lower stage and lack of MYCN amplification [8]. On the contrary, the presence and density of somatostatin receptors in cPNETand, particularly, in medulloblastoma were not significantly correlated with the clinical outcome [8]. The somatostatin peptide gene is also expressed at low levels in cPNET, where it does not correlate with the clinical course as well [8]. Radio-labeled octreotide scintigraphy is useful in the diagnostic work-up and follow-up of patients with medulloblastoma. Although the technique of SSTR imaging is not specific for these neoplasms, it can help neuroradiologists if a differentiation between recurrent tumor tissue and scar tissue has to be performed [9]. In some medulloblastoma cell-lines, octreotide inhibits cell proliferation when measured by the decrease in 3H-thymidine uptake [8]. According to Fruhwald et al., besides having a direct anti-proliferative effect, somatostatin could play an indirect effect in vivo, based on the inhibition of GH and IGF-1 secretion [8]. A trial with octreotide, in combination with standard therapeutic agents, is therefore recommended in patients with recurrent or high risk medulloblastoma or cPNET [8].

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Astrocytic gliomas

SSTRs [18,19]; therefore, radiolabeled octreotide cannot reach SSTRs in astrocytoma WHO grade 2, where the BBB is intact, while in high-grade gliomas, where the BBB is disrupted, there is a non-specific accumulation of the tracer [18-20]. In conclusion, radiolabeled-octreotide scintigraphy does not add information to routine CTand MRI scans in the differential diagnosis of intracranial lesions [20]. For the same reasons, radionuclide-labeled long-acting somatostatin analogues also do not seem to be useful in low-grade gliomas [20], because the intact BBB would prevent the therapeutic agent from reaching the target SSTR-2. Recently, a pilot study has proposed the use of a radio-labeled, diffusible somatostostatin analogue in a loco-regional approach to overcome the intact BBB, [23]. The vector, a somatostatin analogue conjugated with the radiometal chelator DOTA (DOTATOC or 90Y-labeled DOTA°-d-Phe'-Tyr3-octreotide) was inserted in one to four fractions into a stereotactically inserted Port-a-cath; the total cumulative activity was up to 550 Gy. Selected patients had low-grade glioma (five astrocytoma and two oligodendroglioma WHO grade 2) or high-grade glioma (one oligodendroglioma WHO grade 3 and three glioblastomas) with documented disease progression, despite previous surgery, external beam radiotherapy, brachytherapy and/or chemotherapy. The authors did not observe any vector diffusion into the adjacent normal brain, and reported the shrinking of a cystic low-grade astrocytoma in addition to six disease stabilizations. Accordingly, the activity: dose ratio (MBq:Gy) was a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. A trend toward longer progressionfree survival in low-grade glioma patients with an activity: dose ratio < 5 was observed [23].

The majority of low-grade gliomas (WHO grade 2) and a smaller fraction of anaplastic astrocytomas (WHO grade 3) have been reported to contain SSTRs, as assessed with various receptor binding techniques [17, 18, 19]. Recent gene expression studies (RT-PCR ) have shown that low-grade astrocytomas highly express SSTR-2, alone or in combination with SSTR-1 [10, 20], while high-grade gliomas scarcely express, or do not express, SSTR-2 [20]. Therefore, it has been supposed that SSTRs are important only in programming cell differentiation, and lose this significance with progres- References sive dedifferentiation [20]. 1. O'Dorisio M, O'Dorisio T. Neural crest tumors: Rationale for Non-neoplastic cultured astrocytes express only low somatostatin and its analogs in diagnosis and therapy. In Mazzalevels of SSTR-1,2,4 [21], whereas low-grade gliomas are ferri E, Jamaan N (eds): Endocrine Tumors. Cambridge, UK: believed to overexpress SSTR-2, in accordance withe the Blackwell Scientific Publications 1993; 531-42. 2. Patel YC. General aspect of the biology and function of somatosoverexpression of SSTRs seen in different tumors [10]. tatin. In Muller EE, Thorner MO, Weil C (eds): The Role of However, the overexpressed SSTR-2 in human glioma Somatostatin: Basic and Clinical Aspects of Neuroscience Series. cells was found to be intact (SSTR-2A splice variant is Berlin: Springer-Verlag 1992; 1-16. predominantly expressed) and functional [22]. In fact, 3. O'Dorisio MS, Chen F, O'Dorisio D. Characterization of somano gene mutation was detected and the receptor showed tostatin receptors on human neuroblastoma tumors. Cell Growth Diff 1994, 5: 1-8. functional properties similar to those of non-neoplastic 4. Fruhwald MC, O'Dorisio MS, Cottingham SL et al. Neuroastrocytes [22]. peptides in developmental tumors of the central and peripheral Unfortunately, use of the different expression of nervous system. Ann N Y Acad Sci 1998, 865: 420-6. SSTR-2 in low- vs. high-grade gliomas in radiolabeled5. Kleihues P, Cavenee WK. WHO Classification of tumours. Tuoctreotide scintigraphy is not useful in the differential mours of the nervous system. Pathology and genetics. IARC, Lyon, 2000. diagnosis of gliomas [20]. Discrepancies between in vivo 6. Rorke LB, Gilles FH, Davis RL, Becker LE. Revision of the scintigraphy with labeled-octreotide and the SSTRs staWHO classification of brain tumors for pediatric brain tumors. J tus in vitro were repeatedly observed [17,18]. They can be Neuropathol Exp Neurol 1985, 56:1869. explained by the fact that in vivo uptake of radiolabeled 7. Gould VE, Jansson DS, Molenaar WM et al. Primitive neurooctreotide in gliomas is due to the disruption of the ectodermal tumors of the central nervous system. Lab Invest 1990, 62: 498-509. blood brain barrier (BBB) rather than to the presence of

