9th June 2023

Types of endocrine paraneoplastic syndromes

Cushing’s Syndrome

Cushing’s Syndrome is a collection of biochemical and physiological abnormalities caused by excess serum cortisol. This excess can be extrinsic (i.e. a person taking glucocorticoid therapy) or intrinsic (i.e. an excess of cortisol production), the latter of which can be caused by abnormal function at various points along the production pathway. Cortisol production is stimulated by adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary gland, which itself is stimulated by corticotropin releasing hormone (CRH) secreted by the hypothalamus.

Paraneoplastic Cushing’s is due to the secretion of ACTH (or, rarely, CRH) by malignant cells that are outside of the pituitary gland, hence considered ectopic. Whilst a rare entity, 5-10% of all Cushing Syndromes are of paraneoplastic aetiology, and more than half of these are caused by neuroendocrine lung tumours such as small cell lung cancer or bronchial carcinoid. A high dose dexamethasone test can be used to distinguish ectopic secretion of ACTH from abnormal pituitary secretion – if serum cortisol remains high after exogenous administration of dexamethasone (i.e. “failure” of suppression), this indicates ectopic production of ACTH. This, along with pituitary imaging (usually MRI) to exclude a pituitary adenoma, and cross-sectional body imaging to look for malignancy, can identify a malignant cause for the syndrome, often preceding the diagnosis of cancer itself.

The syndrome can be treated by successful treatment of the underlying malignancy, however supportive treatment of any syndrome-associated biochemical and metabolic abnormalities may be required in the short term. In some cases, treatment with inhibitors of steroid production may be required. Resurgence of the syndrome in the context of treated malignancy can indicate cancer progression/relapse.

SIADH

Antidiuretic hormone (ADH), otherwise known as vasopressin, is one of the primary hormones involved in osmotic balance and sodium regulation. ADH is released from the posterior pituitary in response to hypovolaemia or hypernatraemia and causes renal water reabsorption. Syndrome of inappropriate antidiuretic hormone (SIADH) is, as the name suggests, a syndrome whereby antidiuretic hormone secretion continues despite low serum sodium, in the context of euvolaemia. It is therefore characterised by a low serum sodium and low plasma osmolality, paired with a high urinary sodium and osmolality, in the context of a euvolaemic patient.

Paraneoplastic SIADH is one of the more common syndromes encountered in Oncology, present in up to 2% of all malignancies depending on population demographic. The vast majority (>70%) of cases of paraneoplastic SIADH are due to small cell lung cancer and is often the presenting feature of this malignancy. Breast, Gynaecological and Haematological malignancies (such as Hodgkin’s lymphoma) are the more common of the other malignancies that cause this syndrome.

In paraneoplastic SIADH caused by small cell lung cancer, the malignancy itself is inherently sensitive to chemotherapy and radiotherapy, and as such the successful treatment of the underlying malignancy is usually the primary treatment for the SIADH. In cases where patients present with critically low sodium, or the hyponatraemia is slow to respond to anti-cancer treatment, primary treatment of the SIADH with fluid restriction or pharmacological therapy (such as tolvaptan) is often required. As with many other paraneoplastic syndromes, recurrence of the SIADH following successful Oncological treatment can often indicate cancer relapse.

Hypercalcaemia

Hypercalcaemia is a common biochemical abnormality in cancer patients occurring in approximately 10% of all patients with advanced malignancy, often in patients with bone metastases whereby osteoclastic or osteolytic activity increases serum calcium as a direct result of bone breakdown. Paraneoplastic hypercalcaemia is distinct from this entity, in that (as with the other paraneoplastic endocrine disorders) it is as a result of ectopic secretion of the hormones involved in calcium regulation, most commonly parathyroid hormone related protein (PTHrP) or, more rarely, vitamin D or PTH. In this syndrome, PTHrP is secreted by the tumour cells, binding to PTH receptors in the bone and kidney which upregulates bone reabsorption, renal calcium and phosphate retention and thereby increases serum calcium and phosphate.

Paraneoplastic hypercalcaemia due to ectopic PTHrP is most commonly seen in squamous cancers, particularly of lung origin. Other common squamous malignancies include cancers of the upper aerodigestive tract, skin, cervix, and anus. Ectopic production of vitamin D has been described in haematological malignancy though is uncommon. Patients often present unwell, with common symptoms of hypercalcaemia such as constipation, bone pain, dehydration, and acute confusion, and as such the supportive management of the hypercalcaemia with fluid resuscitation and bisphosphonates often takes precedence over treatment of the malignancy.