Pathophysiology of oncologic
emergencies
VLA - spring 2019
7. 5. 2019
Oncologic emergencies
 can occur at any time during the course of
a malignancy, from the presenting
symptom to end-stage disease.
 Although some of these conditions are
related to cancer therapy, they are by no
means confined to the period of initial
diagnosis and active treatment.
 Prompt identification of and intervention in
these emergencies can prolong survival and
improve quality of life, even in the setting
of terminal illness.
Hypercalcemia
 Hypercalcemia will be experienced by up
to one-third of cancer patients at some
point in their disease course. Among
patients hospitalized for hypercalcemia,
malignancy is the most common cause
 Breast, lung, and renal cell carcinomas;
multiple myeloma; and adult T-cell
leukemia/lymphoma are the prevailing
causes of hypercalcemia.
Hypercalcemia
 Bone metastases may cause a local paracrine effect by
producing several factors that stimulate osteoclasts,
leading to bone resorption with resultant hypercalcemia
and bone destruction.This is most commonly seen in
metastatic breast cancer and multiple myeloma. Prostate
cancer, despite the frequency with which it metastasizes
to bone, only rarely causes hypercalcemia, underscoring
that it is not just osseous involvement but the specific
tumor-bone interaction that determines calcium
liberation from bone.
 Very rarely, a tumor will manufacture PTH itself.
 Tumor production of vitamin D analogues is a less
common etiology of malignant hypercalcemia.
Hypercalcemia
 Up to 80% of malignant hypercalcemia is caused by
PTHrP released by the tumor into the systemic
circulation. Given its homology to parathyroid
hormone (PTH), PTHrP can mimic the action of PTH on
the bones and kidneys but, unlike PTH, PTHrP does
not influence intestinal absorption of calcium.
 The effects of PTHrP represent a true paraneoplastic
syndrome (ie, systemic signs and symptoms caused
by a tumor), with circulating PTHrP causing bone
resorption and renal retention of calcium. Squamous
cell carcinomas from the aerodigestive and
genitourinary tracts commonly cause this type of
“humoral” hypercalcemia but this can also be seen in
breast, kidney, cervical, endometrial, and ovarian
cancer.
Parathyroid Hormone Relation Peptide (PTHrP)
 PTHrP was discoverde as mediator of syndrome "humoral
hypercalcemia of malignancy" (HHM).
 During the syndrome inn different type of cancer (in
absebce of metastases) similar compounds to PTH are
produceds which is related to:
 Hypercalcemia
 Hypophosphatemia
 Increased cAMP exctretion by urine
 The effects are similar to those caused by PTH; no PTH levels
are detected.
OPG/RANK/RANKL as a common effector in bone immune
system and a vascular system ( to the previous figure)
 OPG, RANK and RANKL are selectively produced by
many cell types in diferent tissue: lymphocytes,
osteoblasts and endothelial cells.
 RANKL is functioning as a survival factor for dendritic cells
and as a osteoclastogenic factor after RANK ligation.
 OPG inhibits osteolysis and blocks RANKL/RANK
interaction.
 OPG/RANKL/RANK triad is considered a
osteoimmunomodulating complex.
Genetic families of PTH and PTHrP: PTHrP, PTH and TIP39 are
probably members of the same genetic family. Their receptors
PTH1R and PTH2R are 7 transmembrane G protein-coupled
receptors.
Production of PTHrP regulated by growth factor (GF) in tumor states. Tumor cells
are able to be stimulated at a distance (outside the bone) by autocrine
growth factors to an increased production of PTHrP. It reaches via circulation
the bone tissue and supports bone resorption. Metastatic tumor cells in the
bone are able to secrete PTHrP supporting bone resorption and paracrine
growth factors which further support PTHrP production.
Oncogenic osteomalacia
 Oncogenic osteomalacia is a
paraneoplastic syndrome in which a
bone or soft tissue tumor or tumor-like
lesion induces hypophosphatemia and
low vitamin D levels that reverse when
the inciting lesion is resected.
Oncogenic osteomalacia
 In the past 15 or so years, a humoral factor,
phosphotonin, has been identified in clinical and
experimental studies as being responsible for the serum
biochemical changes.
 Phosphotonin causes hyperphosphaturia by inhibiting
the reabsorption of phosphate by the proximal renal
tubules.
 Fibroblast growth factor 23, phosphate-regulating gene
with homologies to endopeptides located on the ‘x’
chromosome (PHEX) and matrix extracellular
phosphoglycoprotein (MEPE) are candidates proposed
for the production of phosphatonin and the altered
pathophysiology in oncogenic osteomalacia.
