SUPERIOR VENA CAVA SYNDROME
Superior vena cava syndrome (SVCS) is the clinical manifestation of superior vena cava (SVC) obstruction, with severe reduction in venous return from the head, neck, and upper extremities. Malignant tumors, such as lung cancer, lymphoma, and metastatic tumors, are responsible for the majority of SVCS cases. With the expanding use of intravascular devices (e.g., permanent central venous access catheters, pacemaker/defibrillator leads), the prevalence of benign causes of SVCS is increasing now, accounting for at least 40% of cases. Lung cancer, particularly of small cell and squamous cell histologies, accounts for approximately 85% of all cases of malignant origin. In young adults, malignant lymphoma is a leading cause of SVCS. Hodgkin's lymphoma involves the mediastinum more commonly than other lymphomas but rarely causes SVCS. When SVCS is noted in a young man with a mediastinal mass, the differential diagnosis is lymphoma vs primary mediastinal germ cell tumor. Metastatic cancers to the mediastinum, such as testicular and breast carcinomas, account for a small proportion of cases. Other causes include benign tumors, aortic aneurysm, thyromegaly, thrombosis, and fibrosing mediastinitis from prior irradiation, histoplasmosis, or Behçet's syndrome. SVCS as the initial manifestation of Behçet's syndrome may be due to inflammation of the SVC associated with thrombosis.
Patients with SVCS usually present with neck and facial swelling (especially around the eyes), dyspnea, and cough. Other symptoms include hoarseness, tongue swelling, headaches, nasal congestion, epistaxis, hemoptysis, dysphagia, pain, dizziness, syncope, and lethargy. Bending forward or lying down may aggravate the symptoms. The characteristic physical findings are dilated neck veins; an increased number of collateral veins covering the anterior chest wall; cyanosis; and edema of the face, arms, and chest. More severe cases include proptosis, glossal and laryngeal edema, and obtundation. The clinical picture is milder if the obstruction is located above the azygos vein. Symptoms are usually progressive, but in some cases, they may improve as collateral circulation develops.
Signs and symptoms of cerebral and/or laryngeal edema, though rare, are associated with a poorer prognosis and require urgent evaluation. Seizures are more likely related to brain metastases than to cerebral edema from venous occlusion. Patients with small cell lung cancer and SVCS have a higher incidence of brain metastases than those without SVCS.
Cardiorespiratory symptoms at rest, particularly with positional changes, suggest significant airway and vascular obstruction and limited physiologic reserve. Cardiac arrest or respiratory failure can occur, particularly in patients receiving sedatives or undergoing general anesthesia.
Rarely, esophageal varices may develop. These are "downhill" varices based on the direction of blood flow from cephalad to caudad (in contrast to "uphill" varices associated with caudad to cephalad flow from portal hypertension). If the obstruction to the SVC is proximal to the azygous vein, varices develop in the upper one-third of the esophagus. If the obstruction involves or is distal to the azygous vein, varices occur in the entire length of the esophagus. Variceal bleeding may be a late complication of chronic SVCS.
The diagnosis of SVCS is a clinical one. The most significant chest radiographic finding is widening of the superior mediastinum, most commonly on the right side. Pleural effusion occurs in only 25% of patients, often on the right side. The majority of these effusions are exudative and occasionally chylous. However, a normal chest radiograph is still compatible with the diagnosis if other characteristic findings are present. Computed tomography (CT) provides the most reliable view of the mediastinal anatomy. The diagnosis of SVCS requires diminished or absent opacification of central venous structures with prominent collateral venous circulation. Magnetic resonance imaging (MRI) has no advantages over CT. Invasive procedures, including bronchoscopy, percutaneous needle biopsy, mediastinoscopy, and even thoracotomy, can be performed by a skilled clinician without any major risk of bleeding. For patients with a known cancer, a detailed workup usually is not necessary, and appropriate treatment may be started after obtaining a CT scan of the thorax. For those with no history of malignancy, a detailed evaluation is essential to rule out benign causes and determine a specific diagnosis to direct the appropriate therapy.
TREATMENT: Superior Vena Cava Syndrome
The one potentially life-threatening complication of a superior mediastinal mass is tracheal obstruction. Upper airway obstruction demands emergent therapy. Diuretics with a low-salt diet, head elevation, and oxygen may produce temporary symptomatic relief. Glucocorticoids may be useful at shrinking lymphoma masses; they are of no benefit in patients with lung cancer.
