Review of Hematology-Oncology Emergencies for Internal Medicine Residents

The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer continues to increase. Internal medicine residents can see patients admitted to the hospital for cancer-related emergencies. Early identification and appropriate management of these emergencies have been shown to improve mortality and morbidity. In this article, we aim to review the recent updates in the management of commonly encountered oncologic emergencies in the practice of internal medicine residents. This review will cover spinal cord compression, superior vena cava syndrome, tumor lysis syndrome, hypercalcemia, pericardial tamponade, hypoglycemia, hyponatremia, bowel obstruction, increased intracranial pressure, leukostasis, hyperviscosity syndrome, neutropenic fever, and hypersensitivity reactions.


Introduction And Background
In 2020, an estimated 1,806,509 new cases of cancer were diagnosed in the United States, with 606,520 anticipated deaths. Cancer mortality rates have decreased since the early 1990s, with 1.8% per year among men and 1.4% per year among women. As such, the number of survivors has increased. As of January 2019, there were an estimated 16.9 million cancer survivors, an increase of 22.2 million by 2030 [1]. Some oncologic emergencies are insidious and take months to develop, whereas others manifest over hours, causing significant mortality and morbidity [2]. Prompt identification of these emergencies and timely intervention can improve survival and the quality of life [3]. Internal medicine residents should be aware of the following hematology-oncology emergencies, which they are likely to encounter during their training and later on, in independent practice: spinal cord compressions, superior vena cava (SVC) syndrome, tumor lysis syndrome (TLS), hypercalcemia, pericardial tamponade, hypoglycemia, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, bowel obstruction, increased intracranial pressure (ICP), leukostasis, hyperviscosity syndrome, neutropenic fever, and hypersensitivity reactions. In this article, we provide a review of these emergencies.

Review Spinal cord compression
Metastatic spinal cordcompression is a catastrophiconcologicemergencythat occurs in10%-20% of patientswith cancer. It promptsearly diagnosis and treatment topreserve the quality of life, including the prevention of functional loss.Reportedly, up to 21% of patients experience spinal cord compression due to metastasis as a diagnostic event [4,5]. Prostate, lung,breast, renalcell cancer, multiple myeloma, and Hodgkin lymphoma are some that can lead to spinal cord compression [5].Varied clinical presentations pose a diagnostic challenge. New onset back pain, with or withoutfocalneurologicaldeficits, is some of the common symptoms.Patients without neurologicaldeficitsshould be evaluated within 24-48hof symptoms onset, whereas thosewith neurologicaldeficits should beevaluated promptly. Magnetic resonance imaging (MRI) and computed tomography (CT) myelograms are the mainstays in diagnosis [6].Treatment consists of steroids, radiation therapy (RT), chemotherapy, andsurgery.A standard dose of steroids (16 mg dexamethasone IV bolus followedby 4-6 mg Q4-6 H) followed by rapid tapering after initiatingRT is preferred early in management. Spine instability neoplastic scores ( Table 1)is avaluabletool that can be used universally to determine the need for surgical stabilization. A score ≥ 7 in these patients warrantsimmediate neurosurgical evaluation and possible intervention. Management often requires a multimodal approach afterdiscussing the goals of care with the patient [5][6][7].

Location
Junctional (occiput-C2, T7-T2, T11-L1m L5-S1)  3   Mobile spine (C3-C6, L2-L4)  2 Semirigid spine (T3-T10) 1 Rigid spine (S2-S5) 0 Pain with recumbency and /or movement of the spine Yes 3 Occasional, but not mechanical 1  Although selective venography is the gold standard test, chest CT with contrast is preferred, given its availability and with a sensitivity and specificity of 96% and 92%, respectively [2,3,7].Vein dilation, a pathognomonic sign of SVC, can take up to two weeks to develop [3].The treatment depends on the etiology and severity of the symptoms [8]. Airway protection and endovascular stenting remain a mainstay in emergencies. Surgery, palliative or active chemotherapy, and radiotherapy are other options in nonemergent cases. Treatment of SVC caused by thrombosis involves thrombolysis and/or device removal.

