Original contributionIncreased SSTR2A and SSTR3 expression in succinate dehydrogenase–deficient pheochromocytomas and paragangliomas☆,☆☆
Introduction
Pheochromocytomas (PCs) and paragangliomas (PGLs) are rare catecholamine-producing tumors arising from chromaffin cells in the adrenal glands or extraadrenal neural crest tissue. These catecholamine-secreting tumors are frequently hereditary, resulting from germline mutations in various tumor predisposition genes. Of these genes, succinate dehydrogenase subunit B (SDHB) is of particular interest due to increased malignant potential of associated PC/PGLs (metastatic rate of 30% versus 10% of all PC/PGLs) [1]. Determining whether PC/PGLs are benign or malignant in the absence of metastatic disease is limited by lack of reliable criteria to predict malignant behavior. Currently, the only effective treatment of PC/PGLs is surgery. Patients with inoperable malignant PC/PGLs may die of metastatic disease or from complications due to excess catecholamine production such as sudden death or heart failure. Nonsurgical treatment options for malignant disease are limited, and there is a lack of survival data available from randomized controlled trials using chemotherapy and radiolabeled therapies [2], [3], [4], in part resulting from the rarity of these tumors. Improved understanding of the biology of SDHB-associated and/or malignant PC/PGLs would assist in identifying new nonsurgical therapies.
Many neuroendocrine tumors, including PC/PGLs, express one or more somatostatin receptor subtypes (SSTR1-5). Somatostatin is a neuropeptide with affinity for all 5 receptor subtypes and can inhibit both hormone secretion and cell proliferation. Analogues of somatostatin (octreotide, octreotide LAR, and lanreotide) demonstrate high affinity for SSTR2 and, to a lesser extent, SSTR5. Although they are very successfully used in the treatment of some tumors types, such as SSTR2-expressing growth hormone–secreting pituitary tumors, and have been demonstrated to not only control symptoms but also increase progression-free survival in patients with metastatic small intestinal neuroendocrine tumors [5], [6], treatment for patients with chromaffin cell tumors has been variable and overall disappointing [7], [8], [9], [10], [11], [12], [13].
A number of studies have assessed SSTR subtypes in PC/PGL [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Results have been conflicting as to the frequency of receptor subtype expression. Although SSTR3 has been detected in most tumors studied, SSTR2A expression has varied from less than 15% [15], [16] to up to 100% of tumors [18], [24]. Similarly, results for SSTR1 have varied, and when assessed, SSTR5 has been shown to be positive in less than 50% of tumors in most studies [14], [15], [16], [18]. Differences in SSTR subtypes between tumors from patients with familial tumor syndromes and those with sporadic tumors have only been assessed in one study with only small numbers of hereditary tumors, and differences in SSTR expression were not identified [18]. A further study identified SSTR2a staining in 2 patients with a germline SDHD mutation, but there was no control group [25]. Studies assessing SSTR expression have used a variety of methods including reverse transcriptase polymerase chain reaction and immunohistochemistry (IHC). In addition to varying methods used, until recently interpretation has further been hampered by the lack of specific monoclonal antibodies against the 5 SSTR subtypes. Fischer et al [27] briefly reported the use of the monoclonal antibody UMB-1 against SSTR2A in a number of normal and neoplastic tissues including PCs, in which most tumors demonstrated positive staining. Use of monoclonal antibodies against the other SSTRs has not been reported in PC/PGLs. Recently, a novel somatostatin analogue has been developed, pasireotide, which has activity at a wider range of SSTRs than octreotide (all SSTRs with the exception of SSTR4) [28]. The role of pasireotide in patients with metastatic and/or inoperable PC/PGL is not known, but cell culture studies have suggested that it is more promising than octreotide [21]. Based on the results of SSTR status, evidence of expression of SSTRs other than SSTR4 would support a targeted trial of this agent (unlabeled and/or labeled to radionuclides) in patients with metastatic/inoperable PC/PGL.