Radiation therapy is the primary treatment for SVCS caused by non-small cell lung cancer (NSCLC) and other metastatic solid tumors. Chemotherapy is effective when the underlying cancer is small cell carcinoma of the lung, lymphoma, or germ cell tumor. SVCS recurs in 10–30% of patients; it may be palliated with the use of intravascular self-expanding stents (Fig. 54-1). Early stenting may be necessary in patients with severe symptoms; however, the prompt increase in venous return after stenting may precipitate heart failure and pulmonary edema. Surgery may provide immediate relief for patients in whom a benign process is the cause.
Clinical improvement occurs in most patients, although this improvement may be due to the development of adequate collateral circulation. The mortality associated with SVCS does not relate to caval obstruction but rather to the underlying cause.
SVCS AND CENTRAL VENOUS CATHETERS IN ADULTS The use of long-term central venous catheters has become common practice in patients with cancer. Major vessel thrombosis may occur. In these cases, catheter removal should be combined with anticoagulation to prevent embolization. SVCS in this setting, if detected early, can be treated by fibrinolytic therapy without sacrificing the catheter. The routine use of low-dose warfarin or low-molecular-weight heparin to prevent thrombosis related to permanent central venous access catheters in cancer patients is not recommended.
Superior vena cava syndrome (SVCS). A. Chest radiographs of a 59-year-old man with recurrent SVCS caused by non-small cell lung cancer showing right paratracheal mass with right pleural effusion. B. Computed tomography of same patient demonstrating obstruction of SVC with thrombosis (arrow) by the lung cancer (square) and collaterals (arrowheads). C. Balloon angioplasty (arrowhead) with Wallstent (arrow) in same patient.
PERICARDIAL EFFUSION OR TAMPONADE
Malignant pericardial disease is found at autopsy in 5–10% of patients with cancer, most frequently with lung cancer, breast cancer, leukemias, and lymphomas. Cardiac tamponade as the initial presentation of extrathoracic malignancy is rare. The origin is not malignancy in about 50% of cancer patients with symptomatic pericardial disease, but it can be related to irradiation, drug-induced pericarditis, hypothyroidism, idiopathic pericarditis, infection, or autoimmune diseases. Two types of radiation pericarditis occur: an acute inflammatory, effusive pericarditis occurring within months of irradiation, which usually resolves spontaneously, and a chronic effusive pericarditis that may appear up to 20 years after radiation therapy and is accompanied by a thickened pericardium.
Most patients with pericardial metastasis are asymptomatic. However, the common symptoms are dyspnea, cough, chest pain, orthopnea, and weakness. Pleural effusion, sinus tachycardia, jugular venous distention, hepatomegaly, peripheral edema, and cyanosis are the most frequent physical findings. Relatively specific diagnostic findings, such as paradoxical pulse, diminished heart sounds, pulsus alternans (pulse waves alternating between those of greater and lesser amplitude with successive beats), and friction rub are less common than with nonmalignant pericardial disease. Chest radiographs and electrocardiography reveal abnormalities in 90% of patients, but half of these abnormalities are nonspecific. Echocardiography is the most helpful diagnostic test. Pericardial fluid may be serous, serosanguineous, or hemorrhagic, and cytologic examination of pericardial fluid is diagnostic in most patients. Cancer patients with pericardial effusion containing malignant cells on cytology have a very poor survival, about 7 weeks.
TREATMENT: Pericardial Effusion or Tamponade
Pericardiocentesis with or without the introduction of sclerosing agents, the creation of a pericardial window, complete pericardial stripping, cardiac irradiation, or systemic chemotherapy are effective treatments. Acute pericardial tamponade with life-threatening hemodynamic instability requires immediate drainage of fluid. This can be quickly achieved by pericardiocentesis. The recurrence rate after percutaneous catheter drainage is about 20%. Sclerotherapy (pericardial instillation of bleomycin, mitomycin C, or tetracycline) may decrease recurrences. Alternatively, subxiphoid pericardiotomy can be performed in 45 min under local anesthesia. Thoracoscopic pericardial fenestration can be employed for benign causes; however, 60% of malignant pericardial effusions recur after this procedure.
Intestinal obstruction and reobstruction are common problems in patients with advanced cancer, particularly colorectal or ovarian carcinoma. However, other cancers, such as lung or breast cancer and melanoma, can metastasize within the abdomen, leading to intestinal obstruction. Typically, obstruction occurs at multiple sites in peritoneal carcinomatosis. Melanoma has a predilection to involve the small bowel; this involvement may be isolated and resection may result in prolonged survival. Intestinal pseudoobstruction is caused by infiltration of the mesentery or bowel muscle by tumor, involvement of the celiac plexus, or paraneoplastic neuropathy in patients with small cell lung cancer. Paraneoplastic neuropathy is associated with IgG antibodies reactive to neurons of the myenteric and submucosal plexuses of the jejunum and stomach. Ovarian cancer can lead to authentic luminal obstruction or to pseudoobstruction that results when circumferential invasion of a bowel segment arrests the forward progression of peristaltic contractions.
