Oncologic Emergencies

Authors:

Joseph Shiber, MD, FACP, FACEP, FCCM, Associate Professor, Departments of Medicine, Emergency Medicine, and Surgical Critical Care, University of Florida College of Medicine, Jacksonville, FL

Emily Fontane, MD, FAAP, FACEP, Associate Professor, Departments of Emergency Medicine and Pediatrics, University of Florida College of Medicine, Jacksonville, FL

Peer Reviewer:

John P. Gaillard, MD, FACEP, FCCP, Assistant Professor, Department of AnesthesiologyCritical Care, Department of Emergency Medicine, Department of Internal Medicine-Pulmonary/ Critical Care, Wake Forest Baptist Health, Winston-Salem, NC

Cancer remains one of the leading causes of morbidity and mortality in developed countries, and is the second most common cause of death in the United States. With an increasing incidence of cancer attributed to the increasing life expectancy and generally decreasing mortality rates for all malignancies, the prevalence of cancers will continue to rise. This rise in incidence will bring more patients with emergencies due to their cancer and cancer treatments into emergency departments (ED). Most cancer patients experience at least one emergency at some point during the course of their disease.^1-6

Emergencies due to cancer may present as the initial manifestation of the neoplasm or may develop during the disease course as progression occurs, or as a complication of the treatments, such as chemotherapy, surgical resection, or indwelling venous catheters. Oncologic emergencies, thus, can be broadly divided into categories such as primary versus secondary (or iatrogenic), mechanical versus metabolic, or focal versus systemic. They can also be categorized based on the organ system involved, such as central nervous system (CNS), cardiovascular, pulmonary, cutaneous, hematologic, etc. The presentations of these emergencies may be subtle and insidious or may be sudden and dramatic. A delay in diagnosis and treatment may cause worsened outcomes, so the emergency physician must be ready to recognize and initiate therapies for these disorders. It may be especially challenging when the patient does not already have a diagnosis of cancer, requiring a level of suspicion and low threshold for investigation and diagnostic testing.^7-9

This article will review the 10 most common causes of oncologic emergencies, defined as any acute, potentially life-threatening event due to direct or indirect effects of the patient’s cancer or its treatment. Five mechanical/focal and five metabolic/systemic disorders will be discussed (see Table 1).

Brain Metastases

Epidemiology. There are approximately 200,000 cases of brain metastases diagnosed each year in the United States. They are the most common form of CNS involvement from systemic malignancies, and are typically due to lung, breast, renal, and melanoma. They may occur in 25–40% of all cancer patients, with more than half who are asymptomatic being diagnosed incidentally or post-mortem. Eight to 10% of cancer patients actually have symptomatic brain metastases. Gastrointestinal, prostate, uterine, and ovarian cancer uncommonly causes brain metastases, while leukemia and lymphoma more likely result in leptomeningeal disease.^10-12

Pathophysiology. The majority of brain metastases (80%) occur in the cerebral hemispheres, most commonly at the grey-white junction in accordance with the higher supratentorial blood flow, allowing hematogenous deposit of malignant cells via the cerebral arterioles and capillaries. The cerebellum and brainstem receive relatively lower percentages of blood volume, thus, the occurrence of metastases are likewise lower. Local growth of the tumor causes mass effect on surrounding tissue, which may increase intracranial pressure (ICP). ICP can also be increased by vasogenic edema caused by neoplastic disruption of the blood-brain barrier from tumor secretion of several cytokines and growth factors, such as vascular endothelial growth factor (VEGF), and by hydrocephalus from tumor obstruction of normal cerebrospinal fluid (CSF) circulation. Metastases are prone to acute hemorrhage from angiogenesis due to VGEF, which may cause sudden symptoms even when the underlying mass has been well tolerated.^13-15

Presentation. Headache is the most common complaint, which typically worsens with Valsalva or dependent position so that it is often more severe in the early morning and improves during the day after arising from bed. Symptoms of increased ICP, such as nausea and vomiting or altered mental status, may occur. Focal neurologic symptoms, such as aphasia, focal weakness or numbness, or ataxia, may occur. Cranial neuropathies or simultaneous symptoms localizing to more than one area of the neuroaxis indicates likely diffuse metastatic leptomeningeal disease. Seizures have a 10–20% incidence with brain metastases, which are almost entirely caused by supratentorial masses. Seizures may be simple focal, complex partial, generalized, or even manifest as status epilepticus.^10,16,17

Diagnosis. Non-contrast head computed tomography (CT) scan is the study most commonly available rapidly for evaluation of hemorrhage or hydrocephalus when a patient has an acute presentation. The addition of intravenous contrast may improve diagnostic yield if attempting to confirm metastases. If differentiating cerebral metastases from other possible intracranial lesions such as abscess, granuloma, or primary brain neoplasm, then magnetic resonance imaging (MRI) with and without contrast is the preferred method.^10,12,18

