Not all flushing is carcinoid syndrome

If people read wider and use authoritative sources, it becomes obvious that Cutaneous flushing is a common presenting complaint in endocrine disorders (not just in carcinoid syndrome). The issue we have today is that the word “carcinoid” and been used incorrectly for decades by doctors and medical establishments (this continues today in some quarters). Not all hormone-induced flushing is associated with so-called “carcinoid syndrome”, other types of NET syndromes/types can have a flushing symptom, including:

Pheochromocytoma/Paraganglioma – hypertension mainly due to the release of catecholamines and other hormones.  Also causes sweating which may appear to be flushing/hot flash. Flushing in pheo/para is not carcinoid syndrome.

Medullary Thyroid Carcinoma (MTC) – MTC is derived from the neural crest and secretes a variety of biologically active substances including calcitonin, prostaglandins, histamine, substance P, ketacalcin, levodopa, adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone, which can cause flushing and sweating.  This is not the same as carcinoid syndrome.

Pancreatic NETs – only around 1% of pNETs are associated with so-called “carcinoid syndrome”.  When you look at that figure in conjunction with feedback in patient groups, it becomes obvious that carcinoid syndrome is being attributed to some of the symptoms of Pancreatic and other NETs incorrectly.  While most pancreatic NETs are non-functional, they can secrete several hormones and peptides leading to functional syndromes, including VIP, gastric inhibitory polypeptide, prostaglandin, insulin, gastrin, glucagon, ACTH, somatostatin, growth hormone–releasing factor (GRF), neurotensin, parathyroid hormone-related peptide, pancreatic polypeptide, and melanocyte-stimulating hormone. Most individuals usually only have symptoms relating to the hormone that is chiefly produced.  Flushing can sometimes be seen in all forms of PNETs i.e. with a VIPoma around 15-30% will have a flushing symptom as part of the associated syndrome.  Insulinomas can cause flushing during hypoglycemic episodes, Gastrinomas can flush although this is rare. Glucagonoma can present with characteristic necrolytic migratory erythema rash which may be confused for flushing in mild cases.  ………. It does not mean these pancreatic NET patients have so-called carcinoid syndrome.

Cushing’s Syndrome – Endogenous Cushing syndrome is the result of chronic glucocorticoid excess from either an ACTH-secreting pituitary tumor, cortisol-producing adenoma, adrenal hyperplasia, or ectopic production of ACTH and/or CRH from a neuroendocrine tumor. Patients classically present with facial plethora, central body weight gain with limb thinning, glucose intolerance or diabetes with extensive acanthosis nigricans, hypertension, proximal muscle weakness, easy bruising and striae. Flushing is rarely a presenting complaint and is usually subjective, i.e. it’s Cushing’s, not carcinoid syndrome. Facial plethora is consistent and unlike flushing rarely episodic; it is also decreased after surgery, due to a reduction of blood volume perfusion.  Cushing’s syndrome is known to be ectopically related to certain NETs, particularly Lung and Pancreatic. 

Other misc causes – see reference link above (there are many including but not limited to the following comorbidities: central hypogonadism in men, malignant histiocytoma, neuroblastoma, and ganglioneuroma, from increased production of VIP; TSH-secreting pituitary adenoma causing hyperthyroidism, the use of systemic hormone therapy (estrogen +/− progestogen), selective serotonin reuptake inhibitors, gabapentin, clonidine.  None of these is carcinoid syndrome!

Another source for flush descriptions comes from a paid article written by a well-known NET Endocrinologist – Kjell Öberg.

Four different types of flushing have been described in the literature.
Endocrinology: Adult and Pediatric – 7th Edition 2016.

The first type is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest (i.e., normal flushing area). This flush is commonly of short duration, lasting from 1 to 5 minutes, and is related to early stages of malignant midgut NETs.

The second type is violaceous flush, which affects the same areas of the body and has roughly the same time course or sometimes lasts a little longer. These patients also may have facial telangiectasia. This flush is related to the later stages of malignant midgut NETs and is normally not felt by the patients because they have become accustomed to the flushing reaction.

The third type is prolonged flushing, lasting for hours up to several days. It sometimes involves the whole body and is associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial edema. These symptoms are usually associated with malignant bronchial carcinoids.

Finally, the fourth type of flushing reaction is bright red, patchy flushing, which is seen in patients with chronic atrophic gastritis and ECLomas (derived from enterochromaffin-like cells) of the gastric mucosa with evidence of increased histamine production.