The onset of obstruction is usually insidious. Pain is the most common symptom and is usually colicky in nature. Pain can also be due to abdominal distention, tumor masses, or hepatomegaly. Vomiting can be intermittent or continuous. Patients with complete obstruction usually have constipation. Physical examination may reveal abdominal distention with tympany, ascites, visible peristalsis, high-pitched bowel sounds, and tumor masses. Erect plain abdominal films may reveal multiple air-fluid levels and dilation of the small or large bowel. Acute cecal dilation to >12–14 cm is considered a surgical emergency because of the high likelihood of rupture. CT scan is useful in differentiating benign from malignant causes of obstruction in patients who have undergone surgery for malignancy. Malignant obstruction is suggested by a mass at the site of obstruction or prior surgery, adenopathy, or an abrupt transition zone and irregular bowel thickening at the obstruction site. Benign obstruction is more likely when CT shows mesenteric vascular changes, a large volume of ascites, or a smooth transition zone and smooth bowel thickening at the obstruction site. The prognosis for the patient with cancer who develops intestinal obstruction is poor; median survival is 3–4 months. About 25–30% of patients are found to have intestinal obstruction due to causes other than cancer. Adhesions from previous operations are a common benign cause. Ileus induced by vinca alkaloids, narcotics, or other drugs is another reversible cause.
TREATMENT: Intestinal Obstruction
The management of intestinal obstruction in patients with advanced malignancy depends on the extent of the underlying malignancy and the functional status of the major organs. The initial management should include surgical evaluation. Operation is not always successful and may lead to further complications with a substantial mortality rate (10–20%). Laparoscopy can diagnose and treat malignant bowel obstruction in some cases. Self-expanding metal stents placed in the gastric outlet, duodenum, proximal jejunum, colon, or rectum may palliate obstructive symptoms at those sites without major surgery. Patients known to have advanced intraabdominal malignancy should receive a prolonged course of conservative management, including nasogastric decompression. Percutaneous endoscopic or surgical gastrostomy tube placement is an option for palliation of nausea and vomiting, the so-called "venting gastrostomy." Treatment with antiemetics, antispasmodics, and analgesics may allow patients to remain outside the hospital. Octreotide may relieve obstructive symptoms through its inhibitory effect on gastrointestinal secretion.
Urinary obstruction may occur in patients with prostatic or gynecologic malignancies, particularly cervical carcinoma; metastatic disease from other primary sites such as carcinomas of the breast, stomach, lung, colon, and pancreas; or lymphomas. Radiation therapy to pelvic tumors may cause fibrosis and subsequent ureteral obstruction. Bladder outlet obstruction is usually due to prostate and cervical cancers and may lead to bilateral hydronephrosis and renal failure.
Flank pain is the most common symptom. Persistent urinary tract infection, persistent proteinuria, or hematuria in patients with cancer should raise suspicion of ureteral obstruction. Total anuria and/or anuria alternating with polyuria may occur. A slow, continuous rise in the serum creatinine level necessitates immediate evaluation. Renal ultrasound is the safest and cheapest way to identify hydronephrosis. The function of an obstructed kidney can be evaluated by a nuclear scan. CT scan can reveal the point of obstruction and identify a retroperitoneal mass or adenopathy.
TREATMENT: Urinary Obstruction
Obstruction associated with flank pain, sepsis, or fistula formation is an indication for immediate palliative urinary diversion. Internal ureteral stents can be placed under local anesthesia. Percutaneous nephrostomy offers an alternative approach for drainage. In the case of bladder outlet obstruction due to malignancy, a suprapubic cystostomy can be used for urinary drainage.
MALIGNANT BILIARY OBSTRUCTION
This common clinical problem can be caused by a primary carcinoma arising in the pancreas, ampulla of Vater, bile duct, or liver or by metastatic disease to the periductal lymph nodes or liver parenchyma. The most common metastatic tumors causing biliary obstruction are gastric, colon, breast, and lung cancers. Jaundice, light-colored stools, dark urine, pruritus, and weight loss due to malabsorption are usual symptoms. Pain and secondary infection are uncommon in malignant biliary obstruction. Ultrasound, CT scan, or percutaneous transhepatic or endoscopic retrograde cholangiography will identify the site and nature of the biliary obstruction.
TREATMENT: Malignant Biliary Obstruction
Palliative intervention is indicated only in patients with disabling pruritus resistant to medical treatment, severe malabsorption, or infection. Stenting under radiographic control, surgical bypass, or radiation therapy with or without chemotherapy may alleviate the obstruction. The choice of therapy should be based on the site of obstruction (proximal vs distal), the type of tumor (sensitive to radiotherapy, chemotherapy, or neither), and the general condition of the patient. In the absence of pruritus, biliary obstruction may be a largely asymptomatic cause of death.