Oncogenic osteomalacia
Symptoms of hypercalcemia
 The symptoms of hypercalcemia
are nonspecific, and delayed
recognition of this metabolic
derangement can worsen morbidity
and mortality. The mnemonic
“bones, stones, moans, and
groans” is used to emphasize
 skeletal pain,
 nephrolithiasis,
 abdominal discomfort, and
 altered mentation
Symptoms of hypercalcemia
 Bone pain is usually related to discrete
metastases rather than diffuse liberation of
calcium.
 Even in the setting of profound hypercalciuria,
not all patients will form kidney stones, which
may be due to differences in the urine mineral
concentration needed to precipitate calculi.
 Abdominal pain can arise from dysregulated
intestinal motility, pancreatitis, or severe
constipation.
 Changes in sensorium can occur along a
spectrum from lethargy to coma.
 In addition, hypercalcemia shortens the QT
interval and can produce arrhythmias.
Hyponatremia
 The assessment of hyponatremia in cancer patients,
as in all patients, requires a critical determination of
volume status.
 The sodium concentration is the largest contributor to
plasma osmolarity and reflects how much water is
present in the blood relative to the cells, in which the
majority of the body's water is stored. Laboratory
measurement of the sodium concentration thus
reveals the distribution of water among the body's
fluid compartments, and hyponatremia means that
intravascular water is present in excess relative to
sodium, either through water retention and/or sodium
loss.
Hyponatremia
 The amount of sodium in the body, not the plasma
sodium concentration, determines the volume of fluid
outside the cells, and this volume can be readily
measured by physical examination.
 If the total body sodium is high, then the extracellular
fluid volume is large and the patient will appear
edematous.
 If the total body sodium is low, then the extracellular
space (including the circulatory volume) will contract and
the patient will progressively develop hypotension and
tachycardia.
 A low plasma sodium concentration can thereby be
associated with clinical hypervolemia, hypovolemia, or
euvolemia, depending upon total sodium content. The
physician must correctly evaluate the hyponatremic
patient's volume to understand both their sodium and
water balance and then select the appropriate treatment.
Syndrome of inappropriate antidiuretic hormone secretion
Physiology state
SIADH
 Euvolemic hyponatremic patients with cancer have
normal extracellular fluid volume, reflecting
appropriate total sodium content, but excessive water
in the intravascular space can be observed, most
commonly mediated through the syndrome of
inappropriate antidiuretic hormone (SIADH).
 Antidiuretic hormone promotes free water uptake in
the distal tubules by binding to the vasopressin 2 (V2)
receptor. Compounding the problem is continued free
water intake because the thirst mechanism is not
sufficiently inhibited.
SIADH
 SIADH should be suspected based upon the location of
primary and metastatic tumors because SIADH is more
commonly encountered in diseases originating in or
involving the lungs, pleura, thymus, and brain. Between
10% to 45% of patients with small cell lung cancer will
show evidence of SIADH.
 Iatrogenic causes of hyponatremia include cisplatin,
cyclophosphamide, ifosfamide, the vinca alkaloids, and
imatinib. Each of these drugs can cause SIADH, but all can
also produce hyponatremia through a variety of other
mechanisms (eg, platinum-induced salt-wasting
nephropathy), and therefore careful evaluation is required
to determine the underlying etiology of hyponatremia in
patients receiving these medications. Drugs with high
emetogenic potential can stimulate ADH release through
nausea, an appropriate physiologic response that may be
confused with SIADH.
Hyponatremia
 Hyponatremia can be classified as mild (131-135
mmol/L), moderate (126-130 mmol/L), or severe
(<125 mmol/L). Serum glucose should be measured
to ensure that hyperglycemia is not creating a
spurious finding of hyponatremia.
 SIADH is diagnosed when, after exclusion of adrenal
insufficiency and hypothyroidism, the effective
osmolality (calculated by subtracting [blood urea
nitrogen (BUN)/2.8] from the measured osmolality) is
less than 275 milliosmoles (mOsm)/kg of water, and
the urine osmolality exceeds 100 mOsm/kg of water.
Urine sodium greater than 40 mmol/L in the absence
of excessive dietary sodium intake, hypouricemia less
than 4 mg/dL, and BUN less than 10 mg/dL all
support the diagnosis of SIADH.
Hypoglycemia
 Hypoglycemia can arise in the patient with cancer through
several etiologies. Some tumors are capable of ectopic
production of substances that affect glucose metabolism.
Insulin is made in excess by insulinomas and
nesidioblastosis.
