Neuroendocrine cancer

Closing the GAPP on predicting metastases

A promising grading system to predict metastasis in patients with phaeochromocytoma and paraganglioma assigns risk according to selected histological and other criteria. Such risk stratification might be useful for personalized management and screening programmes, as it could limit the costs of follow-up and reduce the risk of disseminated disease.

Accurate classification of the type and nature of a given tumour ultimately depends on histopathology. Determining whether a tumour is benign or malignant is particularly important for guiding therapeutic interventions and patient management. However, for some neoplasms, reliable prediction of whether a tumour is benign or malignant on the basis of histopathology is not possible. Phaeochromocytomas and paragangliomas (PPGLs) pose exactly this type of challenge to pathologists. Currently, these catecholamine-producing neuroendocrine tumours can be diagnosed as malignant only after the development of metastases, which leaves pathologists powerless to affect clinical decision-making. To address this shortcoming, Kimura and colleagues developed a system, which they called 'grading for adrenal phaeochromocytoma and paraganglioma' (GAPP), to stratify primary tumours to enable prediction of the risk of metastasis.1 Now, the authors have extended their findings in an attempt to validate the GAPP grading system in a large multicentre study.2

“...the GAPP system assigns numerical points to different histological features...”

The GAPP system includes morphological parameters from an earlier grading system, phaeochromocytoma of the adrenal scaled score (PASS), that was proposed in 2002 to distinguish benign from malignant phaeochromocytomas.3 GAPP differs from PASS in that it omits some elements from PASS, includes additional parameters and applies to both adrenal phaeochromocytomas and paragangliomas arising from extra-adrenal chromaffin cells. In essence, the GAPP system assigns numerical points to different histological features, such as cellularity, comedonecrosis, vascular or capsular invasion and Ki67 labelling index. Additional points are assigned according to the catecholamine-secretory profile of a given tumour.

Using the assigned points, the GAPP system divides PPGLs into three groups (well-differentiated, moderately differentiated and poorly differentiated) that have different levels of risk depending on the degree of differentiation. Metastases were seen in four of 111 (3.6%) tumours that were scored as well-differentiated, 21 of 35 (60.0%) moderately differentiated tumours and 14 of 17 (82.4%) tumours classified as poorly differentiated.2 The 5-year survival of the patients was also found to be correlated with GAPP scores.2

The available literature on PPGLs suggests that any risk stratification system involving more than histopathology should include tumour location, size and assessment of mutations in the gene that encodes succinate dehydrogenase type B (SDHB).4,5,6,7 Extra-adrenal paragangliomas have a particularly increased risk of metastasis compared with adrenal tumours.5 In the current study, these variables were considered by the authors but not included in the GAPP grading system. This decision was made despite findings that loss of SDHB staining, which is indicative of mutations in SDHB, was restricted to the groups at high and intermediate risk of metastases, and that mean diameters were larger for metastasizing than for nonmetastasizing tumours (8.7 cm versus 5.1 cm).2 While the difference in tumour diameter might seem trivial, it translates to a fivefold difference in tumour volume, which is a measure that best reflects the number of cell divisions that have occurred and might affect progression to metastasis.

The high risk of metastatic disease among patients with PPGLs due to mutations in SDHB is attributable to both the extra-adrenal locations of primary tumours and their large size at diagnosis.7 The large size might occur secondarily to either or both rapid proliferation of tumour cells, or a delay in diagnosis due to poorly differentiated phenotypic features and a lack of catecholamine-related symptoms.7

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Kimura and colleagues did not routinely determine the SDHB mutation status of the study participants. Appropriate recording of tumour size and location might counter this deficiency, but still neglects the importance of testing for SDHB mutations to identify family members who also have SDHB mutations and who should be screened for tumours. Proactive screening programmes provide opportunities for identification and resection of tumours at an early stage, before a volume critical for metastasis is reached.7 Related to this consideration is the exclusion of paediatric patients from the study. Up to 15% of PPGLs occur in children, a substantial proportion of whom develop metastatic disease.8 Sadly, paediatric and adult endocrine or oncological research and medical services are often disconnected, partly as a result of ostensible ethical constraints that can hamper implementation of screening programmes and, therefore, cost-effective prevention of metastasis in paediatric patients.