Treatment. Immediate administration of intravenous dexamethasone 8–24 mg bolus is recommended for reducing peritumoral edema. It is a pure glucocorticoid without unnecessary mineralocorticoid effects, such as hypertension and tissue edema due to sodium and water retention, so is the preferred steroid in this circumstance. If the edema is severe and causing elevated ICP with possible herniation syndromes, then mannitol or hypertonic saline may be useful, in addition to airway control and mild hyperventilation. Consultations to neurosurgery and radiation oncology should be made for consideration of expedited evaluation and intervention, especially if there is impending herniation or hydrocephalus requiring cranial decompression or external ventriculostomy. Current studies show encouraging results with biologic VGEF antagonists such as cediranib and bevacizumab. Seizure prophylaxis is not beneficial and is not recommended unless hemorrhage of metastatic lesions is present, since they are at a higher risk for seizures. Although the treatment of status epilepticus in these patients does not differ from the standard protocols for patients without cancer, it is preferable to avoid older generation antiepileptics (phenytoin, carbamazepine, phenobarbital) if starting a patient on a regimen for prophylaxis or adding another agent for breakthrough seizures. Newer antiepileptics, such as levetiracetam, lamotrigine, and lacosamide, are effective, well tolerated, and lack the enzyme induction and drug interactions with chemotherapy regimens.^10,12,18-20

Airway Obstruction

Epidemiology. This section will discuss supraglottic, glottic, and tracheal obstructions. Bronchogenic carcinoma is the primary cause of airway obstruction, but it can also be caused by locally invasive tumors of the tongue, oropharynx, thyroid, esophagus, trachea, and mediastinum such as lymphoma, thymic, and germ cell tumors. Metastatic disease of the mediastinum and thoracic lymph nodes from breast, colon, melanoma, and sarcomas can also cause airway obstruction.^21,22

Pathophysiology. The mechanism can be either due to external compression of the airway from the mass or involved lymph nodes, or from growth within the airway narrowing the lumen. There may be sudden progression of the obstruction if the mass has local hemorrhage or edema. Either of these may occur spontaneously or with initiation of radiation or chemotherapy. Vocal cord paralysis may occur due to recurrent laryngeal nerve dysfunction from tumor infiltration or due to iatrogenic nerve injury during surgical resection.^23,24

Presentation. Dyspnea is the most common presenting complaint, classically worse at night while lying supine. Cough, wheezing, and stridor are also common, and hemoptysis may occur in up to 45% of patients with neoplastic airway involvement. The symptoms may mimic pneumonia, asthma, chronic obstructive pulmonary disease (COPD), or heart failure exacerbation, particularly if the onset was sub-acute due to a slowly developing obstruction.^8,21

Diagnosis. Physical examination may reveal the nonspecific findings of stridor, wheezing, or abnormal regional breath sounds. Chest radiography and possibly soft-tissue neck films can be initial tests, but CT scanning has much higher sensitivity and will delineate the anatomy for interventions by pulmonology or surgery. Spirometry with flow-volume loops for determining extrathoracic or intrathoracic airway obstructions is more suited for stable patients in the outpatient setting. Diagnostic flexible bronchoscopy or nasopharyngoscopy can be performed in the appropriate patient, but should be done with caution using a natural airway since it may induce acute worsening of respiratory symptoms.^8,21,25

Treatment. Establishing an airway for adequate oxygenation and ventilation is the primary and most urgent goal. This may be established via endotracheal intubation or may require a surgical airway via either emergent cricothyroidotomy or tracheostomy. Medical therapies, such as nebulized racemic epinephrine or albuterol and intravenous steroids, are not typically effective. Non-invasive positive pressure ventilation (NPPV) may be temporarily helpful when preparing for a definitive airway. Urgent consultation to pulmonology or thoracic surgery is indicated since stent placement for extrinsic compression and laser resection for tumor resection within the airway using flexible or rigid bronchoscopy are the treatments of choice. Surgical resection, as well as radiation and chemotherapy, may also be further definitive treatment options.^23,26-28

Superior Vena Cava Syndrome

Epidemiology. Superior vena cava (SVC) syndrome occurs due to malignancy in more than 90% of cases, primarily due to lung cancer and non-Hodgkin’s lymphoma. The remaining 5-10% of the cases are due to benign conditions such as aortic aneurysms, goiters, tuberculosis, sarcoidosis, and indwelling vascular devices. Approximately 2-4% of all patients with lung cancer will develop SVC syndrome, but 10% of patients with small cell lung cancer will develop it.^6,21,29

Pathophysiology. Compression of the SVC occurs from extrinsic tumor mass or lymph nodes with metastatic involvement. The SVC is thin-walled and under minimal pressure so that it is easily compressed. Thrombosis can occur secondary to sluggish flow or tumor infiltration, inciting endothelial damage. If the compression occurs slowly, then collateral vessel recruitment and dilation of the azygous system, internal mammary, and chest wall veins can occur to compensate for the venous circulatory obstruction. If the compression or thrombosis occurs quickly or occurs below the level of the azygous vein, then the symptom onset and severity will be more acute since the compensatory collaterals will not have formed.^3,21,23

Presentation. Facial swelling, which initially may be present upon awakening from sleep and improve after being upright, is the most common complaint. It is often associated with erythema or plethora of the face and upper torso. Dilated veins may be seen across the chest wall and in the upper extremities (see Figure 1), which remain engorged even when the arm is raised, in contrast to normal veins. Dyspnea, hoarseness, and dysphagia also occur. Headache is a concerning complaint since it suggests cerebral venous dilation, which may progress to somnolence and then coma as cerebral edema and elevated ICP occur. Raising the arms overhead will often worsen the dyspnea and headache as gravity returns blood toward to the chest and head without reaching the right heart. This is known as Pemberton’s sign.^29-32

