Postgraduate Medicine

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Emergent signs of cancer Neil Love MD To cite this article: Neil Love MD (1990) Emergent signs of cancer, Postgraduate Medicine, 88:8, 125-138, DOI: 10.1080/00325481.1990.11704773 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704773

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CME credit article

Emergent signs of cancer Recognizing them early in the office or ER

Neil Love, MD

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Preview In all medical situations, it is important to know what you are dealing with. Prompt recognition of the problem is especially crucial in patients who may have undiscovered cancer or a recurrence. The best therapy not only controls the underlying tumor but also arrests complications. Dr Love uses two illustrative case reports to describe frequently seen complications of cancer, their clinical presentations, and methods to confirm the diagnosis.

Primary care physicians have a crucial role in the early recognition of malignant rumors. In one center, 40% of all cancer cases were first identified in the emergency department. 1 Oncologic emergencies are often discussed from the clinical perspective of the patient who is known to have cancer. However, physicians may be confronted with these conditions in a patient whose cancer is not yet diagnosed. In this situation, prompt recognition and treatment are even more essential than in the "average" cancer case. This article focuses on disease mechanisms and clinical findings in two case presentations designed to reinforce physicians' awareness of these potentially catastrophic complications.

IDustrative case 1 A 60-year-old man is examined because of swelling of the face that developed over the last few days. He also is dyspneic. The patient is a heavy cigarette smoker who has had multiple bouts of exacerbated chron-

ic obstructive pulmonary disease. The chest film reveals a mass in the right upper lobe and an enlarged cardiac silhouette. COMMENT-This patient probably has primary lung cancer. Diagnostic workup must be expedited because of the possible presence of two potentially emergent conditions: superior vena cava syndrome and malignant pericardia! effusion. Both conditions may occur in newly presenting cancer patients. 2.l SUPERIOR VENA CAVA SYN-

DROME-Diagnostic and therapeutic approaches to this condition have changed dramatically in recent years. Previously, superior vena cava syndrome was considered an emergency requiring immediate radiation therapy, which was often initiated without a specific tissue diagnosis. The more recent approach is to quickly do a series of diagnostic procedures that culminate in a definitive biopsy. Subsequent antitumor therapy is individualized to the rumor's histologic characteristics.

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PATIIOGENESIS-The superior vena cava is a distensible vessel that is surrounded by several relatively rigid structures in the middle mediastinum. Superior vena cava syndrome is usually the result of extrinsic compression from contiguous mediastinal lymph nodes. Thrombosis and rumor invasion may also occur. 4 More than 90% of patients with superior vena cava syndrome have cancer (table 1); two thirds have lung cancer. The most common histologic subtype is small-cell carcinoma, which is highly sensitive to chemotherapy. 5 Benign causes are also important considerations. With the increasing use of indwelling central venous catheters, superior vena cava syndrome from thrombosis has become more common.6 CLINICAL PRESENTATION-The diagnosis is usually quite evident from swelling and venous dilatation of the face, neck, and arms. Periorbital edema and cyanosis of the face may be present. In its most dramatic form, superior vena cava syndrome may cause compromised cardiac output and laryngeal and cerebral edema. Headache and confusion may be present, and such symptoms as dyspnea may worsen when the patient leans forward, stoops, or lies down. Collateral veins may be evident on the abdominal wall, upper chest, and back. The most important initial diagnostic procedure is continued

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Superior vena cava syndrome is usually quite evident from swelling and venous dilatation of the face, neck, and arms.