 Mesenchymal tumors like sarcoma, including
gastrointestinal stromal tumor and solitary fibrous tumor,
can produce insulin-like growth factors (IGFs) such as IGF-
2, which increases glucose utilization by tissues and blunts
the secretion of growth hormone.
 Levels of a related protein, IGF-1, have been reported to be
elevated in rare cases of lung cancer. Rapidly proliferating
neoplasms can consume glucose prodigiously.
Overexpression of the mitochondrial enzyme hexokinase II
allows some cancer cells to maintain glycolysis even in the
presence of oxygen.
Hypoglycemia
 In fact, this disproportionate uptake through the Warburg
effect is exploited in fluorodeoxyglucose positron emission
tomography imaging to visualize tumors against a
background of normal tissue. Given the anabolic and
biosynthetic demands of dividing cells, tumors with high
mitotic rates may consume glucose with sufficient briskness
as to induce hypoglycemia; this is most often seen in
aggressive lymphomas (eg, Burkitt lymphoma) but has also
been described in small cell lung cancer. The swift
proliferation may be associated with increased lactic acid,
even in the absence of hypoxemia. Tumors can infiltrate
organs that play crucial roles in normal glucose metabolism,
such as hepatocellular carcinoma replacing the liver
parenchyma or pheochromocytoma overtaking the adrenal
gland. It is rare for metastases to the adrenal gland to
precipitate hypoadrenalism.
Warburg effect
Signs and symptoms
 of hypoglycemia arise both from neuroglycopenia and
adrenergic counterregulation.
 Neurologic manifestations range from confusion and
blurred vision to seizures and coma.
 The catecholamine response to hypoglycemia can result
in diaphoresis, palpitations, and dilation of the pupils.
Tumor Lysis Syndrome (TLS)
 Tumor lysis occurs when cancer cells release their
contents into the bloodstream, either spontaneously
or following antineoplastic therapy, leading to an
influx of electrolytes and nucleic acids into the
circulation.
 The sudden development of hyperkalemia, ammonia,
hyperuricemia, and hyperphosphatemia can have lifethreatening
end-organ effects on the myocardium,
kidneys, and central nervous system (CNS).
 Hypocalcemia, a consequence of hyperphosphatemia,
is included in the constellation of metabolic
disturbances known as tumor lysis syndrome (TLS).
TLS
TLS
 Patients are variably symptomatic from the metabolic
derangements of TLS. Clinical TLS is diagnosed when
one or more of 3 conditions arise:
 acute renal failure (defined as a rise in creatinine to
1.5 times or more the upper limit of normal that is not
attributable to medications),
 arrhythmias (including sudden cardiac death), and
 seizures
 Acute renal failure can manifest as a decrease in urine
output, uremia-related altered sensorium, or
crystalline obstructive uropathy.
 Arthralgias can arise from gout flare.
TLS
 TLS is more common in the rapidly proliferative
hematologic malignancies such as acute lymphoblastic
leukemia (ALL), acute myeloid leukemia (AML), and
Burkitt lymphoma, but has been documented in solid
tumors, notably small cell lung cancer, germ cell
tumors, inflammatory breast cancer, and melanoma.
Liver metastases may increase TLS risk.
 Treatment-provoked TLS can occur following
chemotherapy, treatment with single-agent
corticosteroids in patients with sensitive tumors,
radiation, surgery, or ablation procedures.
The onset of TLS can be delayed by days to weeks in
a patient with a solid malignancy.
 The pericardial sac is distensible up to a
volume of 2 L, if stretching occurs over a
slow time period.
 Rising intrapericardial pressure affects all 4
cardiac chambers, but the right ventricular
wall is much thinner and more susceptible
to extrinsic compression. Diastolic
pressures throughout the chambers begin
to equalize and adversely affect cardiac
output by compromising filling.
 At this point, tamponade pathophysiology
emerges.
Cardiovascular Emergencies
Pericardial Effusion and Cardiac Tamponade
 Malignant pericardial effusions develop through direct
or metastatic involvement of the pericardial sac.
Direct extension is most common in those tumors
with sites of origin adjacent to the heart: lung cancer,
breast cancer, and mediastinal lymphoma.
 Metastases to the epicardium are seen in
noncontiguous breast and lung cancer, as well as in
melanoma.
 Primary neoplasms of the pericardium are exceedingly
rare, but include mesothelioma.
 Cancer treatment, especially thoracic irradiation, can
cause transudative effusions. Immunosuppression can
also allow suppurative infections to develop in the
pericardial space.
Cardiovascular Emergencies
Pericardial Effusion and Cardiac
Tamponade
Pericardial Effusion and Cardiac
Tamponade
 Pericardial effusions can be asymptomatic, although their
presence portends a poor prognosis, especially if larger
than 350 mL.
