Neuroendocrine tumours (NETs) are rare malignancies often presenting with diagnostic challenges. This case discusses a 62-year-old male with hypercalcemia and acute kidney injury in May 2024. Imaging played a crucial role in diagnosing and characterizing the tumour. Initial CT scans revealed a large retrosternal thyroid goitre and extensive liver deposits, raising suspicion of metastatic disease. Octreotide scans confirmed somatostatin receptor expression, while FDG-PET imaging showed widespread metastasis, with high uptake in the sigmoid colon, suggesting a likely colonic primary. Further imaging identified new lung nodules, extensive liver metastases with necrotic cores, pleural effusions, and vascular encasement, indicating aggressive disease progression. The discordance between octreotide and FDG-PET uptake in the sigmoid mass raised concerns about de-differentiation or tumour heterogeneity. Although initial biopsy was reported as well-differentiated NET but subsequent re-review was carried out due to FDG-PET positivity and radiological progression, which revealed areas of poor differentiation NET, with high Ki-67 index, correlating with the tumour’s aggressive behaviour. Based on the FDG-PET findings, the patient was treated with carboplatin and etoposide starting in July 2024, but despite initial response, recurrent hypercalcemia episodes delayed further chemotherapy. Cinacalcet was introduced, but electrolyte abnormalities led to discontinuation of chemotherapy, and rapid disease progression occurred. An attempt was made to develop mathematical equation to predict the transformation probability with predictor variable such as genetic mutation and other relevant factors. This case illustrates how refractory hypercalcemia, coupled with discordant imaging and histological findings, may suggest tumour heterogeneity, complicating diagnosis and treatment in NETs.