Tumor lysis syndrome
TLS results from the release of contents from cancer cells, resulting in hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia.TLS is most common in patients with hematologic malignancies andsolid tumors (small cell lung cancer, germ cell tumors, inflammatorybreast cancer, and melanoma) [7,8].It can be provoked bychemotherapy, RT, surgery, or ablation, occurring soon after treatmentordelayedbyseveral weeks.
The expert risk panel developed a risk stratification tool dividing all patients at low (<1% chance of TLS), medium (1%-5%), and high risk (>5%) based on age, histology, the extent of disease, type of cytotoxic agents used, andpretreatmentrenalfunction [8,9]. The medium-risk patients are recommended to have adequate hydration and allopurinol for the primary prevention of TLS, while high-risk patients are recommended Rasburicasein addition [8,10,11].

Hypercalcemia
The incidence of hypercalcemia in malignancy has been reported to be between 10%-33% [12]. Hypercalcemia is most commonly caused by humoral mechanisms (80%) and osteolytic metastases (20%) [2]. Humoral mechanisms include the secretion of parathyroid hormone-related protein (PTHrP) or extrarenal 1,25 dihydroxy vitamin D (calcitriol).PTHrP can be secreted by squamous cell carcinoma, breast cancer, renal carcinoma, prostate cancer, melanoma, and neuroendocrine tumors. It binds to parathyroid hormone (PTH) receptors in bones and kidneys, enhancing bone resorption and calcium retention [13]. Increased production of calcitriol occurs almost exclusively in Hodgkin and non-Hodgkin lymphomas due to the expression of the 1-alpha-hydroxylase enzyme in macrophages. Rarely, ectopic PTH production by ovarian/lung cancers and some neuroendocrine tumors can occur. At the same time,osteolytic bone metastases increase calcium levels in multiple myeloma, leukemia, and metastatic breast carcinoma.
Hypercalcemia of malignancy is severe due to very high calcium (serum calcium >14 mg/dL, >3.5 mmol/L), occurring over weeks to months. Symptoms are usually nonspecific, including anorexia, nausea, vomiting, apathy, constipation,polydipsia, polyuria, abdominal pain, and muscle weakness. Severe cases may result in neuropsychiatric manifestations like malaise and lassitude, progression to confusion, and coma. QT interval shortening and dysrhythmias may also occur [12].
Initial workup includes ionized calcium, albumin, PTH,PTHrP, 25-hydroxyvitamin D, and calcitriol levels. In humoral hypercalcemia of malignancy,PTHrPis elevated, with low to low-normal PTH, phosphorus, and calcitriol. Metastatic causes result in low PTH and calcitriol, with undetectablePTHrP. Lymphoma with increased calcitriol levels also demonstrated low 25-hydroxyvitamin D and undetectablePTHrP [12].
Treatment includes hydration using intravenous isotonic saline (initial 1-2 L bolus, followed by continuous fluids). After euvolemia is achieved, intravenous Lasix is initiated 1-2 times/day to facilitate calcium excretion, especially in patients with oliguric renal failure, congestive heart failure, or symptomatic volume overload following aggressive hydration. Intramuscular or subcutaneous calcitonin is then administered. The onset of action occurs within 4-6 hours, and the effect lasts up to 48-72 h.Calcitonin acts by inhibiting osteoclasts and enhancing urine calcium excretion. However, the standard of careisan intravenous bisphosphonate (pamidronate/zoledronate), with an onset of action within 2-4 days until which calcitonin exerts its effect. Zoledronate is ~1,000 times more potent than pamidronate because of the superior inhibition of osteoclastic enzymes. Some adverse effects include fever, bone pain during infusion, osteonecrosis of the maxilla and mandible (<1% of patients), uveitis, and nephrotoxicity. Bisphosphonatesshould be renally dosed andgenerally avoided in patients with GFR <30 mL/min. Glucocorticoids are reserved forcalcitriol-mediated hypercalcemia because they inhibit 1-alpha hydroxylasemediated calcitriol production.Denosumab (receptor activator of nuclear factor kappa-Β ligand (RANKL) antibody that inhibits osteoclast maturation and activation) is used to manage bisphosphonate-resistant malignant hypercalcemia [14]. Dialysis is reserved for refractory cases.The prognosis is poor, with a median survival time of 35 days [2].
Pericardial mesothelioma, lung cancer, andlymphoma are the most common causes of malignant pericardial effusion [15].It canalsodevelop as a complication of RT. Diagnostic tests that detect pericardial effusion includechest radiography (bottle-shapedheart), electrocardiogram, point-of-care ultrasonography,orCT. Every patient with signs, symptoms, or additional workup suggestive of pericardial effusion should undergo the bedside echocardiogramto evaluate for ultrasound signs of tamponade: diastolic right ventricular collapse, and systolic right atrial collapse, plethotic, non-collapsible inferior vena cava, and dondgraphic pulsus paradosux [16].
Hemodynamically unstable patientsrequire emergency pericardiocentesis. Pericardiocentesis under echocardiographicguidance is recommended in nonemergent cases. The recurrence rate is decreased in pericardiocentesis with extended catheter drainage or balloonpericardiotomy. Patients should be treated for primary malignancy (chemotherapy vs. RT). Alternative treatment options for recurrent effusions include pericardial window,pericardiectomy, catheter placement,balloon pericardiotomy, andpericardial sclerotherapy [3,15].