Malignant spinal cord compression (MSCC) is defined as compression of the spinal cord and/or cauda equina by an extradural tumor mass. The minimum radiologic evidence for cord compression is indentation of the theca at the level of clinical features. Spinal cord compression occurs in 5–10% of patients with cancer. Epidural tumor is the first manifestation of malignancy in about 10% of patients. The underlying cancer is usually identified during the initial evaluation; lung cancer is the most common cause of MSCC.
Metastatic tumor involves the vertebral column more often than any other part of the bony skeleton. Lung, breast, and prostate cancer are the most frequent offenders. Multiple myeloma also has a high incidence of spine involvement. Lymphomas, melanoma, renal cell cancer, and genitourinary cancers also cause cord compression. The thoracic spine is the most common site (70%), followed by the lumbosacral spine (20%) and the cervical spine (10%). Involvement of multiple sites is most frequent in patients with breast and prostate carcinoma. Cord injury develops when metastases to the vertebral body or pedicle enlarge and compress the underlying dura. Another cause of cord compression is direct extension of a paravertebral lesion through the intervertebral foramen. These cases usually involve a lymphoma, myeloma, or pediatric neoplasm. Parenchymal spinal cord metastasis due to hematogenous spread is rare. Intramedullary metastases can be seen in lung cancer, multiple myeloma, renal cell cancer, and breast cancer and are frequently associated with brain metastases and leptomeningeal disease.
Expanding extradural tumors induce injury through several mechanisms. Obstruction of the epidural venous plexus leads to edema. Local production of inflammatory cytokines enhances blood flow and edema formation. Compression compromises blood flow leading to ischemia. Production of vascular endothelial growth factor is associated with spinal cord hypoxia and has been implicated as a potential cause of damage after spinal cord injury.
The most common initial symptom in patients with spinal cord compression is localized back pain and tenderness due to involvement of vertebrae by tumor. Pain is usually present for days or months before other neurologic findings appear. It is exacerbated by movement and by coughing or sneezing. It can be differentiated from the pain of disk disease by the fact that it worsens when the patient is supine. Radicular pain is less common than localized back pain and usually develops later. Radicular pain in the cervical or lumbosacral areas may be unilateral or bilateral. Radicular pain from the thoracic roots is often bilateral and is described by patients as a feeling of tight, band-like constriction around the thorax and abdomen. Typical cervical radicular pain radiates down the arm; in the lumbar region, the radiation is down the legs. Lhermitte's sign, a tingling or electric sensation down the back and upper and lower limbs upon flexing or extending the neck, may be an early sign of cord compression. Loss of bowel or bladder control may be the presenting symptom but usually occurs late in the course. Occasionally, patients present with ataxia of gait without motor and sensory involvement due to involvement of the spinocerebellar tract.
On physical examination, pain induced by straight leg raising, neck flexion, or vertebral percussion may help to determine the level of cord compression. Patients develop numbness and paresthesias in the extremities or trunk. Loss of sensibility to pinprick is as common as loss of sensibility to vibration or position. The upper limit of the zone of sensory loss is often one or two vertebrae below the site of compression. Motor findings include weakness, spasticity, and abnormal muscle stretching. An extensor plantar reflex reflects significant compression. Deep tendon reflexes may be brisk. Motor and sensory loss usually precedes sphincter disturbance. Patients with autonomic dysfunction may present with decreased anal tonus, decreased perineal sensibility, and a distended bladder. The absence of the anal wink reflex or the bulbocavernosus reflex confirms cord involvement. In doubtful cases, evaluation of postvoiding urinary residual volume can be helpful. A residual volume of >150 mL suggests bladder dysfunction. Autonomic dysfunction is an unfavorable prognostic factor. Patients with progressive neurologic symptoms should have frequent neurologic examinations and rapid therapeutic intervention. Other illnesses that may mimic cord compression include osteoporotic vertebral collapse, disk disease, pyogenic abscess or vertebral tuberculosis, radiation myelopathy, neoplastic leptomeningitis, benign tumors, epidural hematoma, and spinal lipomatosis.
Cauda equina syndrome is characterized by low back pain; diminished sensation over the buttocks, posterior-superior thighs, and perineal area in a saddle distribution; rectal and bladder dysfunction; sexual impotence; absent bulbocavernous, patellar, and Achilles' reflexes; and variable amount of lower-extremity weakness. This reflects compression of nerve roots as they form the cauda equina after leaving the spinal cord.
