The flushing patient:

Differential diagnosis,
workup, and treatment
J Am Acad Dermatol 2006;55:193-208
 Introduction
• Cutaneous flushing
– Resulting from changes in cutaneous blood
flow triggered by multiple conditions
– Common, benign diseases, such as rosacea
or climacterum
– Other serious diagnoses; carcinoid syndrome,
pheochromocytoma, mastocytosis, and
anaphylaxis
 Definition
• Defined as a sensation of
warmth accompanied by
visible reddening of the skin.
• Usu. Most prominent in the
classis “bluish area,”
including the face, neck and
upper portion of the chest,
and upper limbs
 Definition II
• Flushing – episodic or constant
• Episodic attacks are generally mediated
by release of endogenous vasoactive
mediators or by drugs
• Repetitive episodes over long periods
(persistent flushing)
• May produce fixed facial erythema with
telangiectases and a cyanotic tinge
Differential Diagnosis
 Fever
• Most common cause of “hot flushes”,
associated with night sweats
• Prompt a fever workup, which may reveal
an infectious or noninfectious cause
 Benign Cutaneous Flushing
• Triggered by emotion, exercise,
temperature changes, and foods or
beverages, esp. spicy foods
• Associated findings – a feeling of warmth
and cognitive dysfunction
• Hyperthermia, Emotional flushing, Foods,
beverages, and alcohol
 Rosacea
• Acne rosacea- another common cause
• May present with transient or persistent
central facial flushing, erythmea, visible
blood vessels, and often papules and
pustules
• 4 broad subtypes: erythematotelangiectatic,
papulopustular, phymatous, and ocular
Rosacea
 Rosacea II
• Primary manifestation
– Persistent erythema, usu. Longer than 3
months
– Flushing episodes, lasting longer than 10
mins
• Important to exclude polycythemia vera,
connective tissue disease, carcinoid
syndrome, systemic mastocytosis
 Climacteric Flushing
• Common cause of flushing, affecting 50%~85%
of women who undergo natural menopause
• Perimenopausal flushing presents as transient
episodes of intense heat sensation, flushing of
the chest, head, and neck, and profuse
drenching sweats
• Frequently followed by chills, palpitations and a
sense of anxiety
• Episodes last 3-5 mins and may occur as many
as 20 times a day
 Carcinoid Syndrome
• Classical triad: flushing, GI hypermotility and Rt
sided cardiac failure. Lesser incidence of
bronchoconstriction
• 95% of p’ts have flushing at some point during
disease; the most frequent sign
• CS occurs in 10% of p’ts with carcinoid tumors;
malignant enterochromaffin or Kulchitsky cells
derived from neuroendocrine lineage
• 13% had metastasis at time of diagnosis and
24% carcinoid p’ts had more than 1 tumor
 Carcinoid Syndrome II
• Flushes ossicated with gastric tumors are
reddish-brown with variegated margination and
occurs as wheals over the entire body, including
palms and soles and intensely pruritic
• Flushes assoicated with bronchoconstriction are
bright red and confluent, cover most of the body,
last hours to days, and usu. Associated with
chemosis, facial edema, severe hypotension,
and oliguria
• P’ts with CS flushing may develop thick skin
changes with venous telangiectasia and bluish
coloration of the chin, nose and malar area
 Carcinoid Syndrome III
• P’ts generally presents with hypotension
and tachycardia during flushing
• Flushing may be provoked by foods,
pharmalocologic triggers and any stimuli
that increase adrenergic activity
• Likelihood of flushing in CS is dependent
on tumor-derived mediators and the extent
of liver metastasis
 Carcinoid Syndrome IV
• Tumor derived vasodilator : 5-HT,
substance P, histamine, serotonin,
catecholamines, PG, kallikrein, kinins,
tachykinins, neuropeptide P, VIP, motilin,
and gastric related peptides
• CS diagnosed by measuring 24-hr urine 5-
HIAA, a major urinary metabolite of 5-HT
• Flushing in CS can be blocked with
somatostatin, analogs also decrease
tumor progression
 Pheochromocytoma
• Also known as chromaffin tumor, present with
flushing and hypertension
• Chromaffin cells derived most often from the
adrenal medulla, produce, store and release
catecholamines
• HTN most common finding.
• Attacks last a few minutes to a few hours
• Associated with flushing or pallor, elevated BP
and tachycardia
• Commonly present with headaches, sweating,
palpitations, a sense of apprehension and
impending doom, chest or abd pain.
 Pheochromocytoma II
• Diagnosed by 24hr urine fractionated
metanephrines, metabolites of
catecholamines
• Abdominal CT, abdominal aortography or
nuclear scintigraphy with radioactive
iodine
• Surgical resection by laparoscopic
adrenalectomy is the definitive treatment
and may be curative
 Mastocytosis
• A rare disease caused by tissue infiltration
with increased numbers of mast cells
• More common in childhood than in
adulthood
• Presents in the children with the
characteristic skin eruption of urticaria
pigmentosa (>90%)
Urticaria pigmentosa
 Darier sign
• Darier sign is a change observed after
stroking the skin of a person with systemic
mastocytosis or urticaria pigmentosa. In
general, the skin becomes swollen, itchy
and red.
• Result of stimulation; mast cells release
several potent vasodilators; histamine and
PG D2, TNF α
 Mastocytosis II
• Diagnosis usu. straightforward if characteristic
lesions of urticaria pigmentosa present
• Elevated plasma concentrations of mast cell
mediators, such as histamine and tryptase
• Elevated 24hr urine excretion of histamine and
PG D2
• Histopathologic analysis of cutaneous
mastocytosis lesions revealing multifocal or
diffuse mast cell aggregates
 Mastocytosis III
• Classified into 4 categories
I. Indolent mastocytosis, cutaneous or
systemic
II. Mastocytosis associated with hematologic
disease
III. Lymphadenopathic mastocytosis with
eosinophilia
IV. Mast cell leukemia
 Mastocytosis IV
• No cure for mastocytosis
• Avoidance of precipitating factors
• Flushing and hypotension from
mastocytosis can be reversed with IV
epinephrine
• Combined blockade pf H1 and H2
receptors prevents the vasodilatory effects
of histamine
 Anaphylaxis
• Life threatening condition that may present
with flushing
• Most often presents with flushing, urticaria
and angioedema
• Hypotension, upper airway edema,
pulmonary symptoms, rhinitis, headaches
and substernal chest pain
 Medullary Ca. of the thyroid
• Malignant tumor of the parafollicular C
cells
• May present with protracted flushing of the
face and upper extremities, discoloration,
and telangiectasias
• Neoplastic cells are derived from neural
crest
• Inheritance pattern may be sporadic or AD
 Pancreatic cell tumor
• Vasoactive intestinal polypeptide (VIP)
tumor classically present with Verner-
Morrison syndrome: watery diarrhea,
hypokalemia, and achlorhydria
• Also rarely present with flushing during
attacks
• VIP tumor is diagnosed by a high plasma
VIP level in the setting of stool volume
greater than 1L per day
 Renal cell carcinoma
• RCC may cause flushing via secretion of
prostaglandin or via pituitary
downregulation from release of
gonatotropins
• Classic triad: gross hematuria, flank pain
and abdominal mass
• Tx of choice: Nephrectomy
Pharmacologic mediators
Pharmacologic mediators
Differential Diagnosis
 Unilateral flushing
• May result from
contralateral sympathetic
nerve lesions that produce
Horner syndrome (ptosis,
miosis, and anhidrosis)
• Leading to contralateral,
unaffected facial
reddening
Medications
Summary
Summary