Diagnosis. A chest radiograph may show typically a right upper lobe mass (see Figure 2) or superior mediastinal widening, but chest CT with IV contrast timed for venography is the preferred study and has replaced the former "gold standard" of invasive venogram.^21,33

Treatment. Elevating the patient’s head will reduce ICP, while airway management may be necessary if obtunded. IV steroids may reduce local edema and be effective, particularly for lymphoma. Crystalloids may be necessary if hypotensive, but optimally should be administered via lower extremity access since venous return from the upper body is limited. Diuretics, although previously recommended, should be avoided since the patient does not have increased vascular volume but simply a sequestering of blood volume and interstitial fluid in the upper body so that diuresis may cause acute hypovolemia and hemodynamic compromise. The most rapidly effective treatment has been shown to be angioplasty and stenting of the SVC by interventional radiology. If thrombus is also present, then catheter-directed fibrinolytic therapy or systemic anticoagulation may be indicated if no severe risk of bleeding is present. Radiation therapy and chemotherapy are typically useful treatments for the underlying malignancy, but are much slower at reducing the symptomatic compression of the SVC.^23,34-37

Spinal Cord Compression

Epidemiology. Metastatic spinal cord compression (MSCC) can be found in 70% of all cancer patients at autopsy, although only approximately 15% were symptomatic. Lung, breast, prostate, and renal cancers are the most common solid tumors causing MSCC, while lymphoma and multiple myeloma are also culprits. Patients may occasionally have MSCC as their initial presentation of cancer, but it is much more common in patients with an established diagnosis. The vertebral column is the most common location of osseous metastasis, and the spine is the third most common site for metastasis, in general, behind the liver and lungs. It portends a poor prognosis with the median survival being less than six months.^3,10,38,39

Pathophysiology. Compression of the thecal sac occurs almost exclusively by epidural metastasis, while only rarely from intradural metastases. The spread is primarily hematogenous, but can also occur by direct extension of locally advanced paraspinal masses. Vertebral bodies are the location of the MSCC in 90% of cases, while the impingement occurs via neural foramina in 10% of cases. The thoracic spine is the most common site of MSCC, but multilevel disease occurs in up to 50% of cases. The tumor itself, or a bony fragment from the collapse of the vertebral body due to pathological fracture, causes impingement of the epidural space leading to cord edema, then ischemia, followed by infarction.^10,11,40

Presentation. Progressive back pain that worsens while lying flat or with valsalva is the most common initial complaint and typically precedes the neurologic symptoms (sensory, motor, autonomic) by 1–2 months. Localized tenderness to palpation or percussion is also characteristic. Weakness, sensory deficits, and autonomic dysfunction, such as bowel or bladder incontinence or retention, indicate more advanced MSCC. Ambulatory function on presentation is the main prognostic factor for neurologic outcome in these patients, as the majority of patients walking at admission continue to do so, but only 10% of patients non-ambulatory for more than 24 hours regain their mobility.^21,26,41,42

Diagnosis. MRI of the entire spine, with and without gadolinium, is the preferred diagnostic test. CT myelogram scanning can be done if the patient has contraindications or MRI is not readily available. Plain radiographic films have very low sensitivity for MSCC and will only show evidence of overt osteolytic or blast lesions and should not be used as a screening test for this disorder.^11,43,44

Treatment. Immediate IV dexamethasone should be given even prior to the confirmation by radiologic imaging if the clinical suspicion is high. Ten milligrams, considered to be moderate-dose, should be given if the neurologic examination is normal, with high-dose 100 mg reserved for when the examination is abnormal.³ The higher dose has been shown to reduce cord edema more effectively, but has serious associated adverse effects such as uncontrolled hyperglycemia and increased rates of upper gastrointestinal ulceration and nosocomial infections. Emergent neurosurgical consultation for spinal decompression and possible stabilization is the recommended treatment option resulting in preserved neurologic function. Radiation therapy may also be effective, but is not nearly as rapid so that irreversible cord injury may continue. Chemotherapy has only a limited role in selected responsive tumors.^10,45,46

Pericardial Tamponade

Epidemiology. Pericardial effusions are common in cancer patients, with more than 30% of patients having malignant pericardial disease. Cancer remains one of the leading causes of pericardial tamponade requiring emergent drainage in the United States. Hematogenous spread from non-contiguous cancer such as lung, breast, leukemia, and melanoma is the most common etiology. Lymphatic spread of malignancy from involved mediastinal lymph nodes and direct pericardial extension from adjacent tumor can also occur from lung and breast cancer and lymphoma. Primary tumors of the heart and pericardium, such as rhabdomyosarcoma and mesothelioma, are quite rare.^3,47,48