Hypoglycemia
Hypoglycemia is a blood glucose level < 72 or 4 mmol/L. It causes various autonomic symptoms, such as paresthesia, sweating, palpitations, weakness, mydriasis, tremor, hunger, tachycardia, and anxiety due to adrenergic counter-regulation, and neuroglycopenic symptoms such as irritability, dizziness, blurring of vision, confusion, altered mental status, transient focal neurological deficits, seizures, and coma. The most common malignant causes of hypoglycemia include excessive insulin production (insulinomas), pancreatic beta-cell dysfunction (nesidioblastosis), and hypersecretion of catecholamines (pheochromocytoma) and insulin-like growth factor (IGF) (IGF-2 by sarcomas, gastrointestinal stromal tumors, solitary fibrous tumors, and IGF 3 by lung cancer). Altered metabolism due to parenchymal destruction in hepatocellular carcinomas and increased consumption in rapidly multiplying neoplasms (Burkittlymphoma, small cell lung cancer) are other causes [3,17]. Diagnosis involves history, clinical signs andsymptoms, and physical examination. Whipple's triad includes low blood glucose levels, symptoms of hypoglycemia, and relief of symptoms with the restoration of normal blood glucose levels.
When there is high clinical suspicion without symptoms or hypoglycemia, patients should undergo a 72hour fasting test. Insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels should be measured during hypoglycemic episodes. IGF-1,2 is measured if other results are non-diagnostic.
CT, transabdominal ultrasound (US), and MRI are used to diagnose insulinomas [18]. Endoscopic US and fine-needle aspiration may be required if localization is not possible noninvasively. A selective arterial calcium stimulation test with hepatic venous sampling can be used to distinguish insulinomas from nesidioblastosis and islet cell hypertrophy [19]. Acute hypoglycemia is managed with 25g of 50% dextrose intravenously. 0.5-1.0 mg of subcutaneous, intramuscular, or intranasal glucagon can be administered until intravenousaccess is established.
Surgical tumor removal is the optimal approach to avoid future hypoglycemic episodes. Medical management of insulinoma includes diazoxide, octreotide, orlanreotide. Diazoxide decreases insulin secretion but can cause marked edema and hirsutism [20]. Diazoxide and somatostatin analogs do not play a role in non-islet cell tumors. Non-selective beta-blockers are sometimes used to reduce the sympathetic symptoms of hypoglycemia. The mainstem of treatment for unresectable tumors is chemotherapy or RT (to decrease hormonal activity) andglucocorticoids, with frequent carbohydrate intake to control hypoglycemic symptoms. For hypoglycemia, refractory to high-dose glucocorticoids, long-term intravenous glucagon infusion, or recombinant human growth hormone (prevents IGF binding to insulin receptors) is an option. However, growth hormones can also increase IGF-1 levels and tumor growth [21].