The aims of this study were (1) to assess the somatostatin receptor status of PC/PGLs using specific monoclonal antibodies against somatostatin receptor subtypes 1 to 5 and (2) to determine whether somatostatin receptor subtype expression varies in SDH-deficient tumors when compared with tumors showing a normal pattern of SDHB staining.
Section snippets
Materials and methods
Patients who had undergone previous surgery for PC or PGL were identified from the Waikato Hospital endocrine unit, Hamilton, New Zealand, and the Royal North Shore Hospital anatomical pathology department, Sydney, Australia. Ethical approval was obtained from the Northern Y Regional Ethics Committee (NTY/11/05/049) and in accordance with the Human Tissue Act for the New Zealand and Australian samples, respectively. Results of germline genetic testing for PC/PGL predisposition genes (SDHA, SDHB
Results
A total of 182 PC/PGL specimens were identified from 174 patients. Of the 182 tumors, 129 were adrenal, 44 extra-adrenal (of which 18 were head and neck), and 9 metastases (all from PC).
Discussion
SSTR immunostaining of PC or PGLs varies according to receptor subtype. Most tumors demonstrated positive staining for SSTR1, whereas most tumors did not stain for SSTR4 or SSTR5, irrespective of whether tumors were SDH deficient or not. SSTR2a and SSTR3 expression patterns were more variable.
Both SSTR2A and SSTR3 staining was significantly different between SDH deficient and those with normal SDH staining patterns. We have found SDHB IHC to be a robust and reliable marker of SDH mutation [30],
Conclusion
SDH-deficient tumors are more likely to demonstrate positive SSTR2a and SSTR3 immunostaining than tumors with a normal SDH staining pattern. These findings suggest that the role of somatostatin analogue therapy (unlabeled or radiolabeled) should be reexamined in the context of the underlying SDH status. Somatostatin analogue therapy may have a particular therapeutic role in patients with an underlying SDH germline mutation and for HNPGLs in patients without an underlying SDH mutation.
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Recent Advances in Radiopharmaceutical Theranostics of Pheochromocytoma and Paraganglioma
2023, Seminars in Nuclear MedicineConsensus on molecular imaging and theranostics in neuroendocrine neoplasms
2021, European Journal of CancerCitation Excerpt :The development of more user-friendly, standardised, accurate, and simplified dosimetry methods may facilitate more routine use of dosimetry and strengthen the evidence-base for or against its utility [84,85]. For the assessment of PPGL, the choice of the imaging modality should take into account the physiological biodistribution (SSTR imaging is not ideal for small tumours due to uptake by healthy adrenal cortex), availability ([18F]FDOPA is difficult to synthesise and not available in all centres) [12], genetics (e.g. succinate dehydrogenase mutation, SDHx) [86], and clinical need (patients presenting significant SSTR expression may be selected for PRRT for control of catecholamine excess). EANM Focus 3 consensus favoured the use of CT/MRI to assess an adrenal mass suspicious for pheochromocytoma, while in cases of extra-adrenal PGL, the majority of panellists preferred two options: [68Ga]Ga-DOTA-SSA PET/CT (16 (80%) of 20), followed by MRI/CT (13 (65%) of 20).
Variable somatostatin receptor subtype expression in 151 primary pheochromocytomas and paragangliomas
2019, Human PathologyCitation Excerpt :Choice of scoring system for IHC is essential for reliable results. At least 3 systems have been published [7,17,18], which are based on membranous staining of the SSTR2 antibody. No broad consensus for scoring SSTR1, 3-5 exist in the literature.
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Funding/Support: The authors acknowledge Novartis Pharmaceuticals Ltd for donating monoclonal antibodies against SSTR1, SSTR3, and SSTR4. This work was supported by a Waikato Medical Research Foundation project grant (WMRF Grant Nos. 188, 2011) to M.S.E. and by the Cancer Institute NSW through the translational cancer research center program.
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Competing interest: The authors declare no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.