Consideration of the biochemical phenotype of PPGLs is clearly important. However, a limitation of the GAPP system is that plasma or urinary levels of catecholamines are used as measures of biochemical differentiation. Tumours that secrete epinephrine are assigned a well-differentiated score (0 points), whereas those that secrete only norepinephrine are assigned 1 point. The authors also noted a subset of tumours not showing any catecholamine secretion that, without explanation, were assigned a contradictory well-differentiated (0 point) score.2 However, measurement of catecholamines not only provides inferior diagnostic sensitivity, but also does not adequately assess differences in the production of catecholamines by tumours compared with their O-methylated metabolites.5 This score assignment also ignores the catecholamine biosynthetic profiles of adrenal versus extra-adrenal chromaffin cells.

“...increased risk of metastasis is associated with a more poorly differentiated biochemical phenotype...”

As shown previously, higher metastatic risk for norepinephrine-producing tumours than for epinephrine-producing tumours is reflected by the location of the tumours (adrenergic tumours occur almost exclusively at adrenal sites, whereas most extra-adrenal tumours are noradrenergic).7 By contrast, excess production of dopamine (best assessed by measuring plasma levels of methoxytyramine) can be used to predict the risk of metastasis, independently of tumour location.7 Thus, the underlying premise advanced by the authors (that an increased risk of metastasis is associated with a more poorly differentiated biochemical phenotype) is fundamentally correct. However, the risk of metastasis is best assessed from dopaminergic versus noradrenergic and adrenergic features rather than from the latter alone.

The GAPP system does have potential to affect patient care, but several issues must be resolved before it can be considered widely. Foremost of these issues is that all tumours in this study were scored by a single pathologist. Although the PASS system initially showed promise when scored by a single pathologist, subsequent scoring by a group of expert endocrine pathologists demonstrated poor concordance.9 Therefore, determining whether concordance is also a problem with GAPP scores is important. Concordance among pathologists' scores might ultimately be improved by issuance of clear guidelines and explanatory notes according to a standardized synoptic reporting system.10

Predicting metastasis will probably rely on a combination of morphological, biochemical and other parameters. The best promise for achieving this goal lies in the efforts of multi-institutional and/or national consortia, such as the phaeochromocytoma and paraganglioma research support organization (PRESSOR), the European network for the study of adrenal tumours (ENS@T) and now the phaeochromocytoma study group in Japan (PHEO-J, as described by Kimura and colleagues). Of note, although 2,920 patients with PPGLs are registered in PHEO-J, only 163 (5.6%) are included in the present study, an increase of just 17 above a report on the same grading system in 2005.1 Hopefully, progress in the collection of multi-institutional data and specimens in Japan will expand through participating investigators committing to common objectives and the development of an appropriately coordinated and funded research program.

Validation of the GAPP system, or any other grading system, requires confirmation through multiple centres, with reproducibility verified through blinded analyses by different pathologists. The relative weight and utility of individual GAPP components might also be reassessed in longer and larger series than that of Kimura and colleagues and with tumours that have a known genotype. However, before such testing is conducted, it seems prudent to consider the inclusion of other parameters, such as tumour location, size, the presence of mutations in SDHB and the production of methoxytyramine. Until then, pathologists remain powerless to accurately predict the risk of metastasis and periodic follow-up of all patients with PPGLs will remain mandatory.


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The authors would like to acknowledge the support of Deutsche Forschungsgemeinschaft EI855/1/1, European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 259735 (ENS@T-Cancer).

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Correspondence to Graeme Eisenhofer.

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Eisenhofer, G., Tischler, A. Closing the GAPP on predicting metastases. Nat Rev Endocrinol 10, 315–316 (2014).

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