Pathophysiology. The pericardial sac typically only contains 50 mL of serous fluid, but can accommodate a large amount of fluid (up to 2 L) if formed slowly. Tamponade can develop with as little as 100–200 mL if accumulated very rapidly. (See Figure 3.) Tamponade results from pericardial fluid under pressure that exceeds the cardiac chamber filling pressure, causing decreased cardiac output and hypotension. The effusion may be serous from pericardial lymphatic obstruction, altered vascular permeability from tumor cell implants, or may be frankly hemorrhagic. Suppurative effusions from contiguous thoracic infections (pneumonia, empyema, infectious endocarditis) or bacteremic seeding of a sterile pericardial effusion with associated immunosuppression can also rapidly cause tamponade. Pericardial inflammation (pericarditis) can occur from thoracic radiation or chemotherapeutic agents, with resultant thickening and scarring of the pericardium leading to cardiac constriction even when only small effusions are present.^49,50

Presentation. Dyspnea followed by chest pain, which is typically positional, are the most common complaints associated with malignant pericardial disease. Tachycardia is nearly universal unless masked by medications or a fixed-rate pacemaker. The cardiac compensation for falling stroke volume due to tamponade is to increase heart rate in order to maintain cardiac output. Beck’s triad of hypotension, increased jugular venous pressure, and quiet heart sounds occurs in one-third of patients with acute tamponade but less often with chronic effusions.^51,52,53

Diagnosis. More than 75% of patients with malignant pericardial tamponade will have pulsus paradoxus, which is a more than 10 mmHg drop in blood pressure during inspiration. This can be challenging to accurately determine using non-invasive blood pressure monitoring in an acutely ill patient in a noisy ED. The chest radiograph may show an enlarged pericardial shadow if the effusion has formed slowly. The film may be normal-appearing in the face of outright acute tamponade. EKG may show evidence of pericarditis, such as diffuse ST segment elevation and PR segment depression or electrical alternans indicating a large effusion, but these findings are not necessarily helpful for evaluating tamponade physiology. Bedside echocardiography (see Figure 4) is the most expeditious manner to determine if an effusion is indeed causing restriction of cardiac chamber filling; a circumferential effusion (see Figure 5) with right atrial or right ventricular diastolic collapse with resultant dilation of the inferior vena cava (IVC) would confirm tamponade.^53,54,55

Treatment. An initial intravenous crystalloid bolus should be given since, if hypovolemia is present, the central venous pressure may fall below the intrapericardial pressure even if only a small effusion is present. This concept of "low pressure cardiac tamponade" classically occurs in chronically ill and malnourished patients, such as those with cancer when an effusion under relatively low pressure results in cardiac compression due to intravascular depletion and extremely low filling pressures. If hypovolemia or low central venous pressure is not present, then a volume challenge will not improve cardiac filling or systemic perfusion. Pericardial drainage is the only emergent treatment, and it may need to be performed at the bedside if the patient is in extremis. Ultrasound guidance should be used, if available, as it has vastly improved the effectiveness and safety of pericardiocentesis over blind technique. A catheter can be left in place for ongoing drainage since the effusion is very likely to recur. Cardiothoracic or general surgery consultation for pericardial window formation or pericardiectomy is the definitive treatment. Vasopressor administration is not effective, and neither are closed chest compressions in the event of cardiac arrest.^56-59

Neutropenic Fever

Epidemiology. Febrile neutropenia is one of the most common complications of cancer treatment and is the leading cause of death for patients with leukemia, lymphoma, and solid tumors. Virtually all chemotherapeutic agents are capable of producing some degree of neutropenia, with certain regimens for leukemia being known to cause the most profound marrow suppression.^1,41,60

Pathophysiology. Although the absolute neutrophil count (ANC) may decline through the direct effects of cancer on hematopoiesis and white blood cell maturation, the majority of neutropenia is due to the cytotoxic effects of chemotherapy. Anthracyclines, taxanes, platinums, topoisomerase inhibitors, and alkylating agents have the highest risk of causing neutropenia. The nadir, or lowest ANC, is expected to occur 5–10 days after the chemotherapy administration. Vulnerability to overwhelming infection increases as ANC drops below 1000/mm³ and continues to rise as the ANC falls.^1,8

Presentation. Neutropenia is defined as an ANC less than 1000/mm³ when expected to continue falling, while less than 500 is considered severe. A single oral temperature of 38.3° C (101° F) or higher, or an oral temperature of 38.0° C (100.4° F) or higher lasting for more than one hour is defined as fever. A somewhat lowered threshold is set to potentially improve the sensitivity of using detection of fever as a screening test.^61,62

Diagnosis. Complete blood counts will determine the ANC, and an oral temperature should be taken, avoiding rectal temperatures or digital rectal examination due to the risk of inducing bacteremia. The only presenting complaint may be fever. A thorough physical examination should be done, including inspection of venous catheter sites and skin and mucous membranes. Pain or tenderness alone may indicate infection, since localizing signs of inflammation and infection may be absent or subtle in the absence of neutrophils. Cutaneous infections may lack erythema and induration, and pulmonary infections may lack adventitial lung sounds and radiographic infiltrates. If a perirectal or prostatic infection is suspected, then a gentle rectal examination can be performed after administration of empiric antibiotics. Blood from peripheral and indwelling catheters, sputum, and urine cultures should be sent even if a screening urinalysis has no WBCs; additional cultures, such as CSF or stool, can be sent if clinical suspicion warrants. Chest radiographs should be obtained despite the poor sensitivity since pneumonia is the source of 50% of the documented infections.^{1,60,61,63,64}