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Table 1. Causes of superior vena cava syndrome Malignant Lung cancer Lymphoma Metastasis (eg, from breast, ovarian, testicular cancer) Benign Indwelling catheter, pacemaker wires Sclerosing mediastinitis (eg, histoplasmosis, tuberculosis) Benign mediastinal tumor (eg, thyroid goiter, teratoma) Vascular disorder (eg, aortic aneurysm, arteriovenous fistula) Other (eg, Behc;et's disease, mediastinal emphysema)

the chest film, which shows an abnormality in most cases. DIAGNOSis-Concerns about cardiovascular and neurologic deterioration and fears about invasive procedures in this setting led to the traditional immediate-treatment approach. However, this was reconsidered when follow-up of patients with superior vena cava syndrome showed that relatively few died of acute complications. Decades earlier, investigators had seen that collateral circulation gradually developed in patients with superior vena cava syndrome &om benign causes, and lifethreatening complications rarely ensued. It became increasingly apparent that in superior vena cava syndrome &om cancer, the usual cause of death was progressive metastases. As emphasis on identification, appropriate antitumor therapy, and treatment of the overall neoplastic condition grew, prolonged

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survival in some patients with superior vena cava syndrome became evident.' Many patients with newly diagnosed superior vena cava syndrome do not have severe symptoms, because collateral venous circulation, particularly through the azygos system (figure 1), has developed. Patients with extensive tumor leading to collateral circulation through the inferior vena cava are more likely to have life-threatening symptoms.For many patients with cancerinduced superior vena cava syndrome, the best initial treatment of the primary tumor is chemotherapy. For example, cytotoxic agents play an essential role in extending survival and relieving symptoms in many patients with small-cell carcinoma and lymphoma. For other cancers, such as non-small-cell lung cancer, radiation therapy may be the optimal initial method. Thus, a specific tissue

diagnosis is usually aggressively pursued to allow individualization of antitumor treatment. In the past, there was some reluctance to perform invasive biopsy procedures in these patients because of increased venous pressure in the thoracic cavity. However, many centers have now demonstrated that bronchoscopy, thoracentesis, mediastinoscopy, and even thoracotomy incur minimal morbidity in selected patients with superior vena cava syndrome.4 Although death is usually the result of progressive metastases, it may be caused by airway obstruction or cerebral hemorrhage. In lifethreatening situations, emergency surgical venous bypass may be attempted.' MAUGNANf PERICARDIAL EFRJSION-The

enlarged cardiac silhouette in case 1 suggests pericardia! effusion. Metastases to the heart are found in more than 10% of cancer patients during autopsy. 8 Myocardial tumor implants may occur and are usually located in the ventricles.') The most common site of cardiac metastases is the pericardium. These lesions are ofi:en silent, as evidenced by one autopsy study reporting that less than a third of patients with malignant pericardia! effusion had antemonem evidence of impaired cardiac function. 10 PATHOGENESis-In more than half of malignant pericardia! effusion cases, the primary tumor is in the lung or breast. Metastases may occur

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Most patients with malignant pericardial effusion are asymptomatic or have such nonspecific complaints as dyspnea and cough.

by lymphatic or hematogenous spread or by direct extension from mediastinal tumor. Lymphoma and leukemias are common causes in young patients.9 Hemodynamic consequences of malignant pericardia! effusion relate to a number of factors. Cardiac tamponade occurs in about one of six patients. This life-threatening complication is more likely when rapid accumulation of fluid compromises a heart whose myocardial compliance is diminished because of tumor infiltration. In this situation, as little as 200 rnL of pericardia! fluid may lead to tamponade. Impaired diastolic filling leads to a variety of adrenergic compensatory mechanisms (eg, increased peripheral vascular resistance, tachycardia, increased myocardial contractility). In more indolent cases, a liter or more of pericardia! fluid may accumulate before tamponade develops. 11 CLINICAL PRESENTATION-Most

patients with malignant pericardia! effusion are asymptomatic or have nonspecific complaints, such as dyspnea and cough (table 2). Classic findings, such as an inspiratory increase in jugular venous pressure (Kussmaul's sign) or an abnormally large inspiratory decrease in arterial systolic pressure (paradoxical pulse), are often absent. DIAGNOSis-Echocardiography is an extremely accurate method of diagnosis, although a chest x-ray film and electrocardiogram also reveal abcontinued

Figure 1. Collateral circulation of superior vena cava. a. Partial obstruction with patency of azygos system. b. Nearly complete obstruction with patency and antegrade flow in azygos system. c. Nearly complete obstruction with reversal of azygos flow. d. Complete obstruction of superior vena cava and azygos systems.