 Pericarditis symptoms may precede the emergence of
tamponade. Tamponade classically presents with the Beck
triad: hypotension, elevated jugular venous pressure, and a
muffled precordium. However, only a minority of patients
actually demonstrate all 3 signs. Most patients complain of
dyspnea and chest discomfort, which may begin abruptly.
 Tamponade pathophysiology can arise from volumes of as
little as 100 mL if they accumulate rapidly. Even if the
effusion forms over a longer period of time, the “last drop”
phenomenon describes the critical point of pathophysiologic
collapse at which intrapericardial pressure finally overcomes
the compensatory mechanisms of the heart and causes
cardiac output to drop precipitously. In this manner, a
chronic effusion can cause hyperacute symptomatology.
Diagnosis
 The diagnostic utility of the physical examination
should not be discounted but should be coupled with
appropriate studies. Tachycardia is nearly universal,
and pulsus paradoxus is an ominous finding, with a
value greater than 10 mm Hg having been arbitrarily
defined as abnormal.
 Chest x-rays may show cardiomegaly and the classic
“water bottle” cardiac silhouette.
 Electrocardiography can show low voltage and
electrical alternans from the shifting axis of the heart
as it moves like a pendulum within the fluid-filled sac.
 Echocardiography is the definitive test, demonstrating
right ventricular collapse during early diastole.
Superior Vena Cava Syndrome
 The thin-walled superior vena cava (SVC) returns all
blood from the cranial, neck, and upper extremity
vasculature to the right side of the heart.
 Primary or metastatic tumors can cause compression.
 Non-oncologic etiologies include syphilitic aortic
aneurysms (vanishingly rare since the advent of
penicillin), fibrosing mediastinitis (classically
associated with histoplasmosis), substernal
hypertrophy of the thyroid, granulomatous disease
(such as tuberculosis and sarcoidosis), and
thrombosis, particularly that due to an underlying
hypercoagulable state or endothelial damage from an
indwelling vascular device.
Superior Vena Cava Syndrome
 The extent of SVC obstruction and acuity of development dictate
the patient's presentation. Blockage is better tolerated when there
has been time for collateral veins to develop in adjacent venous
systems like the azygos and internal mammary, a process that
usually takes weeks.
 The veins on the patient's chest wall may be visibly distended.
 Edema in the arms, facial plethora (not necessarily unilateral),
chemosis, and periorbital edema may also occur. Stridor is an
alarming sign that edema is narrowing the luminal diameter of the
pharynx and larynx.
 Hoarseness and dysphagia can result from edema around the
aerodigestive tracts.
 Presyncope or syncope is more common early on, when cardiac
output declines without compensation.
 Headaches stem from distention of cerebral vessels against the
dura, but confusion may indicate cerebral edema. All of these
symptoms may be more noticeable when the patient is supine.
Diagnosis
 Cancers classically associated with SVC
syndrome include lung cancer (particularly
right-sided), breast cancer, primary
mediastinal lymphoma, lymphoblastic
lymphoma, thymoma, and germ cell tumors
(either primary or metastatic to the
mediastinum).
 Radiographic imaging is crucial to diagnosis
and treatment planning, especially if
radiation and endovascular stents are
potential interventions.
Infectious Emergencies
 Neutropenic Fever
 A patient's absolute neutrophil count (ANC) can decline through a
cancer's direct interference with hematopoiesis, as in leukemia or
metastatic replacement of the bone marrow, but neutropenia is
most commonly seen as an effect of cytotoxic therapy.
 Other risk factors include the rapidity of the ANC decline; exposure
to prior chemotherapy or current immunosuppression;
pretreatment elevations in alkaline phosphatase, bilirubin, or
aspartate aminotransferase levels; reduced glomerular filtration
rate; and cardiovascular comorbidities.
 The classes of chemotherapy with the highest risk of inducing
neutropenia are the anthracyclines, taxanes, topoisomerase
inhibitors, platinums, gemcitabine, vinorelbine, and certain
alkylators like cyclophosphamide and ifosfamide.
Neutropenic fever
 Infection is responsible for at least half of the cases of
neutropenic fever. Fever is a single oral temperature
of 38.3°C (101°F) or higher, or temperatures of
38.0°C (100.4°F) or higher measured 1 hour apart.
 A patient's reduced ability to mount an inflammatory
response can limit localizing signs and symptoms, and
therefore fever may be the only abnormal finding at
presentation. Skin and soft tissue infections may not
be associated with erythema or induration, and
abscesses will not accumulate in the absence of pusgenerating
neutrophils. Pulmonary infections may not
result in audible or radiographically visible.