Hyponatremia
Hyponatremia is defined as a serum sodium level <135mEq/L. The incidence of hyponatremia is the highestwith small-cell lung cancer [22].Per observational studies, hyponatremia is associated with extended hospital stays and increased mortality among cancer patients [23].

Bowel obstruction
Bowel obstruction is a frequent complication in advanced malignancies. It may be caused by intrinsicor extrinsiccompression by the tumor (colonic, pancreatic,ovarian, or stomach), ascitic fluid (peritoneal carcinomatosis), postsurgical and radiotherapy adhesions, or due to opioids [26].
The initial management steps are to keep the patient nil per oral, place a nasogastric tube (NGT) for decompression,and use intravenous fluids to cover gastrointestinal loss, antiemetics, and correction of electrolyte and acid-base disorders. Surgical evaluation is required immediately, followed by abdominal CT. Prokinetic agents may be beneficial in partial obstruction, and some studies have demonstrated successful corticosteroid application for short-term relief from malignant obstruction. Emergent surgery is indicated if bowel necrosis/perforation is suspected [27].Uncomplicated obstructioncan bemanaged by surgical resection of the tumor withanastomosis, proximaldiversionwithan ostomy, or bypass. Self-expanding metal stents can be placed if surgical intervention is not possible [28].Some trials have demonstrated the effectiveness of somatostatin analog,lanreotide,as an antiemetic in inoperable obstruction caused by peritonealcarcinomatosis, allowing for the removal of the NGT to optimize patient comfort [29].

Increased ICP
About20%-40%of cancer patients are at risk of developing brain metastases [30]. Melanoma, lung, renal, breast, and colon cancers are thecommon primary tumors to metastasize.Increased ICP is usually caused by the mass effect of primary and metastatic brain tumors, vasogenic edema from increased vascular permeability, or inflammatory reaction secondary to RT [30,31]. Elevated ICP is managed with dexamethasone 10-24 mg IV bolusfollowed by 4 mg every 6-8 h.Mannitol, an osmotic diuretic, can be used temporarily in patients without dehydration. Intubation with hyperventilationisreservedfor patients withrapidly declining mentation asa bridgingtherapy to emergent craniotomy [32].
Definitive treatment likestereotactic radiation therapy, surgery, and systemic or intrathecal chemotherapy (lymphomas,germ cell tumors, and small cell carcinoma)isoften necessary to reduce tumor burden.Whole-brain radiationis reservedfor patients with poor prognoses due to adverse neurological effects [31].

Leukostasis
Leukostasisis associated with leukocytosis and is often seeninacute myelocytic leukemia (AML) (5%-13%) or acute lymphocytic leukemia (ALL) (10%-30%) [3,33].The most common subtypes areM3,M4, and M5 of AML,ALL with 11q23 mutation, or Philadelphia chromosome [3,33].Children, especially infants, are the most affected, with up to 40%mortality if not treated timely [3]. The pathophysiology involvesincreased blood viscosity, complement-mediated granulocyte aggregation, and the interaction between leukemic blasts and endothelium. The severity of symptoms depends on the cell size (more pronounced in AML) and response to chemotactic cytokines but is not related to the number of blasts [3,34].