Treatment. There is approximately a 50% incidence of occult infection with febrile neutropenia. The vast majority of infections at initial presentation are bacterial, while subsequent fevers during prolonged neutropenia in patients already receiving antibiotics are more likely to indicate viral or fungal infection. Administer antibiotics immediately after obtaining cultures. If signs of septic shock, such as hypotension or cardiovascular insufficiency, are present, then antibiotics should not be delayed even if prior to obtaining all cultures. After appropriate testing, collection of cultures, and discussion with the patient’s oncologist or treating physician, well-appearing low-risk patients (see Table 2) can be started on an oral antibiotic and discharged with close follow-up. Ill-appearing low-risk patients should be started on single drug treatment with an antipseudomonal beta-lactam (penicillin, cephalosporin, or carbapenem), while any high-risk patient should receive regimens with double coverage for pseudomonas typically including an aminoglycoside as well as an agent active against resistant staphylococcus (MRSA).^8,61,64,65

Hypercalcemia of Malignancy

Epidemiology. Hypercalcemia is the most common oncologic emergency, occurring in 10–30% of all cancer patients. It is mostly associated with multiple myeloma, lymphoma, lung, breast, kidney, and head and neck cancers. Although prostate cancer frequently involves bony metastases, it rarely results in hypercalcemia. It signals a very poor prognosis, as half of patients die within one month of their diagnosis of malignancy-associated hypercalcemia.^66-68

Pathophysiology. Serum calcium rises during the course of cancer due to increased release from bone and decreased renal excretion. The three mechanisms are: production of parathyroid hormone-related protein (PTHrP) from the cancer itself, which stimulates osteoclast activity, mobilizing calcium from bone, and increases renal tubular reabsorption of calcium; direct local bone destruction and osteolysis due to extensive metastases; increased production of calcitriol (1,25-vitamin D), the active form of vitamin D, which occurs primarily with lymphoma, as well as non-malignant granulomatous diseases such as sarcoidosis. Ongoing elevated serum calcium induces nephrogenic diabetes insipidus, leading to potentially profound dehydration.^68-70

Presentation. The most common symptoms, although nonspecific, include fatigue, anorexia, weight loss, nausea, constipation, and bone pain with focal tenderness. Polyuria and resultant polydipsia are present due to the inability to resorb water from the renal tubules. Neurologic symptoms include diffuse muscle weakness, lethargy, confusion, and coma. As with other electrolyte abnormalities, the body tolerates gradual changes even of large magnitude better than a smaller change that occurs very rapidly. Hence, not only the degree of hypercalcemia, but also the rapidity of which it occurred, influence the severity of clinical symptoms.^3,8,21,66,68

Diagnosis. Measuring serum calcium will give the degree of hypercalcemia, which is classified as mild (10.5–11.9 mg/dL), moderate (12.0–13.9 mg/dL), or severe (> 14.0 mg/dL). Since 40-50% of serum calcium is protein bound, levels will need to be corrected for hypoalbuminemia, which is very commonly present. The formula is 0.8 × (4 – measured albumin g/dL) added to the serum calcium level. Ionized calcium is the most accurate test to detect hypercalcemia defined as greater than 1.29 mmol/L. EKG abnormalities, such as prolonged PR interval, widened QRS complex, and shortened QT interval, may be present.^68,71-73 (See Figure 6.)

Treatment. (See Table 3.) Infusing intravenous fluids is the initial step to restoring intravascular volume as well as the extravascular fluid lost to dehydration. An isotonic crystalloid bolus and then infusion will improve glomerular filtration rate (GFR) to decrease renal tubule calcium reabsorption. This improved excretion will lower serum calcium modestly. If there are no cardiovascular contraindications to ongoing crystalloid infusion, it should continue adjusted for a urine output of 1-2 mL/kg. Intravenous loop diuretics may be considered, after euvolemia is achieved, to further increase urinary calcium excretion. Hemodialysis may be necessary for concomitant congestive heart failure, severe acute kidney injury (GFR < 20 mL/min), profound neurologic abnormalities (obtundation, coma), or calcium level greater than 18 mg/dL. Calcitonin 4–8 IU/kg given intramuscularly (IM) has the most rapid onset lowering serum calcium, but tachyphylaxis typically develops. Glucocorticoids (prednisone 60 mg orally or hydrocortisone 100 mg IV) can also be effective, primarily for hypercalcemia due to lymphoma and myeloma. Bisphosphonates pamidronate and zoledronate are the main therapy for effective and sustained correction of malignancy-induced hypercalcemia by inhibiting osteoclastic activity. Pamidronate 90 mg given as an infusion over 2-4 hours achieves normocalcemia within 48 hours in up to 90% of patients and maintains it for four weeks.²⁰ Zoledronate 4–8 mg can be given more rapidly (over 5-15 minutes) and is also very effective, but should be avoided when GFR is less than 30 mL/min or creatinine is greater than 3.0 mg/dL due to increased risk of acute tubular necrosis. Any possible medication that may be contributing to the hypercalcemia, for example thiazides, NSAIDs, vitamin D, and lithium, should be stopped. Hypophosphatemia may also be present, but it should be replaced enterally and slowly to prevent calciphylaxis when the Ca – PO4 product is greater than 70 mg/dL.^{68,69,71,74,75}