Infectious Emergencies
 A minority of cases of febrile neutropenia will have an offending
infectious agent identified. Of those that do have a documented
infectious source, a variety of organisms can be responsible.
 Gram-positive cocci, which are now responsible for the majority of
culture-positive cases of neutropenic fever, include Staphylococcus
aureus, Staphylococcus epidermidis (especially in patients with
indwelling devices), Streptococcus pneumoniae, Streptococcus
pyogenes, the Streptococci viridans, and Enterococcus faecalis and
faecium. Corynebacterium is the most likely gram-positive bacillus.
 Gram-negative bacilli include Escherichia coli, Klebsiella species,
and Pseudomonas aeruginosa.
 Candida is the most common fungal infection, but Aspergillus and
Zygomycetes are more feared for their angioinvasive predilection.
Neurologic Emergencies
 Malignant spinal cord compression (MSCC) was first
described in 1925 by Spiller and remains a common
oncologic emergency that requires prompt treatment
to relieve pain and preserve neurological function.
 Although all tumor types have the potential to cause
MSCC, breast, prostate, and lung cancer each
account for approximately 15% to 20% of the cases,
with non-Hodgkin lymphoma, renal cell carcinoma,
and myeloma each causing 5% to 10% of cases.
 Although most cases of MSCC occur in patients with a
known diagnosis of malignancy, 5% to 25% of MSCC
cases occur as the initial presentation of malignancy.
Neurologic Emergencies
 MSCC is defined as the compressive indentation,
displacement, or encasement of the thecal sac that
surrounds the spinal cord or cauda equina by cancer.
 Compression can occur by posterior extension of a
vertebral body mass, by anterior extension of a mass
arising from the dorsal elements, or by growth of a
mass invading the vertebral foramen.
 The majority of the cases occur when metastatic
tumor reaches the vertebral bodies via hematogenous
spread, with secondary erosion into the epidural
space.
Neurologic Emergencies
 Early detection is critical because the single most important prognostic
factor for regaining ambulation after treatment of MSCC is pretreatment
neurologic status.
 The clinical presentation of MSCC can vary significantly depending on
severity, location, and duration of the compression.
 The most common initial symptom is back pain, which occurs in
approximately 90% of the cases. Because back pain is a common symptom
and has multiple causes, clinicians must always keep MSCC in their
differential diagnosis. It is also important to remember that MSCC can be
the initial presentation of malignancy. In a retrospective series of 337
patients with MSCC at the Mayo Clinic, compression was the first sign of
malignancy in 20% of the cases, with lung cancer, multiple myeloma, and
non-Hodgkin lymphoma accounting for approximately 75% of these initial
presentations manifested by spinal epidural metastases.
 The back pain associated with MSCC may gradually worsen over time and
usually precedes neurologic symptoms by weeks to months. Referred pain
is common and varies according to the location of the offending lesion.
Cervical compression can present as subscapular pain, thoracic compression
as lumbosacral or hip pain, and lumbosacral compression as thoracic pain.6
Neurologic Emergencies
 Once symptoms other than pain are present, the progression can
be quite rapid. These symptoms include motor weakness, sensory
impairment, and autonomic dysfunction. Cauda equina syndrome
may present as urinary retention and overflow incontinence (90%
sensitivity and 95% specificity). Other symptoms include
decreased sensation over the buttocks, posterior superior thighs,
and perineal region.
 Physical examination findings depend on the location of the
lesion(s) as well as the degree and duration of impingement.
 Most patients have tenderness to percussion over the affected
spinal region.
 The Valsalva maneuver may worsen their back pain.
 Hyperreflexia, spasticity, and loss of sensation (position,
temperature, pinprick, and vibratory) can occur early.
 Deep tendon reflexes may then become hypoactive or absent.
 Late signs include weakness, Babinski sign, and decreased anal
sphincter tone.
Malignant spinal cord compression (MSCC)
 Because there is no clinical model to rule out
MSCC in cancer patients with back pain, all
reports of new-onset back pain should
prompt an immediate assessment. For those
patients with only back pain and a normal
neurologic examination, imaging of the
spinal axis should be completed within the
next 48 to 72 hours. Those with neurologic
deficits need emergent evaluation before
nerve damage becomes permanent.
 The gold standard for the diagnosis of MSCC
is MRI, with a sensitivity of 93%, a
specificity of 97%, and an overall accuracy
of 95%.