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SSTR-2A was demonstrated by immunohistochemistry and Western blot analysis [12]. However, somatostatin receptor scintigraphy is not part of the routine pre-operative work-up of a patient suspected to have meningioma. This is partly explained by discrepancies among different groups. While some authors reported positive inIn-octreotide scintigraphy in 100% meningiomas [13, 14], others claimed that a low percentage of smaller meningiomas (<2.7 cm in diameter) were negative by scintigraphy [15]. Unexpectedly, in cultured meningiomas, somatostatin and octreotide do not inhibit cell proliferation, but rather slightly increase it, and this was accomplished through the inhibition of adenylate cyclase [16]. However, it cannot be excluded that somatostatin-analogues in vivo may have antisecretory effects on para/autocrine growth factors, such as FGF, which in turn stimulates tumor growth [16]. Furthermore, somatostatin-analogues, even if inactive in inhibiting proliferation, could still play a role in meningioma therapy, contrasting secretory phenomena associated with the formation of edema around the tumor [16]. In conclusion, therapeutic trials in patients with recurrent or inoperable meningiomas with somatostatin analogues have to be carried out with great caution.

134 17. Reubi JC, Lang W, Maurer R et al. Distribution and biochemical characterization of somatostatin receptors in tumors of the human central nervous system. Cancer Res 1987; 47: 5758-64. 18. Haldelmann AR, Rosier H, Barth A et al. Somatostatin receptor scintigraphy in CNS tumors: Role of the blood brain barrier permeability. J Nucl Med 1995; 36: 403-10. 19. Luyken C, Hildebrandt G, Scheidhauer K et al. llllndium (DTPA)-octerotide scintigraphy in patients with cerebral gliomas. Acta Neurochir 1994; 127: 60-4. 20. Lamzus K_, Meyerhof W, Westphal M. Somatostatin and somatostatin receptors in the diagnosis and treatment of gliomas. J Neurooncol 1997; 35: 353-64. 21. Feindt J, Becker I, Blomer U et al. Expression of somatostatin receptor subtypes in cultured astrocytes and gliomas. J Neurochem 1995; 65: 1997-2005. 22. Feindt J, Krisch B, Mentlein R. Molecular analysis of the somatostatin receptor subtype 2 in human glioma cells. Mol Brain Res 1999; 64: 101-7. 23. Merlo A, Hausmann O, Wasner M et al. Loco-regional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phel-Tyr3-octerotide (DOTATOC): A pilot study in human gliomas. Clin Cancer Res 1999; 5: 1025-33. Correspondence to: Dr P. Cavalla Dipartimento di Neuroscienze Via Cherasco 15 10126, Torino Italy E-mail: [email protected]

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8. Fruhwald MC, O'Dorisio MS, Pietsch T, Reubi JC. High expression of somatostatin receptor subtype 2 (sst2) in medulloblastoma: Implications for diagnosis and therapy. Ped Res 1999,48: 697-708. 9. Muller HI, Fruhwald MC, Schenbeck M et al. A possible role for somatostatin receptor scintigraphy in the follow-up of children with medulloblastoma (MB). J Neurooncol 1998, 38: 27^(5. 10. Patel YC. Molecular pharmacology of somatostatin receptor subtypes. J Endocr Invest 1997, 20: 348-67. 11. Reubi JC, Schaer JC, Waser B, Mengod G. Expression and localization of somatostatin receptor SSTR1, SSTR2 and SSSTR3 messenger RNA in primary human tumors using in situ hybridization. Cancer Res 1994, 54: 3455-9. 12. Schulz S, Pauli SU, Schulz S et al. Imrnunohistochemical determination of five somatostatin receptors in meningioma reveals frequent overexpression of somatostatin receptor subtype sst2A. Clin Cancer Res 2000; 6: 1865-74. 13. Hildebrandt G, Scheidhauer K, Luyken C et al. High sensitivity of the in vivo detection of somatostatin receptors by Ill-indium (DTPA-octreotide)-scintigraphy in meningioma patients. Acta Neurochir 1994; 126: 63-71. 14. Maini CL, Sciuto R, Tofani A et al. Somatostatin receptor imaging in CNS tumors using 111-In-octreotide. Nucl Med Commun 1995; 16: 756-66. 15. Bohuslavizki KH, Brenner W, Braunsdorf WEK et al. Somatostatin receptor scintigraphy in the differential diagnosis of meningioma. Nucl Med Commun 1996,17: 302-10. 16. (Coper JW, Markstein R, Kohler C et al. Somatostatin inhibits the activity of adenilate cyclase cultured human meningioma cells and stimulates their growth. J Clin Endocrinol Metab 1992, 74: 543-7.