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The incidence of most common cancers increases dramatically after age 65.

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Table 2. Clinical findings In symptomatic malignant pericardia! effusion Finding Symptoms Dyspnea Cough Chest pain Orthopnea Signs Tachycardia Jugular vein distention Paradoxical pulse Hypotension Distant heart sounds Pericardia! rub Diagnostic test results Fluid on echocardiogram Abnormal finding on electrocardiogram Abnormal finding on chest film

Patients (%)

79 47 27 26 50 45 31 31 17

12 100 91

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Adapted from Press and Livingston.' p 1089.

normal findings in most cases.8 To assess the degree of cardiovascular compromise, catheterization of the right ventricle may be required. Pericardiocentesis yields positive cytologic findings in about 80% of patients with malignant pericardia! effusion. 8 This procedure may also improve cardiovascular function, even when only a small amount of fluid is removed.

illustrative case 2 A 74-year-old woman is examined because of confusion that developed

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over a 3-week period. She has been treated for progressive lower back pain for 2 months. Her medical history is unremarkable except for a mastectomy performed for cancer 6 years previously. X-ray films of the lumbar spine reveal a lyric lesion in the pedicle ofT 11. Her serum calcium level is 15 mgldL. COMMENT-Neurologic problems are the most common cancerrelated complications necessitating hospital admission. 12 This patient requires immediate evaluation for hypercalcemia, altered mentation, and

the possibility of spinal-epidural metastases. This case also demonstrates two important points in identification of patients at high risk for malignancy: • Age is one of the most important general risk factors for cancer. ~e many uncommon tumors occur m children and young adults, cancer is primarily a disease of older people. According to one analysis, 13 more than 50% of cancer cases occur in the elderly, and the incidence of most common cancers increases dramatically after age 65. • Tumors may recur many years after initial diagnosis. Most patients who survive 5 years without evidence of metastasis are considered "cured," but more delayed tumor recurrence can occur. Breast cancer is the most common example of this fascinating and clinically important phenomenon. One long-term study of more than 700 women with breast cancer14 revealed that the cause of one fourth of deaths that occurred 20 or more years after the original diagnosis was recurrent breast cancer. Therefore, any patient with a history of breast cancer must be followed closely for the emergence of metastases. BACK OR NECK PAIN-The clinical approach to this situation has changed dramatically in recent years. SPINAL-EPIDURAL METASTASis--

For more than a decade, physicians

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Many tumors causing spinal-epidural metastases are highly treatable, but effective therapy does not reverse spinal cord infarction that has already occurred.

have known that if spinal-epidural metastaSeS progress to the point of causing significant neurologic compromise, patients often fail to improve even when the offending cancer is sensitive to antitumor therapy. 15 This complication may become irreversible because the end result of rumor compression is ischemic necrosis of the spinal cord. 16 Spinal-epidural metasrases may occur with a variety of solid and hematologic malignant rumors, including many that are sensitive to systemic and radiation treatment (table 3). The most common rumor location is the thoracic area, but multiple deposits may be present. Spinal-epidural metastaSeS may be the initial manifestation of a primary cancer or of delayed rumor recurrence. In one series, 15 10% of cases of spinal cord compression in breast cancer patients were diagnosed 12 or more years after mastectomy. Although spinal cord or cauda equina compression may occur from intradural metastaSeS or extension of paravenebral masses, most of these patients have bone involvement, which is usually evident on x-ray films.16

CLINICAL PRESENTATION-Neck

or back pain, which may be radicular, is the earliest manifestation of spinal-epidural metastaSeS. The pain often precedes neurologic dysfunction by weeks to months. 15 If the