Increased Intracranial Pressure
 Elevated intracranial pressure (ICP) secondary to
malignancy in the brain can cause devastating
neurologic injury. Successful management requires
prompt recognition and therapy. The vast majority of
all intracranial neoplasms are metastatic, with lung
cancer (20%), breast cancer (5%), melanoma (7%),
renal cancer (10%), and colorectal cancer (1%) being
the most common tumors of origin.
 Untreated patients have a median survival of
approximately 4 weeks.
Increased Intracranial Pressure
 The majority of metastases travel to the brain via
hematogenous spread.
 Tumor microemboli tend to lodge in the distal arteries
and small capillaries of the “watershed” areas and the
gray-white matter junctions. The distribution of
metastases also follows the relative blood flow volume
of the brain, with most occurring in the cerebrum,
then the cerebellum, followed by the brainstem.
 Increased ICP is due to both the mass effect of the
tumor as well as cerebral edema caused by neoplastic
disruption of the blood-brain barrier, which is caused
in part by local production of vascular endothelial
growth factor (VEGF).
The clinical presentation of brain
metastases
 will vary depending on the location, size, and rate of growth of the tumor.
In a series of 111 patients with brain metastases, the most common
presentation was headache, seen in 48% of patients and most often
described as tension (in 77%).
 In contrast to benign tension headaches, however, these headaches tended
to worsen with bending over or with Valsalva maneuvers, and in many
cases were also accompanied by nausea or emesis.
 The “classic” tumor-associated headache pattern, consisting of an early
morning headache that improves during the day, occurred in only 36% of
the cases.
 Seizures range from 10% to 20% in incidence and are almost exclusively
caused by supratentorial lesions.
 Strokes occur if the tumor embolizes, bleeds, or compresses an artery.
Melanoma, choriocarcinoma, thyroid cancer, and renal cell carcinoma are
more likely to cause hemorrhagic strokes.
 Focal neurologic dysfunction is dependent on the location of the lesion.
Clinicians must consider brain metastases in patients with cancer who
report new or changing headaches, focal neurologic changes, or cognitive
changes. A physical examination should be performed to evaluate for focal
neurologic deficits and papilledema.
 The triad of signs referred to as the Cushing response (hypertension with
wide pulse pressure, bradycardia, and an irregular respiratory rate) is a late
effect and indicates impending herniation.
Diagnosis
 Once an intracranial malignancy is
suspected, contrast-enhanced MRI is the
preferred method of diagnosis.
 Contrast-enhanced MRI is more sensitive
than either nonenhanced MRI or CT
scanning in differentiating metastases from
other CNS lesions.
 Noncontrast CT scan is the preferred
scanning technique, however, in an acute
situation when hemorrhage or
hydrocephalus is suspected.
Seizures
 Seizures are the presenting symptom
of intracranial metastases in 10% to
20% of patients with intracranial
involvement.
 Seizures may or may not be
associated with ICP.
 Status epilepticus requires emergent
treatment.
Hematologic Emergencies
Hyperviscosity Syndrome
 Hyperviscosity syndrome (HVS) refers to the clinical
sequelae caused by increased blood viscosity.
Increased serum viscosity (SV) is a result of excess
proteins, usually immunoglobulins (Igs), most
commonly arising from Waldenström
macroglobulinemia (WM) (85%) and multiple
myeloma (MM).
 Increased blood viscosity can result from elevated
cellular components seen in hyperproliferative states
such as leukemia and myeloproliferative diseases
such as polycythemia vera (PV).
Hematologic Emergencies
Hyperviscosity Syndrome
 Similarly, polycythemia vera (PV) can cause
elevated blood viscosity due to increased
red blood cell mass.
 PV can cause vascular symptoms and
complications secondary to thrombocytosis
with platelet hyperaggregability,
leukocytosis, and/or high hematocrit,
causing elevated blood viscosity. A
decrease in cerebral blood flow and a high
incidence of thrombotic complications are
seen in these patients.
Hyperviscosity Syndrome
 In normal healthy subjects, hematocrit is the main determinant of
blood viscosity, with fibrinogen being the main determinant of plasma
viscosity due to a combination of its large size, asymmetric shape,
charge, and concentration, even though albumin is the most abundant
protein in the blood.
 In paraproteinemias, such as WM and MM, excessive amounts of
circulating Igs are produced. IgM is the largest Ig (molecular weight,
1,000,000) and is the most likely paraprotein to cause hyperviscosity,
but HVS has also been documented in cases of MM or kappa light chain
disease.
 As the concentration of Igs increases, they form aggregates and bind
water via their carbohydrate content, which causes a rise in oncotic
pressure and increases the resistance to blood flow. Igs are positively
charged and therefore decrease the repellant forces between the
negatively charged red blood cells. When present in excess, these
proteins electrostatically bind to the red blood cells, causing rouleaux
formation as well as decreasing the red blood cell malleability.
