Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms

Abstract

Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.

Keywords: biopsy; cell signalling pathway; gastroenteropancreatic; neuroendocrine neoplasms; neuroendocrine tumour; radioligand therapy; somatostatin analogues; tumour heterogeneity.

Figure 1

Spatial and temporal heterogeneity in NENs. Neuroendocrine neoplasms generally express SSTR2 on the tumour surface, and are well-differentiated tumours in the majority of cases. However, spatial heterogeneity within the primary tumour may lead to the presence of areas with lower expression of SSTR2 and/or a different Ki-67 index. This heterogeneity is also frequent in metastatic sites and can differ significantly from the primary lesion. The mTOR pathway is also commonly involved in the onset of the disease and is particularly relevant in distant metastases, although over time alternative pathways may be involved in tumour survival. Moreover, temporal heterogeneity that can be linked to treatment selective pressure may lead to significant changes in tumour biology that affect prognosis and survival.

Figure 2

Tumour heterogeneity on receptor-based and functional imaging of NENs. Neuroendocrine neoplasms are usually positive on somatostatin receptor-based imaging (i.e., 68Ga-DOTA-peptides PET). However, the presence of tumour heterogeneity with areas that express lower or no somatostatin receptors is common on baseline scans, and often after disease relapse or progression. These areas are often less differentiated and metabolically active. The use of 18F-FDG-PET, especially in combination with receptor-based imaging, can potentially provide a better picture of metabolic spatial intra- and inter-tumour heterogeneity of the disease, especially in higher-grade tumours.

Figure 3

Tumour biopsy in GEP-NENs. Pitfalls and suggestions for tumour biopsy in GEP-NENs. Abbreviations: GEP: gastroenteropancreatic; FNA: fine-needle aspiration; NET: neuroendocrine tumour.