Hyperviscosity Syndrome

Epidemiology. Hyperviscosity syndrome (HVS) refers to the clinical syndrome of decreased blood flow and tissue hypoperfusion leading to organ dysfunction. It occurs with malignancies such as multiple myeloma, monoclonal gammopathies, and acute leukemias. It is most common in Waldenstrom macroglobulinemia and acute lymphocytic leukemia (ALL) in which up to 30% of these patients develop HVS. Most patients will already have a diagnosis of malignancy, but in some cases HVS may be their initial presentation.^76-78

Pathophysiology. HVS may be due to increased blood viscosity from excess proteins or from cell aggregations causing sluggish blood flow and tissue ischemia. Dysproteinemia from excessive amounts of immunoglobulins (Igs) is most pronounced with IgM since it the largest Ig, but dysproteinemia also occurs with IgA and IgG, which, although smaller size and molecular weight, polymerize into aggregates. This process increases blood viscosity and resistance to flow. Since the Igs are cationic, they also lower the repellant forces between anionic erythrocytes. This leads to rouleaux formations and decreased cell malleability, which further impairs blood flow and RBC transit through the microvasculature. HVS can be due to high WBCs, typically blasts, in acute leukemia, but can occur with polycythemia vera or essential thrombocytosis due to RBCs and platelets. Leukemic blasts cause capillary obstruction or limitation of flow in larger vessels not only due to their extremely high numbers, but also due to their much larger size/cell volume and decreased deformability compared to normal WBCs. Blasts also secrete cytokines (TNF and IL-1) and express specific cell adhesion molecules (VCAM-1) that cause endothelial activation and blast adhesion plus aggregation.^78-81

Presentation. Signs and symptoms may be nonspecific, but the classic triad includes neurologic abnormalities (headache, ataxia, altered mental status), visual changes (blurred vision, decreased acuity), and bleeding, which is mostly mucosal. Similar to RBCs, platelets are also coated with Ig, inhibiting their adhesion and aggregation. Concomitant thrombocytopenia may also be present. Gingival bleeding, epistaxis, uterine bleeding, petechiae/purpura, and GI bleeding are common. In addition to the microvascular involvement of the brain and retina, cardiac, pulmonary, and renal organ dysfunction may occur. Fever is invariably present with HVS due to leukemia with leukostasis. Fundoscopic examination may reveal papilledema, hemorrhages, and retinal vein engorgement, often described as "sausage links" or "boxcars." There should be a low threshold for CT imaging of the brain if headache or mental status abnormalities are present, since risk of ischemic stroke (see Figure 7) and spontaneous intracranial hemorrhage (see Figure 8) is significantly elevated.^21,76,82-84

Diagnosis. WBC count greater than 100,000/uL defines hyperleukocytosis, but it is possible to have symptomatic HVS and leukostasis at WBC counts as low as 50,000, typically with acute myelocytic leukemia (AML) since myeloblasts are larger and more rigid than lymphoblasts. It may be necessary to have the blood smear reviewed by a pathologist or hematologist, since the extreme abnormalities usually interfere with automated laboratory CBC devices. Measuring serum Ig levels and serum viscosity (SV) should be done, although the relationship between SV and clinical symptoms is not concise. The normal range for SV is 1.2–2.8 centipoise (cP). Patients only rarely become symptomatic at SV is less than 3 cP, so that a value greater than 4 cP has, by consensus, become the threshold for concern. Paraprotein (Ig) levels above 4 g/L are considered high-risk for developing HVS, and levels greater than 8 g/L virtually always produce symptoms.^8,76-78

Treatment. Crystalloid infusion will expand the intravascular volume and temporarily lower serum viscosity by simple dilution. If RBC mass is sufficient (hemoglobin > 9 g/dL) and global hypoperfusion is not present, then phlebotomy of one unit of whole blood will also rapidly improve symptoms of HVS due to either elevated protein or WBCs. Definitive treatment will be induction chemotherapy, but patients benefit from rapid cytoreduction via emergent apheresis (plasmapheresis or leukapheresis) or oral hydroxyurea, which also reduces the risk and severity of tumor lysis syndrome, leukostasis, or DIC that may occur with induction chemotherapy. Apheresis is typically accomplished after placement of a temporary hemodialysis catheter, but it can be performed adequately with lower procedural risks via two peripheral IVs of 18 g or larger. Although there is little supporting evidence, cranial radiation is still a consideration for hyperleukocytosis with CNS dysfunction due to leukostasis. A conservative transfusion policy is prudent since blood products will certainly increase SV and may exacerbate symptoms. The threshold for platelet transfusion is 20,000/uL due to the extremely high risk of CNS hemorrhage from leukostasis.^{8,21,83,85,86}

Tumor Lysis Syndrome

Epidemiology. Tumor lysis syndrome (TLS) is the release of intracellular contents of tumor cells into the circulation and the resultant metabolic derangements. It is most common with aggressive hematological malignancies with large tumor burdens such as non-Hodgkin lymphomas, ALL, and AML, but can also occur with rapidly proliferative solid tumors such as small-cell lung cancer and germ cell tumors like testicular cancer.^87-89