Eventually, this leads to impaired transit of blood cells, microvascular
congestion, decreased tissue perfusion, and subsequent tissue
damage.
HVS
 The “classic triad” of HVS includes neurologic abnormalities, visual
changes, and bleeding, although all 3 need not be present to make
the diagnosis.
 Hyperviscosity causes impaired microcirculation in the brain that
manifests itself in the form of headache, altered mental status,
nystagmus, vertigo, ataxia, paresthesias, seizures, or even coma.
 Ophthalmologic examination can detect hyperviscosity, revealing
dilated, engorged veins that resemble “sausage links,” a finding
known as fundus paraproteinaemicus. If untreated, this will
progress to complete retinal vein occlusion and flame-shaped
hemorrhages.
 Mucosal bleeding and purpura are also common clinical
manifestations of HVS, with proteins coating the platelets and
hindering their function.
 Other clinical consequences of HVS include congestive heart
failure, ischemic acute tubular necrosis, and pulmonary edema,
with multiorgan system failure and death occurring if treatment is
not promptly initiated.
Leukostasis
 Leukostasis is a hematologic emergency that is associated with
respiratory failure, intracranial hemorrhage, and early death. If it
is not recognized and treated promptly, the mortality rate can be
as high as 40%.
 Risk for leukostasis increases with a white blood cell count (WBC)
greater than 100,000/mm3. The incidence ranges from 5% to 13%
in patients with AML and 10% to 30% in adult patients with ALL.
 Other risk factors include younger age (with presentation in infants
being most common); ALL with 11q23 rearrangement or the
Philadelphia chromosome; and AML subtypes M3, M4, and M5.
 Hyperleukocytosis portends a poor prognosis, with a higher risk of
early mortality, especially in patients with ALL. The WBC count is
the most important prognostic factor in ALL, and patients who
present with a WBC greater than 50,000/m3 have a particularly
poor prognosis; very few children with hyperleukocytosis become
long-term survivors
Leukostasis
 The pathophysiology of leukostasis is not completely understood.
There is believed to be a component of “sludging” by the leukemic
blasts in the microvasculature secondary to increased whole blood
viscosity.
 On average, the leukemic myeloblasts have a mean cell volume
that is almost twice that of the leukemic lymphoblasts and
therefore the manifestations are more common in patients with
AML than those with ALL. There is also differential expression of
adhesion molecules on the lymphoblast and myeloblast cells that
has been implicated in the higher incidence of leukostasis noted in
patients with AML versus patients with ALL.
 Evidence also suggests that there are leukemic blast/endothelial
cell interactions that lead to vascular wall disruption as well as
complement-induced granulocyte aggregation.
 In general, whole blood viscosity is not dramatically increased in
leukostasis because the rise in the WBC is often counterbalanced
by a decrease in the erythrocyte count. This is important to
recognize because packed red blood cell transfusions in patients
with asymptomatic hyperleukocytosis can rapidly lead to
leukostasis.
Leukostasis
 can involve any organ system, but the initial symptoms most commonly are
related to the respiratory system and the CNS.
 Pulmonary symptoms can range from exertional dyspnea to severe
respiratory distress, with diffuse interstitial or alveolar infiltrates often
present on chest x-ray, although these are not required for the diagnosis.
 Neurologic manifestations span the spectrum from mild confusion to
somnolence. Patients commonly report headache, dizziness, tinnitus,
blurred vision, or visual field defects. Physical examination can reveal
papilledema, retinal vein bulging, and retinal hemorrhage. Intracranial
hemorrhage can present with focal neurologic deficits.
 Other symptoms include myocardial infarction, limb ischemia, renal vein
thrombosis, and disseminated intravascular coagulation.
 Fever is almost always seen and can be greater than 39°C. Although
infection is found in only a few cases, it does need to be ruled out because
this syndrome can mimic sepsis.
 Thrombocytopenia is also usually present and underestimated because WBC
fragments can be counted as platelets in some automated cell counters.
 Disseminated intravascular coagulation is often seen in association with this
syndrome, most commonly in the M3 subtype of AML, although it can occur
in all types of leukemia.
Malignant Airway Obstruction
 Airway obstruction may result from
external compression of the trachea
or bronchi by the tumor, or by an
involved lymph node.
 The obstruction can also occur by
infiltration of the tumor within the
oropharynx, trachea, and bronchi,
causing severe narrowing.