Hyperviscosity syndrome
Hyperviscositycan be observed indisorders of theserum andwhole bloodcomponents. The size and shape of the proteins in serum determine their contribution to viscosity. IgM protein has a large axial length and increases viscosity more than IgG and IgA immunoglobulins. Common causes include Waldenstrom macroglobulinemia (WM), multiple myeloma, rituximab IgM flare, type I and IIcryoglobulinemia, polycythemiavera,HbSS, CLL, chronic myeloid leukemia (CML), and ALL. Increased immunoglobulins causing hyperviscosity are also seen in human immunodeficiency virus (HIV) infection, Sjogren's syndrome, high titers of rheumatoid factor, and IVIg infusions [35][36][37].
The classic presentation ofhyperviscosityisseenwith the triad of visual changes(retinal hemorrhages,papilledema),neurological abnormalities (seizure, ataxia, cerebralhemorrhage), and mucosal bleeding (gingival bleeding, epistaxis). Involvement of the cardiovascular system, such as high-output cardiac failure with paraproteins >8 g/L, may also be present. Symptoms occur especially with a paraprotein level of 5-8 g/L [35].
Treatment depends on the presence of symptoms and viscosity levels, and apheresis is considered the gold standard ( Figure 1) [35]. Although not required insymptomatic patients, plasma viscosity measurement helps in guiding treatment.Plasma exchange can effectively reduce 30%-50% viscosityin one session. Daily or every other day, plasma exchange is repeated until symptoms abate (1-3 procedures). Typically, one session is enough to reduce plasma viscosity to levels where mucosal hemorrhage will not occur [35,38,39].Phlebotomy may beusedif plasmapheresis isunavailable. For asymptomatic patients,systemic chemotherapy can be considered. For example, bortezomib-based oribrutinib-rituximab-based treatment effectively decreases protein levels inpatients with WM [38,40].
The initial workup includes a complete blood count,twosets ofblood cultures, cultures of thesuspected sourceof infection (urine, sputum, etc.), basic metabolic panel, liver function tests,andlactatelevels [3]. Several tools have been developed to estimate the necessity of hospital admission for patients with neutropenic fever, such as the Multinational Association of Supportive Care in Cancer (MASCC) index ( Table  2), clinical index of stable febrile neutropenia (CISNE) prognostic class ( Table 3), and Talcott grouping. Talcott classification contains four groups: first group is inpatient, second is outpatient with active comorbidity requiring admission, third is patient without comorbidity and uncontrolled cancer, and fourth is outpatient with well-controlled cancer and no comorbidities. Patients withMASCCindexover21,Talcottgroup 4, andCISNEpoint less than2 meet the outpatientmanagement criteria. They can be treated empirically withacombinationof fluoroquinolones andamoxicillin/clavulanate.Clindamycin may be used in patients allergic to penicillin.Further evaluation is advised ifthe fever recurs or persists after 48 hours [42,43].

Score
Burden of febrile neutropenia with no or mild symptoms 5 No hypotension (systolic blood pressure > 90 mmHg) 5 No chronic obstructive pulmonary disease 4 Solid tumor or hematologic malignancy with no previous fungal infection 4 No dehydration requiring parenteral fluids 3 Burden of febrile neutropenia with moderate symptoms 3 Outpatient status 3 Age <6o years 2  Inpatient treatment is recommended for those who fulfill the criteria or fail outpatient treatment. Ideally, treatment should be started within one hour of presentation withintravenousbroad-spectrumantibioticswith pseudomonal coverage(cefepime, piperacillin-tazobactam,and meropenem), even if risk stratification has not been completed [41]. Delays in initiating antibiotics have been correlated with an increase in the length of hospital stay [42].Vancomycin can be added for suspected catheter-related infections, skin and soft tissue infections, pneumonia, and hemodynamicinstability.Antibiotics are modified once culture results are available.
In severe cases, the infusion must be stopped. Intramuscular epinephrine (0.3-0.5 mg, can be repeated at 3-5 min) should be administered with supportive measures of oxygen supplementation, intravenous fluids, steroids, andantihistamines.In mild cases, the infusion should be temporarily discontinued while administering diphenhydramine and steroids. Infusion canbe restarted ata slowrate, with close patient monitoring if symptoms resolve.
Recent studies have shown the merits of risk-stratifying patients who develophypersensitivity reactionsafter the first drug exposure. Patients with mild or delayed reactions can be desensitized or rechallenged with the treatment agent. It is beneficialin patients with promising responses to chemotherapy or who have limited treatment options [47,48].

Conclusions
In this review article, we covered the most common hematology and oncology emergencies that internal medicine residents can encounter during their practice. Unfortunately, the onset of cancer complications can be insidious and well ahead of symptoms caused by the tumor itself. Thus, proper diagnosis and treatment can be delayed, potentially leading to death or significant morbidity. This review covers several oncology and hematology emergencies and will be helpful to early internal medicine trainees to get familiar with diagnostic and treatment modalities.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Intellectual property info: The copyright rights to reproduce table 1 (Spine Instability Neoplastic score),