Patients with cancer who develop back pain should be evaluated for spinal cord compression as quickly as possible (Fig. 54-2). Treatment is more often successful in patients who are ambulatory and still have sphincter control at the time treatment is initiated. Patients should have a neurologic examination and plain films of the spine. Those whose physical examination suggests cord compression should receive dexamethasone (6 mg intravenously every 6 h), starting immediately.
Management of cancer patients with back pain. MRI, magnetic resonance imaging.
Erosion of the pedicles (the "winking owl" sign) is the earliest radiologic finding of vertebral tumor. Other radiographic changes include increased intrapedicular distance, vertebral destruction, lytic or sclerotic lesions, scalloped vertebral bodies, and vertebral body collapse. Vertebral collapse is not a reliable indicator of the presence of tumor; about 20% of cases of vertebral collapse, particularly those in older patients and postmenopausal women, are due not to cancer but to osteoporosis. Also, a normal appearance on plain films of the spine does not exclude the diagnosis of cancer. The role of bone scans in the detection of cord compression is not clear; this method is sensitive but less specific than spinal radiography.
The full-length image of the cord provided by MRI is the imaging procedure of choice. Multiple epidural metastases are noted in 25% of patients with cord compression, and their presence influences treatment plans. On T1-weighted images, good contrast is noted between the cord, cerebrospinal fluid (CSF), and extradural lesions. Owing to its sensitivity in demonstrating the replacement of bone marrow by tumor, MRI can show which parts of a vertebra are involved by tumor. MRI also visualizes intraspinal extradural masses compressing the cord. T2-weighted images are most useful for the demonstration of intramedullary pathology. Gadolinium-enhanced MRI can help to delineate intramedullary disease. MRI is as good as or better than myelography plus postmyelogram CT scan in detecting metastatic epidural disease with cord compression. Myelography should be reserved for patients who have poor MR images or who cannot undergo MRI promptly. CT scan in conjunction with myelography enhances the detection of small areas of spinal destruction.
In patients with cord compression and an unknown primary tumor, a simple workup including chest radiography, mammography, measurement of prostate-specific antigen, and abdominal CT usually reveals the underlying malignancy.
TREATMENT: Spinal Cord Compression
The treatment of patients with spinal cord compression is aimed at relief of pain and restoration or preservation of neurologic function (Fig. 54-2).
Radiation therapy plus glucocorticoids is generally the initial treatment of choice for most patients with spinal cord compression. Up to 75% of patients treated when still ambulatory remain ambulatory, but only 10% of patients with paraplegia recover walking capacity. Indications for surgical intervention include unknown etiology, failure of radiation therapy, a radioresistant tumor type (e.g., melanoma or renal cell cancer), pathologic fracture dislocation, and rapidly evolving neurologic symptoms. Laminectomy is done for tissue diagnosis and for the removal of posteriorly localized epidural deposits in the absence of vertebral body disease. Because most cases of epidural spinal cord compression are due to anterior or anterolateral extradural disease, resection of the anterior vertebral body along with the tumor, followed by spinal stabilization, has achieved good results. A randomized trial showed that patients who underwent an operation followed by radiotherapy (within 14 days) retained the ability to walk significantly longer than those treated with radiotherapy alone. Surgically treated patients also maintained continence and neurologic function significantly longer than patients in the radiation group. The length of survival was not significantly different in the two groups, although there was a trend toward longer survival in the surgery group. The study drew some criticism for the poorer than expected results in the patients who did not go to surgery. However, patients should be evaluated for surgery if they are expected to survive longer than 3 months. Conventional radiotherapy has a role after surgery. Chemotherapy may have a role in patients with chemosensitive tumors who have had prior radiotherapy to the same region and who are not candidates for surgery. Most patients with prostate cancer who develop cord compression have already had hormonal therapy; however, for those who have not, androgen deprivation is combined with surgery and radiotherapy.
Patients with metastatic vertebral tumors may benefit from percutaneous vertebroplasty or kyphoplasty, the injection of acrylic cement into a collapsed vertebra to stabilize the fracture. Pain palliation is common, and local antitumor effects have been noted. Cement leakage may cause symptoms in about 10% of patients. Bisphosphonates may be helpful in prevention of spinal cord compression (SCC) in patients with bony involvement.
The histology of the tumor is an important determinant of both recovery and survival. Rapid onset and progression of signs and symptoms are poor prognostic features.
INCREASED INTRACRANIAL PRESSURE
About 25% of patients with cancer die with intracranial metastases. The cancers that most often metastasize to the brain are lung and breast cancers and melanoma. Brain metastases often occur in the presence of systemic disease, and they frequently cause major symptoms, disability, and early death. The initial presentation of brain metastases from a previously unknown primary cancer is common. Lung cancer is most commonly the primary malignancy. Chest CT scans and brain MRI as the initial diagnostic studies can identify a biopsy site in most patients.