Table 3. Site of spinal cord compression by primary tumor Primary tumor

Cervical (%)

Thoracic (%)

Lumbosacral (%)

Breast Lung Prostate Lymphoma Melanoma Gastrointestinal

14 38 14 13 14 0

79 57 71 63 57 40

7 5 14 25 29 60

Adapted from Gilbert et a/, " p 42.

natural history of spinal-epidural metastaSeS is not altered by treatment, ischemic myelopathy causes upper motor neuron weakness and spasticity. Untreated patients may become paraplegic or quadriplegic. Therapy at this late stage rarely results in significant rerum of neurologic function. DIAGNOSis-The poor response to treatment of neurologic dysfunction from spinal-epidural merasrases led clinicians to focus on earlier diagnosis. The current approach is to make the diagnosis in patients presenting solely with pain before a neurologic deficit develops. At this point, corticosteroids and radiation therapy often prevent the development of neurologic dysfunction. 15 Surgical laminectomy is usually performed only if a tissue diagnosis has not been established, the patient has previously received maximal radia-

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cion therapy, or the rumor is considered radioresistant. If the new onset of neck or back pain in a cancer patient does not have a benign explanation, the following questions must be addressed immediately 7: • Is any neurologic deficit present? • Is there radiologic evidence of vertebral rumor? • Is the pain radicular? An affirmative answer to any of these questions requires immediate oncologic or neurologic consultation. High-dose corticosteroid therapy is ofren initiated until definitive procedures (eg, myelography, computed tomography [en, magnetic resonance imaging [MRI]) are completed. Many rumors causing spinalepidural merasrases are highly treatable, but effective antitumor therapy does not reverse spinal cord infarction. An astute clinician who apprecontznued

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Initial symptoms of the syndrome of inappropriate antidiuretic hormone are fatigue and headache, which may progress to confusion, psychosis, and coma.

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Table 4. Common causes of confusion in cancer patients Primary or metastatic lesion of brain Meningeal carcinomatosis Paraneoplastic syndrome Metabolic encephalopathy (eg, hypercalcemia, hyponatremia, hypoglycemia) Vascular disorder (eg, embolism from marantic endocarditis, hemorrhage from disseminated intravascular coagulation, thrombosis from hypercoagulable state) Opportunistic factor (eg, infection, cerebral abscess) Medication use (eg, glucocorticoids, chemotherapy, narcotic analgesic)

Table 5. Common causes of the syndrome of inappropriate antidiuretic honnone in cancer patients

Pulmonary disease Infection (eg, pneumonia, lung abscess) Tumor (without ectopic production) Central nervous system disorder Tumor Seizures Infection (eg, meningitis, abscess) Intracranial hemorrhage Medication use (eg, opiates, cyclophosphamide [Cytoxan, Neosar]. vincristine sulfate [Oncovin, Vincasar PFS]) Adapted from Silverman and Distelhorst, •• p 510.

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METASTATIC DISEASE TO THE BRAIN-This is a primary considera-

tion with altered mental status and is usually quite evident on MRI or Cf scanning of the brain. Early diagnosis is essential to prevent neurologic deterioration. Most lesions are accompanied by significant cerebral edema. Often, these patients experience rapid temporary resolution of neurologic impairment when treated with high doses of corticosteroids. MALIGNANCY-ASSOCIATED HYPER-

Ectopic production (eg, small-cell lung cancer)

ciates this pathophysiologic fuct may have a notable impact on the patient's quality oflife after treatment. AliERED MENTAL STATU~The earliest manifestation of this problem may be subtle behavioral changes detected by fumily members. Untreated patients may be-

many of the causative fuctors are reversible with prompt recognition and treatment.

come lethargic, confused (table 4), or comatose. Although always a challenge, differential diagnosis and treatment are particularly complex in elderly patients, who may have coexistent nonneoplastic diseases and may be taking several medications. 18 Of great importance is the fuct that