Respiratory Emergencies
 Malignant Airway Obstruction
 Airway obstruction can be caused by virtually any malignancy, but
the most common culprits include tumors of the tongue,
oropharynx, thyroid, trachea, bronchi, and lungs.
 Mediastinal tumors such as lymphomas and germ cell tumors can
also cause airway obstruction, more commonly in the pediatric
population.
 Primary bronchogenic carcinomas are the most common cause of
malignant airway obstructions, and up to 30% of patients with
primary lung tumors will develop airway obstruction. Airway
obstruction does not appear to adversely affect overall survival,
with a median survival of 8.2 months versus 8.4 months when
comparing patients with airway obstruction with those without.
 Prompt recognition and treatment can lead to a markedly
improved quality of life, with up to 95% of patients reporting a
decrease in dyspnea and a significant increase in quality of life
after treatment.
Malignant Airway Obstruction
 The clinical manifestations of malignant airway obstruction
depend on the severity and location of the obstruction. The
symptoms are nonspecific and can be mistaken for more
common conditions including chronic obstructive pulmonary
disease exacerbations, asthma, or bronchitis.
 The most common presentation of malignant airway
obstruction is dyspnea. The symptoms usually worsen at
night and while lying supine.
 Patients will often have a productive cough and wheezing,
and may also present with stridor, especially if the
obstruction is located in the trachea or carina. In these
cases, the symptoms may be quite minimal until the airway
is critically narrow, but then appear rapidly and pose a lifethreatening
situation.
Chemotherapeutic Emergencies
Extravasation of Chemotherapy
 Extravasation, defined as the unintended leakage of the
chemotherapy drug into the extravascular space, is a dreaded
complication of chemotherapy administration
 Vesicants are chemotherapy agents that have the ability to induce
tissue necrosis, resulting in functional impairment and
disfigurement. Vesicants include the anthracyclines, vinca
alkaloids, and mitomycin C.
 Irritants such as the platinum compounds, taxanes, and
topoisomerase I inhibitors cause an inflammatory reaction but not
tissue necrosis. This classification is not absolute because the
severity of tissue injury is dependent on drug concentration and
volume. For example, platinums or taxanes can behave like
vesicants and induce ulcerations at high concentrations or at large
volumes.
 Nonaggressive agents are drugs that rarely cause any reaction
when extravasation occurs.
 The frequency of extravasation in adults is estimated to be
between 0.1% to 6% of peripheral iv infusions and somewhat less
in implanted venous access port infusions.
Chemotherapeutic Emergencies
Extravasation of Chemotherapy
 Extravasations vary in their clinical presentation and severity. Symptoms
may occur immediately after the incident or develop in subsequent days or
weeks.
 In most cases, initial symptoms include pain, blistering, induration, and
discoloration.
 Ulceration may not appear for several days and may continue to worsen for
months, as the drug diffuses into the adjacent tissue. In severe cases,
necrosis of the skin and the underlying tissues may develop, leading to
infection, scars, treatment delay, functional deficits, amputation, and,
rarely, death.
 In the case of irritant extravasation, symptoms include erythema, swelling,
and tenderness. Phlebitis, hyperpigmentation, and sclerosis can
subsequently develop along the vein. These symptoms usually resolve
within weeks and long-term sequelae are extremely rare.
 Patients with small, deep veins or those with damaged veins secondary to
multiple venipunctures are at higher risk, as are patients with neurologic
deficits because of an inability to follow instructions or secondary to an
impaired ability to detect changes in sensation. Obesity and movement
during chemotherapy administration also increase the risk of extravasation.
Chemotherapeutic Emergencies
Extravasation of Chemotherapy
 Diagnosis
 Extravasation is usually diagnosed by local
symptoms of pain, erythema, and swelling,
or by leakage of fluid around the iv site, but
a change in the rate of infusion or absence
of blood return from the vascular access
may be the initial sign.
 Once suspected, even if asymptomatic, the
infusion needs to be discontinued and
treatment initiated immediately.
Anaphylactic Reactions to
Chemotherapy
 Essentially any chemotherapeutic agent has the
potential to cause an infusion reaction, which can
range significantly in severity. These are often called
hypersensitivity reactions; however, because some do
not have a hypersensitivity component, they are more
properly termed infusion reactions.
 Anaphylaxis is defined as a serious allergic reaction
that is rapid in onset and may cause death. It is rare
with most conventional cytotoxic agents, although it is
well established with platinum drugs and the taxanes.
Other agents known to commonly cause infusion
reactions include cyclophosphamide, ixabepilone,
bleomycin, L-asparaginase, and monoclonal
antibodies such as rituximab.
Thank you for your attention