The signs and symptoms of a metastatic brain tumor are similar to those of other intracranial expanding lesions: headache; nausea; vomiting; behavioral changes; seizures; and focal, progressive neurologic changes. Occasionally, the onset is abrupt, resembling a stroke, with the sudden appearance of headache, nausea, vomiting, and neurologic deficits. This picture is usually due to hemorrhage into the metastasis. Melanoma, germ cell tumors, and renal cell cancers have a particularly high incidence of intracranial bleeding. The tumor mass and surrounding edema may cause obstruction of the circulation of CSF, with resulting hydrocephalus. Patients with increased intracranial pressure may have papilledema with visual disturbances and neck stiffness. As the mass enlarges, brain tissue may be displaced through the fixed cranial openings, producing various herniation syndromes.
CT scan and MRI are equally effective in the diagnosis of brain metastases. CT scan with contrast should be used as a screening procedure. The CT scan shows brain metastases as multiple enhancing lesions of various sizes with surrounding areas of low-density edema. If a single lesion or no metastases are visualized by contrast-enhanced CT, MRI of the brain should be performed. Gadolinium-enhanced MRI is more sensitive than CT at revealing meningeal involvement and small lesions, particularly in the brainstem or cerebellum.
Intracranial hypertension secondary to tretinoin therapy has been reported.
TREATMENT: Increased Intracranial Pressure
Dexamethasone is the best initial treatment for all symptomatic patients with brain metastases. If signs and symptoms of brain herniation (particularly headache, drowsiness, and papilledema) are present, the patient should be intubated and hyperventilated to maintain Pco2 between 25 and 30 mmHg and should receive infusions of mannitol (1–1.5 g/kg) every 6 h. Other measures include head elevation, fluid restriction, and hypertonic saline with diuretics. Patients with multiple lesions should receive whole-brain radiation. Patients with a single brain metastasis and with controlled extracranial disease may be treated with surgical excision followed by whole-brain radiation therapy, especially if they are younger than 60 years. Radioresistant tumors should be resected if possible. Stereotactic radiosurgery is an effective treatment for inaccessible or recurrent lesions. With a gamma knife or linear accelerator, multiple small, well-collimated beams of ionizing radiation destroy lesions seen on MRI. Some patients with increased intracranial pressure associated with hydrocephalus may benefit from shunt placement. If neurologic deterioration is not reversed with medical therapy, ventriculotomy to remove CSF or craniotomy to remove tumors or hematomas may be necessary.
Tumor involving the leptomeninges is a complication of both primary central nervous system (CNS) tumors and tumors that metastasize to the CNS. The incidence is estimated at 3–8% of patients with cancer. Melanoma, breast and lung cancer, lymphoma (including AIDS-associated), and acute leukemia are the most common causes. Synchronous intraparenchymal brain metastases are evident in 11–31% of patients with neoplastic meningitis.
Patients typically present with multifocal neurologic signs and symptoms, including headache, gait abnormality, mental changes, nausea, vomiting, seizures, back or radicular pain, and limb weakness. Signs include cranial nerve palsies, extremity weakness, paresthesia, and decreased deep tendon reflexes.
Diagnosis is made by demonstrating malignant cells in the CSF; however, up to 40% of patients may have false-negative CSF cytology. An elevated CSF protein level is nearly always present (except in human T-lymphotropic virus type I associated adult T cell leukemia). Patients with neurologic signs and symptoms consistent with neoplastic meningitis who have a negative CSF cytology but an elevated CSF protein level should have the spinal tap repeated at least three times for cytologic examination before the diagnosis is rejected. MRI findings suggestive of neoplastic meningitis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus. Spinal cord imaging by MRI is a necessary component of the evaluation of nonleukemia neoplastic meningitis as ~20% of patients have cord abnormalities, including intradural enhancing nodules that are diagnostic for leptomeningeal involvement. Cauda equina lesions are common, but lesions may be seen anywhere in the spinal canal. Radiolabeled CSF flow study results are abnormal in up to 70% of patients with neoplastic meningitis; ventricular outlet obstruction, abnormal flow in the spinal canal, or impaired flow over the cerebral convexities may affect distribution of intrathecal chemotherapy, resulting in decreased efficacy or increased toxicity. Radiation therapy may correct CSF flow abnormalities before use of intrathecal chemotherapy. Neoplastic meningitis can also lead to intracranial hypertension and hydrocephalus. Placement of a ventriculoperitoneal shunt may effectively palliate symptoms in these patients.