CALCEMIA-Metabolic encephalopathy, which may result ftom a variety of conditions, is another frequent cause of altered mentation in cancer patients. Malignancy-associated hypercalcemia is the most common of these conditions and occurs in about 10% of cancer patients. 19 Lung and breast cancer account for more than half of all cases of malignancy-associated hypercalcemia, but it occurs with less common tumors (eg, multiple myeloma, renal cancer, T-cell lymphoma, cholangiocarcinoma) as well. Several pathogenic mechanisms have been described to explain the condition, all of which cause increased bone resorption. 20.2 1 One theory is that local tumor fuctors are elaborated in patients with osteolytic bone metastases. The result is "leakage" of calcium into the circulation. continued

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The most effective therapy for all cancerrelated complications is eradication or control of the underlying tumor.

Neil Love, MD Dr Love is associate professor of oncology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine. His primary career interest is writing and production of medical education materials.

Patients without bone metastaSeS apparently secrete a parathyroid hormone-like substance systemically. Initial clinical presentation of hypercalcemia is often nonspecific and unrecognized. Neurologic symptoms (eg, confusion) usually predominate. Patients also may describe polyuria and polydipsia, which are secondary to nephrogenic diabetes insipidus induced by malignancy-associated hypercalcemia. This diuresis may exacerbate hypercalcemia by causing volume depletion and renal retention of calcium. The severity of clinical symptoms usually reflects the

magnitude of the ionized calcium level, the rapidity of evolution of the process, and the patient's general medical condition. HYPONATREMIA-This is another important cause of metabolic encephalopathy in cancer patients. A key factor in assessing hyponatremia is the patient's volume status. Cancer patients experience decreased effective intravascular volume from a variety of causes (eg, vomiting, diarrhea, ascites, ileus, congestive heart failure). These conditions result in increased secretion of antidiuretic hormone (ADH), retention of free water, and hyponatremia. Another cause of decreased serum sodium is pseudohyponatremia, which may occur with paraproteinemias (eg, multiple myeloma). A primary consideration in any cancer patient with hyponatremia and normal adrenal and renal function is the syndrome of inappropriate ADH. This syndrome should be suspected in normovolemic patients with hyponatremia and inappropriately concentrated urine. Initial symptoms include fatigue and headache, which may progress to confusion, psychosis, and coma. Many causative mechanisms have been described for the syndrome of inappropriate ADH in cancer patients (table 5). It is often a paraneoplastic consequence of ectopic hormone production. As with all cancer-related complications, it is best treated by reducing or eliminat-

continued on page 138 132

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ing the rumor. For example, chemotherapy is extremely effective in patients with small-cell lung cancer, a common cause of this syndrome. Water restriction and demeclocycline hydrochloride (Declomycin) are effective supportive measures and are particularly useful when the primary rumor is difficult to eradicate. HYPOGLYCEMIA-Another cause of abnormal mentation in cancer patients, hypoglycemia is most commonly the result of an insulin-producing pancreatic islet cell rumor. Hypoglycemia in non-islet cell tumors may be the result of a humoral mediator, such as insulinlike growth factor 11. 22 This substance appears to cause hypoglycemia by increasing consumption of glucose in peripheral tissue and the rumor itself It also impairs hepatic glucose output mediated by growth hormone. 22 Large, slow-growing, mesenchymal rumors (eg, mesothelioma, retroperitoneal sarcoma, hemangiopericytoma) may also produce hypoglycemia. As with all cancer-related complications, the most effective therapy of hypoglycemia is eradication or control of the underlying tumor.