Pathophysiology. TLS is caused by the rapid release of intracellular products: potassium, phosphate, and nucleic acids (which form uric acid) from lysis of a large tumor burden. It may occur spontaneously, but it is much more common to occur after cancer treatments, including chemotherapy, radiation therapy, surgery, or tumor ablation procedures. The normal homeostatic metabolism is overwhelmed, leading to hyperkalemia, hyperphosphatemia, hyperuricemia, and resultant hypocalcemia (due to hyperphosphatemia). Acute kidney injury can occur due to calcium-phosphate or uric acid crystalluria with obstructive nephropathy. The risk of developing TLS is greater with pre-existing renal insufficiency or dehydration prior to initiation of cancer therapy.^87,90,91

Presentation. Clinical symptoms typically between 6–72 hours after cancer treatments were initiated, but may be delayed in patients with solid tumors. Weakness, muscle cramps with tetany, and gastrointestinal distress (nausea, vomiting, and diarrhea) are the most common complaints. Patients may also present with seizures or cardiac dysrhythmias. Oliguria may be the first indication of developing acute renal failure.^8,87,91

Diagnosis. Blood work will reveal the laboratory abnormalities of TLS.(See Table 4.) A temporal relationship with recent cytotoxic cancer treatment will often be evident unless an undiagnosed malignancy with high cell turnover results in spontaneous TLS. Serum lactate dehydrogenase (LDH) will be extremely elevated and, although it does not itself cause pathology, it is a marker for the potential severity of TLS since it indicates death of a large tumor cell burden. EKG tracings may reveal changes from hyperkalemia, such as peaked T-waves, widened QRS, ST elevation giving a pseudo-infarct pattern, or a severe sine-wave morphology (see Figure 9) or hypocalcemia such as a prolonged QT interval (see Figure 10).^3,87,89

Treatment. The initial intervention should be volume loading with isotonic crystalloid to maintain euvolemia and increase GFR, thereby potassium, phosphate, and uric acid excretion. Alkalinizing the urine (pH > 7.0) is not indicated, as it will increase the solubility of uric acid but worsen the precipitation of calcium-phosphate in the renal tubules and potentially worsen the clinical symptoms of hypocalcemia by lowering the serum ionized calcium level. Standard medical treatment for hyperkalemia should be instituted. Calcium can be replaced if the patient is symptomatic or there are EKG findings of hyperkalemia, but should be done conservatively to minimize the risk of further precipitation of calcium-phosphate. Allopurinol 300–900 mg orally may be given to prevent further uric acid production, but it does not reduce the level of uric acid or clear urate crystals already formed. Recombinant urate oxidase (rasburicase) converts uric acid to more soluble allantoin, rapidly lowering plasma uric acid and dissolving urate stones. The dose is 0.2 mg/kg (of ideal body weight) given IV. It is contraindicated in pregnancy and in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the formation of hydrogen peroxide as a catabolic byproduct of uric acid. Renal replacement therapy is indicated for symptomatic severe metabolic abnormalities, significant acute renal injury, or poor response to medical treatment.^92-95

Hyponatremia: Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Epidemiology. Hyponatremia is a common metabolic disorder occurring in approximately 5% of all cancer patients. It is most commonly a complication of malignancies of the lung, pleura (such as mesothelioma), and brain (both primary tumors and metastases). Small cell lung cancer has the highest incidence of hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH), which occurs in 10-45% of patients.^66,96,97

Pathophysiology. Low serum sodium is due to an excess of water relative to sodium, and this occurs either through water retention or sodium loss, although in most cases it is a combination of both mechanisms. Tumor cells may secrete ectopic vasopressin, also known as ADH, which increases water resorption in the distal renal tubules. The resultant volume expansion reduces aldosterone secretion, allowing for increased urinary sodium loss. ADH secretion is also significantly stimulated by nausea and pain. Iatrogenic causes of hyponatremia include SIADH from opiates, numerous psychiatric medications, vinca alkaloids (vincristine and vinblastine), and alkylating agents (cyclophosphamide and chlorambucil), while platinum-based agents cause renal salt wasting.^8,66,67,98

Presentation. The clinical symptoms of hyponatremia depend on both the severity and the rapidity with which the abnormality developed, so that a relatively small drop in serum sodium that occurred quickly may be less tolerated than a larger decrease that happened over a longer period. Early symptoms include fatigue, anorexia, nausea, and headache. Neurologic abnormalities such as confusion, lethargy, seizures, and coma happen with more severe hyponatremia. The patient may have signs of dehydration (flat neck veins, poor skin turgor) if hypovolemic hyponatremic. Signs of volume overload (peripheral edema) may be present if hypervolemic hyponatremic, although the typical presentation for SIADH is euvolemic hyponatremic.^96,97,99

Diagnosis. Hyponatremia is classified as mild (131–135 mEq/L), moderate (126–130 mEq/L), and severe (< 125 mEq/L). Serum glucose should be taken into account so that pseudohyponatremia can be detected if the patient is hyperglycemic. SIADH can be confirmed after excluding adrenal insufficiency and hypothyroidism by a serum osmolality less than 275 mOsm/kg, a urine osmolality greater than 100 mOsm/kg, and a urinary sodium greater than 40 mEq/L. Urinary studies are not accurate if the patient has recently received diuretics. An evaluation should be made of intravascular volume using objective non-invasive methods such as orthostatic vital signs, ultrasound study of inferior vena cava diameter and respiratory variation, cardiac chamber size, or invasive methods such as central venous pressure or stroke volume variation.^66,67,100

