# The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review)

## TL;DR

This review explores risk factors and endocrine-related paraneoplastic syndromes in cholangiocarcinoma, emphasizing the role of hormonal systems and their clinical implications.

## Contribution

The paper provides a narrative review integrating endocrine features into the broader context of cholangiocarcinoma biology and paraneoplastic syndromes.

## Key findings

- Cholangiocarcinoma incidence is rising globally, with multiple risk factors including chronic biliary disease and environmental exposures.
- Humoral hypercalcaemia of malignancy, caused by parathyroid hormone-related protein, is a notable paraneoplastic syndrome in cholangiocarcinoma.
- Endocrine-related biomarkers and hormonal systems like vitamin D and galanin are increasingly recognized in cholangiocarcinoma pathogenesis.

## Abstract

Cholangiocarcinomas, malignant tumours originating from the biliary epithelium, have had an increasing incidence during recent decades; thus, awareness represents the key operating factor nowadays. Our purpose was to overview the tumour field following the constellation of the risk factors and the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. The hormonal burden is reflected by complex interplays such as the galanin system, exposure to sex hormone therapy, interferences with vitamin D system, etc., while humoral hypercalcaemia of malignancy, although rare, has been reported due to parathyroid hormone-related protein over-production in addition to other elements such a fibroblast growth factor receptor-positive or even procalcitonin-positive tumour. The level of endocrine evidence across clinical trials remains far from generous. Further applications such as emergent hormonal biomarkers are expected for daily practice.

Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20–30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.