Summary Primary care physicians have a crucial role in recognition of potentially emergent conditions in

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patients with known or suspected cancer. This task presents a significant challenge because the initial manifestations of these conditions are usually nonspecific. In most cases, therapy is far more effective when diagnosis is made at the earliest possible point. Thus, physicians should become f.uniliar with conditions commonly seen in cancer patients, such as superior vena cava syndrome, malignant pericardial effusion, spinal-epidu-

References 1. Han KH, Bradburn OM. Initial presentation of malignant disease to accident and emergency departments. Br J Clin Pract 1987;41 (12): 1056-8 2. Schraufnagel DE, Hill R, Leech JA, et a!. Superior vena caval obstruction: is it a medical emergency' Am J Med 1981;70(6):1169-74 3. Aggarwal P, Shanna SK. Cardiac tamponade as the initial presentation of malignancy. lnt J Cardiol 1989;22(2): 157-9 4. Nieto AF, Doty DB. Superior vena cava obstruction: clinical syndrome, etiology, and treatment. Curr Probl Cancer 1986;10(9):441-84 5. Perez CA, Presant CA, Van Amburg AL 3d. Management of superior vena cava syndrome. Semin Oncol1978;5(2):123-34 6. Sculier JP, Feld R Superior vena cava obstruction syndrome: recommendations for management. Cancer Treat Rev 1985; 12(3):209-18 7. Stanford W, Doty DB. The role of venography and surgery in the management of patients with superior vena cava obstruction. Ann Thorac Surg 1986;41 (2): 158-63 8. Press OW, Livingston R. Management of malignant pericardia] ef!Usion and tamponade. JAMA 1987;257(8): I 088-92 9. SkhvatsaJ,aja LV. Secondary malignant lesions of the heart and pericardium in neoplastic disease. Oncology 1986;43(2): I 03-6 10. Thurber DL, Edwards JE, Achor RW. Secondary malignant tumors of the pericardium. Circulation 1962;26(Aug):228-41 11. Helms SR, Carlson MD. Cardiovascular emergencies. Semin Oncol1989;16(6):463-70 12. Gilbert MR, Grossman SA. Incidence and na-

ral metastasis, and altered mentation from brain metastases, metabolic encephalopathy, or hypoglycemia. ~



Earn credit on this article. See CME Quiz.

Address for correspondence: Neil Love, MD, University of Miami School of Medicine, Calder Medical Library (R-950), PO Box 016950, 1601 NW lOth Ave, Miami, FL 33101.

ture of neurologic problems in patients with solid rumors. Am J Med 1986;81(6):951-4 13. Baranovsky A, Myen MH. Cancer incidence and survival in patients 65 years of age and older. CA 1986;36(1):26-41 14. Brinkley D, Haybittle JL. Long-term survival of women with breast cancer. (Letter) Lancet 1984; 1(8386): 1118 15. Gilbert Rw; KimJH, Posner JB. Epidural spinal cord compression &om metastatic rumor: diagnosis and treatment. Ann Neurol1978;3(1): 40-51 16. WdlsonJK, Masaryk 1). Neurologic emergencies in the cancer patient. Semin Oneal 1989; 16(6):490-503 17. Portenoy RK, Lipton RB, Foley KM. Back pain in the cancer patient: an algorithm for evaluation and management. Neurology 1987;37(1): 134-8 18. McCachren SS, Silbertoan HR Approach to oncologic emergencies in the elderly. Clin Geriatr Med 1987;3(3):575-86 19. Silverman P, Distelhorst CW. Metabolic emergencies in clinical oncology. Semin Oneal 1989; 16(6):504-15 20. lnsogna KL, Broadus AE. Hypercalcemia of malignancy. Annu Rev Med 1987;38:241-56 21. Mundy GR. Pathogenesis of hypercalcaemia of malignancy. Clin Endocrinol (Oxf) 1985;23(6): 705-14 22. Axelrod L, Ron D. Insulin-like growth factor II and the riddle of rumor-induced hypoglycemia. (Editorial) N EnglJ Med 1988;319(22):1477-9

CANCER • VOL 88/NO 8/DECEMBER 1990/POSTGRADUATE MEDICINE

Emergent signs of cancer. Recognizing them early in the office or ER.

Primary care physicians have a crucial role in recognition of potentially emergent conditions in patients with known or suspected cancer. This task pr...
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