Treatment. Hyponatremia due to malignancy is treated based on the underlying cause, volume status, and the severity of symptoms. An asymptomatic patient with euvolemic hyponatremia should have their nausea and pain controlled to remove the stimulus for ADH secretion. Any possible contributing medication should be stopped and free water should be restricted to less than 1 L/day. Ultimately, the underlying malignancy should be treated. This strategy will safely increase the serum sodium slowly since the maximum in asymptomatic or mildly symptomatic patients is 10 mEq increase in 24 hours so as not to cause the devastating complication of central pontine myelinolysis, which may result in quadriparesis or the "locked-in" syndrome. In patients with severe symptoms, such as ongoing seizures or coma, 3% hypertonic saline bolus may be necessary to rapidly increase serum sodium by 5-7 mEq/L, but the sodium level should not exceed an increase of 12-15 mEq in 24 hours. For hypervolemic hypernatremic patients, in addition to free water restriction, it may be necessary to increase water excretion by administering democylcine 300–600 mg orally or a newer ADH receptor antagonist (conivaptan 20 mg IV or tolvaptan 15 mg orally). Vaptans induce a pure aquaresis that may be excessive, so urine output and serum sodium need to be monitored closely. If rapid overcorrection occurs, then oral water or hypotonic IV fluids can be administered to counter the abrupt sodium rise.^97,101,102

Adrenal Insufficiency

Adrenal insufficiency may occur during the course of illness with cancer due to metastatic spread, adrenal hemorrhage, chemotherapeutic inhibition of adrenal function, or, most commonly, suppression from exogenous corticosteroids that are used very commonly for many types of cancer treatments. If a cancer patient appears to be in circulatory shock and is not responding to volume expansion and vasopressor infusion, consider giving intravenous hydrocortisone (100–200 mg) bolus. Dexamethasone 5–10 mg can be considered if an ACTH stimulation test is planned to confirm the diagnosis or adrenal insufficiency.^66,67

Pediatric Considerations

Cancer continues to be the leading cause of death due to disease in children, only behind trauma as overall top cause of death. The types of malignancies in children differ from those in adults and vary with the age of the child. Acute leukemias are the most common cancer type in children, followed by brain tumors, and lymphomas. Neuroblastoma and Wilms’ tumor are uncommon over the age of 5 years, while Hodgkin lymphoma, which is the most common cancer diagnosed in adolescents 15-19 years old, is rare in young children.

The prognosis has improved over the last several decades, with the overall five-year survival rate for childhood cancer being greater than 70%. Symptoms of cancer in children are often vague, nonspecific, and insidious such as fever, fatigue, malaise, vomiting, and weight loss. The most common sign of lymphoma in children is adenopathy; however, in most cases the underlying cause of localized or generalized adenopathy is non-malignant disease such as infections. Enlarging nodes that become confluent, those that do not respond to antibiotic treatment, and supraclavicular adenopathy are concerning for lymphoma and deserve further consideration and evaluation.^104-107

In children with ALL and lymphoma, SVC syndrome may coexist with tracheal obstruction and is referred to as superior mediastinal syndrome (SMS). The child should be kept in a position of comfort, usually sitting upright since being placed supine may exacerbate respiratory obstructive symptoms. Sedatives and induction anesthesia must be used with extreme caution, as the resultant vasodilation and bronchial smooth muscle relaxation may induce circulatory and respiratory failure. Brain tumors in children are predominantly infratentorial and cause symptoms due to increased ICP from obstruction of CSF flow at the third or fourth ventricle. A constant occipital headache that is worse laying down and associated with vomiting is a worrisome presentation and deserves urgent evaluation. In infants and young children, signs of increased ICP include lethargy, irritability, and poor feeding, while macrocephaly may occur and can be assessed by measuring head circumference.^28,29 Dexamethasone 1 mg/kg with maximum of 10 mg should be given IV for reduction of peritumoral CNS edema while arranging urgent neurosurgical evaluation.^{8,105,108,109}

Pediatric spinal cord compression (SCC) occurs due to extension of paravertebral tumor through the neural foramina, as compared to the direct spread form vertebral body metastases in adults. These circumferential tumors are amenable to decompressive laminectomy, so that surgery is more effective in children in retaining and even regaining neurologic function. Abdominal distension may occur in infants from massive hepatomegaly due to malignant infiltration form neuroblastoma and renal tumors such as Wilms’ tumor. Abdominal compartment syndrome may ensue with mechanical compromise of the respiratory, cardiovascular, renal, and gastrointestinal systems. Emergent decompressive laparotomy may be required to enlarge the intra-abdominal volume until chemotherapy or radiation can be effective at reducing the tumor mass.^26,105,106

Conclusion

As the population ages, there will be more people living with cancer. This will certainly bring more patients to the ED for complications of their malignancy or due to its treatment. The emergency physician should contact the cancer patient’s treating physician as well as the appropriate consultant when any of these oncologic emergencies occur.

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