The development of neoplastic meningitis usually occurs in the setting of uncontrolled cancer outside the CNS; thus, prognosis is poor (median survival time, 10–12 weeks). However, treatment of the neoplastic meningitis may successfully alleviate symptoms and control the CNS spread.
TREATMENT: Neoplastic Meningitis
Intrathecal chemotherapy, usually methotrexate, cytarabine, or thiotepa, is delivered by lumbar puncture or by an intraventricular reservoir (Ommaya) three times a week until the CSF is free of malignant cells. Injections are given twice a week for a month and then weekly for a month. An extended-release preparation of cytarabine (Depocyte) has a longer half-life and is more effective than other formulations. Among solid tumors, breast cancer responds best to therapy. Patients with neoplastic meningitis from either acute leukemia or lymphoma may be cured of their CNS disease if the systemic disease can be eliminated.
Seizures occurring in a patient with cancer can be caused by the tumor itself, by metabolic disturbances, by radiation injury, by cerebral infarctions, by chemotherapy-related encephalopathies, or by CNS infections. Metastatic disease to the CNS is the most common cause of seizures in patients with cancer. However, seizures occur more frequently in those with primary brain tumors than in those with metastatic brain lesions. Seizures are a presenting symptom of CNS metastasis in 6–29% of cases. Approximately 10% of patients with CNS metastasis eventually develop seizures. Tumors that affect the frontal, temporal, and parietal lobes are more commonly associated with seizures than are occipital lesions. The presence of frontal lesions correlates with early seizures, and the presence of hemispheric symptoms increases the risk for late seizures. Both early and late seizures are uncommon in patients with posterior fossa and sellar lesions. Seizures are common in patients with CNS metastases from melanoma and low-grade primary brain tumors. Very rarely, cytotoxic drugs such as etoposide, busulfan, and chlorambucil cause seizures. Another cause of seizures related to drug therapy is reversible posterior leukoencephalopathy syndrome (RPLS). RPLS is associated with administration of cisplatin, 5-fluorouracil, bleomycin, vinblastine, vincristine, etoposide, paclitaxel, ifosfamide, cyclophosphamide, doxorubicin, cytarabine, methotrexate, oxaliplatin, cyclosporine, tacrolimus, and bevacizumab. RPLS is characterized by headache, altered consciousness, generalized seizures, visual disturbances, hypertension, and posterior cerebral white matter vasogenic edema on CT or MRI. Seizures may begin focally but are typically generalized.
Patients in whom seizures due to CNS metastases have been demonstrated should receive anticonvulsive treatment with phenytoin. Prophylactic anticonvulsant therapy is not recommended unless the patient is at high risk for late seizures (melanoma primary, hemorrhagic metastases, treatment with radiosurgery). Serum phenytoin levels should be monitored closely and the dosage adjusted according to serum levels. Phenytoin induces the hepatic metabolism of dexamethasone, reducing its half-life, while dexamethasone may decrease phenytoin levels. Most antiseizure medications induce CYP450, which alters the metabolism of antitumor agents, including irinotecan, taxanes, and etoposide as well as molecular targeted agents, including imatinib, gefitinib, erlotinib, and tipifarnib. Levetiracetam and topiramate are anticonvulsant agents not metabolized by the hepatic cytochrome P450 system and do not alter the metabolism of antitumor agents.
PULMONARY AND INTRACEREBRAL LEUKOSTASIS
Hyperleukocytosis and the leukostasis syndrome associated with it is a potentially fatal complication of acute leukemia (particularly myeloid leukemia) that can occur when the peripheral blast cell count is >100,000/mL. The frequency of hyperleukocytosis is 5–13% in acute myelid leukemia (AML) and 10–30% in acute lymphoid leukemia; however, leukostasis is rare in lymphoid leukemia. At such high blast cell counts, blood viscosity is increased, blood flow is slowed by aggregates of tumor cells, and the primitive myeloid leukemic cells are capable of invading through the endothelium and causing hemorrhage. Brain and lung are most commonly affected. Patients with brain leukostasis may experience stupor, headache, dizziness, tinnitus, visual disturbances, ataxia, confusion, coma, or sudden death. Administration of 600 cGy of whole-brain irradiation can protect against this complication and can be followed by rapid institution of antileukemic therapy. Hydroxyurea, 3-5 g, can rapidly reduce a high blast cell count while the accurate diagnostic workup is in progress. Pulmonary leukostasis may present as respiratory distress, hypoxemia, and progress to respiratory failure. Chest radiographs may be normal but usually show interstitial or alveolar infiltrates. Arterial blood gas results should be interpreted cautiously. Rapid consumption of plasma oxygen by the markedly increased number of white blood cells can cause spuriously low arterial oxygen tension. Pulse oximetry is the most accurate way of assessing oxygenation in patients with hyperleukocytosis. Leukapheresis may be helpful in decreasing circulating blast counts. Treatment of the leukemia can result in pulmonary hemorrhage from lysis of blasts in the lung, called leukemic cell lysis pneumopathy. Intravascular volume depletion and unnecessary blood transfusions may increase blood viscosity and worsen the leukostasis syndrome. Leukostasis is very rarely a feature of the high white cell counts associated with chronic lymphoid or chronic myeloid leukemia.
