Final Endo: CH 21 - Humoral/hormonal Manifestations of Malignancy

What is an ectopic hormone?
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What is an ectopic hormone?
hormones produced by tumours derived from tissues that are not normally engaged in the production of that hormone
How can hypercalcemia be caused by malignancy?
- caused by increase in PTH or parathyroid hormone-related protein (PTHrP)

- PTH causes excess osteoclast-mediated bone resorption

Effect on bone:
1. humoral tumor-derived factors

2. local peptide hormones by marrow derived tumor cells

- prognosis is poor, low survival beyond 6 months
What is parathyroid hormone related protein (PTHrP)?
- Expressed normally by MSCs (mesenchymal stem cells found in bone marrow)
- it is occasionally secreted by cancer cells (breast cancer,
certain types of lung cancer including squamous-cell lung carcinoma)

- causes bone resorption (breakdown of bone to release calcium) and kidney reabsorption in kidneys. (holding onto calcium in kidneys) which both cause an increase in blood calcium levels

- can lead to hypercalcemia

- PTHrP lacks normal feedback inhibition as PTH

- however, PTHrP is less likely than PTH to stimulate 1,25D3 production
How is hypercalcemia cause by PTHrP?
Hypercalcemia caused by interaction with PTHR1 (PTH/PTHrP receptor):
- Bone resorption (bone breakdown to release calcium)
- Distal tubule calcium resorption
- Inhibition of proximal tubular phosphate transport
What are hematologic malignancies associated with hypercalcemia of malignancy?
Multiple myeloma:
cancer of plasma cells
- associated with lytic bone lesions/ active bone resorption (increase in osteoclast activity)


Leukemia and lymphoma:
caused by
> local lytic effects analogous to MM
or
> humoral effects of tumor derived 1,25D
How is hypercalcemia of malignancy treated?
Bone resorption is central to all causes of hypercalcemia of malignancy

Treatments:
- Bisphosphonates (mainstay; as Adjuvants (co-preventative care)
- Glucocorticoids?
- Humanized antibodies against PTHrP or RANKL
What is ectopic ACTH syndrome?
Malignant/benign tumors produce the ACTH

example: cushing disease or syndrome?

> High glucocorticoids
> Hypokalemic alkalosis (low potassium; dominant feature)
> Fluid retention
> Glucose intolerance
> Generalized hyperpigmentation
What is SIADH?
syndrome of inappropriate/increased antidiuretic hormone (remember ADH induces water retention)

- tumor is common cause of SIADH

* Excessive ADH leads to an inability to excrete free water
- decreases amount of urine produced
What is hyponatremia?
too much water causing sodium level in blood to be low

- SIADH is the most common cause of hyponatremia

* Excessive ADH leads to an inability to excrete free water
- decreases amount of urine produced
What are therapies for SIADH?
- Water restriction, demeclocycline (traditional)

- Vaptans (ADH antagonists)

- Infusion of hypertonic saline and loop diuretics

- Cancer treatment
What is non-islet cell tumor-induced hypoglycemia?- rare - low blood glucose Causes: - eutopic insulin production by pancreatic islet cell tumors (insulinomas) (more common) - non-islet tumor-derived insulin-like growth factor 2 (IGF2)What is Doege-Potter syndrome?- hypoglycemia due to non-islet tumor-derived insulin-like growth factor 2 (IGF2) - large: slow growing and well differentiated solitary fibrous tumorsWhat is acromegaly?- syndrome caused by increased amounts of GHRH and GH Causes: > primarily due to eutopic production of GH by pituitary adenomas > remainder of cases due to ectopic production of GHRH by well differentiated neuroendocrine tumors (bronchial or pancreatic tumors) - Ectopic GH overproduction is extremely rare - Increased GHRH causes hyperplasia of somatotrophs in the pituitary - elevates GH and IGF1 GHRH-secreting hamartomas, gliomas and gangliocytomas (not Ectopic) Carcinoid tumors (lung, GI, thymus) are most frequent peripheral source of GHRH (>50%) Pheochromocytoma is associated with ectopically GHRH - induced acromegaly Treatments: Surgical resection, somatostatin analogs (multiple receptor subtypes)What does eutopic overproduction of calcitonin result in?Eutopic overproduction of calcitonin occurs in medullary __________ cancer cells. ? Cause: - Neuroendocrine tumors (NETs) of the foregut, are the primary source of ectopic calcitonin secretion