When acute promyelocytic leukemia is treated with differentiating agents like tretinoin and arsenic trioxide, cerebral or pulmonary leukostasis may occur as tumor cells differentiate into mature neutrophils. This complication can be largely avoided by using cytotoxic chemotherapy together with the differentiating agents.
Hemoptysis may be caused by nonmalignant conditions, but lung cancer accounts for a large proportion of cases. Up to 20% of patients with lung cancer have hemoptysis some time in their course. Endobronchial metastases from carcinoid tumors, breast cancer, colon cancer, kidney cancer, and melanoma may also cause hemoptysis. The volume of bleeding is often difficult to gauge. Massive hemoptysis is defined as >200–600 mL of blood produced in 24 h. However, any hemoptysis should be considered massive if it threatens life. When respiratory difficulty occurs, hemoptysis should be treated emergently. The first priorities are to maintain the airway, optimize oxygenation, and stabilize the hemodynamic status. Often patients can tell where the bleeding is occurring. They should be placed bleeding side down and given supplemental oxygen. If large-volume bleeding continues or the airway is compromised, the patient should be intubated and undergo emergency bronchoscopy. If the site of bleeding is detected, either the patient undergoes a definitive surgical procedure or the lesion is treated with a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. The surgical option is preferred. Bronchial artery embolization may control brisk bleeding in 75–90% of patients, permitting the definitive surgical procedure to be done more safely. Embolization without definitive surgery is associated with rebleeding in 20–50% of patients. Recurrent hemoptysis usually responds to a second embolization procedure. A postembolization syndrome characterized by pleuritic pain, fever, dysphagia, and leukocytosis may occur; it lasts 5–7 days and resolves with symptomatic treatment. Bronchial or esophageal wall necrosis, myocardial infarction, and spinal cord infarction are rare complications.
Pulmonary hemorrhage with or without hemoptysis in hematologic malignancies is often associated with fungal infections, particularly Aspergillus spp. After granulocytopenia resolves, the lung infiltrates in aspergillosis may cavitate and cause massive hemoptysis. Thrombocytopenia and coagulation defects should be corrected, if possible. Surgical evaluation is recommended in patients with aspergillosis-related cavitary lesions.
Bevacizumab, an antibody to vascular endothelial growth factor that inhibits angiogenesis, has been associated with life-threatening hemoptysis in patients with NSCLC, particularly squamous cell histology. NSCLC patients with cavitary lesions have higher risk for pulmonary hemorrhage.
Airway obstruction refers to a blockage at the level of the mainstem bronchi or above. It may result either from intraluminal tumor growth or from extrinsic compression of the airway. The most common cause of malignant upper airway obstruction is invasion from an adjacent primary tumor, most commonly lung cancer, followed by esophageal, thyroid, and mediastinal malignancies. Extrathoracic primary tumors such as renal, colon, or breast cancer can cause airway obstruction through endobronchial and/or mediastinal lymph node metastases. Patients may present with dyspnea, hemoptysis, stridor, wheezing, intractable cough, postobstructive pneumonia, or hoarseness. Chest radiographs usually demonstrate obstructing lesions. CT scans reveal the extent of tumor. Cool, humidified oxygen; glucocorticoids; and ventilation with a mixture of helium and oxygen (Heliox) may provide temporary relief. If the obstruction is proximal to the larynx, a tracheostomy may be lifesaving. For more distal obstructions, particularly intrinsic lesions incompletely obstructing the airway, bronchoscopy with laser treatment, photodynamic therapy, or stenting can produce immediate relief in most patients (Fig. 54-3). However, radiation therapy (either external-beam irradiation or brachytherapy) given together with glucocorticoids may also open the airway. Symptomatic extrinsic compression may be palliated by stenting. Patients with primary airway tumors such as squamous cell carcinoma, carcinoid tumor, adenocystic carcinoma, or NSCLC should have surgery.
Airway obstruction. A. CT scan of a 62-year-old man with tracheal obstruction caused by renal carcinoma showing paratracheal mass (A) with tracheal invasion/obstruction (arrow). B. Chest x-ray of same patient after stent (arrows) placement.