Pulmonary complications in cancer patients
Authors: D. E. Stover, R. J. Kaner
Journal: CA A Cancer Journal for Clinicians (1996)

The respiratory system is a common site for complications due to cancer and cancer therapy. Several factors can lead to pulmonary complications. Immunosuppression caused by the underlying disease or the cancer therapy can lead to infectious disease. In addition, the lungs contain an enormous capillary bed through which flows the entire venous circulation, making it a frequent site of metastasis and pulmonary emboli. Finally, the pulmonary capillary bed is uniquely sensitive to side effects of chemotherapy and radiation therapy, which often lead to respiratory symptoms. This article reviews the presentation, diagnosis, and therapy of common infectious and noninfectious disorders of the pulmonary system that occur in cancer patients. Immunosuppression is defined as a relative or absolute defect in antigen processing or effector cell function. Clinically, it is defined by the susceptibility of certain populations to specific types of infections. Immunosuppression caused by the disease or by the treatment can cause qualitative and quantitative immunologic defects. Certain general immunologic defects are associated with specific infectious organisms, and recognition of an immunologic defect can help in the prediction of the infectious agent (Table Besides immunologic defects, other factors, such as environmental exposure, travel history, iatrogenic procedures, recent hospitalization, and/or antibiotic therapy, must be taken into account in determining the infectious agent. Review of the radiologic pattern of infiltration also helps focus the differential diagnosis on a subset of likely etiologic agents. A distinction is often made between processes involving a single lobe or segment (localized) and those involving multiple lobes bilaterally (diffuse). The presence of a localized infiltrate with an appropriate clinical history suggests the diagnosis of a bacterial pneumonia. Diffuse infiltrates suggest either infection, especially Pneumocystis and cytomegalovirus (CMV) pneumonia, or noninfectious etiologies, such as drug toxicity and lymphangitic spread of tumor.2 The presence of infiltrates, cavitation, nodules, adenopathy, or pleural effusions can help focus attention on certain disorders (Table 2). Pulmonary symptoms in cancer patients with normal chest radiographs also need further evaluation. Tests that are more sensitive than the chest radiograph to detect pulmonary disease include measurement of the diffusing capacity, rest and exercise blood-gas determination or oximetry, gallium chest scanning, and computed tomography of the chest. The seriousness and tempo of an illness are also helpful in determining whether there is time to wait for a response to empiric therapy or whether an invasive procedure should be performed immediately. For the very ill cancer patient with pulmonary disease, often the goal is to achieve a specific etiologic diagnosis quickly and safely. Adequate samples of lower respiratory tract secretions and/or lung tissue are usually required for pathologic examination, microbial stains, and cultures. Table 3 lists the invasive procedures available for diagnosing pulmonary infiltrates in cancer patients along with an outline of specific etiologic yields and complication rates. Most procedures have a significant false-negative rate, further complicating the decision making, and in some cases even at autopsy a specific etiologic diagnosis cannot be made. It is important to note that survival is often not affected by making a specific pulmonary diagnosis. Studies do show, however, that morbidity is lessened by making a definitive diagnosis. Thus, bron-choscopy with bronchoalveolar lavage and transbronchial biopsy (if safe) is usually performed as the initial invasive procedure.3, 4 In general video-assisted thoracoscopic surgery has been shown to be a safe and effective method of obtaining lung tissue with less morbidity when compared with conventional thoracotomy, although no studies have been restricted exclusively to immunocompromised hosts (Table 3). Although sputum and serologic examinations are neither sensitive nor specific for most pulmonary diseases, occasionally a definitive diagnosis can be made by these methods. The presence of malignant cells, Legionella antigen, or Pneumocystis carinii in the sputum is specific but not sensitive for these disorders. The indications for sputum induction for diagnosis of pulmonary disorders in non-HIV immunocompromised patients have not been defined, but sputum induction may have a role in diagnosing P. carinii pneumonia and tuberculosis (TB). The presence of Cryptococcus antigen in the serum is highly sensitive and specific for disseminated cryptococcosis but may not be sensitive for pulmonary Cryptococcus infection alone. Serologic tests that demonstrate antibodies for Aspergillus, Blastomyces, and Histoplasma are suggestive of active infection, but the sensitivity of these studies is quite low. More recently, radioimmunoassay for Histoplasma capsulatum antigen has been shown to provide a rapid method for diagnosing disseminated histoplasmosis. The antigen can be detected in 50 percent of blood and 90 percent of urine samples from patients with disseminated histoplasmosis.5 Most of these data come from patients with acquired immunodeficiency syndrome (AIDS). Whether the sensitivity is this high in non-AIDS immunocompromised patients remains unknown. The diagnosis of invasive aspergillo-sis usually requires a biopsy of the infected tissue because the organism is ubiquitous and cultures are nonspecific for invasive disease. However, in neutropenic patients (especially with leukemia) who remain febrile on broad-spectrum antibiotics, the presence of the organism in sputum or bronchoscopic specimens may be a reliable guide to make a diagnosis of pulmonary Aspergillus infection because these patients are at greatest risk to develop invasive disease.6 The type of bacterial pneumonia that develops in a cancer patient depends on several factors, including the underlying immunologic defect, the duration of the immunocompromised state, and whether the infection is community acquired or nosocomial. Streptococcus pneumoniae and Haemophilus influenzae are seen in cancer patients with B-cell defects. Gramnegative organisms including Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species are common in neutropenic patients, but the widespread use of effective gram-negative antibiotic regimens has led to a decrease in the incidence of P. aeruginosa infections and to an increase in gram-positive infections in this patient population. The major risk factors for the occurrence of bacterial pneumonia in cancer patients besides neutropenia include corticosteroid administration, inadequate pulmonary drainage from obstructing tumor, and decreased cough. The clinical signs and symptoms of pneumonia may be typical ones, including acute onset of shaking chills, fever, and productive cough, but in the setting of granulocytopenia, patients may present with atypical or absent findings. Sputum production is seen in fewer than 60 percent of neutropenic patients, and when the absolute neutrophil count is less than 1,000 cells/mm3, purulent sputum is seen in less than eight percent of patients. In cancer patients the most sensitive sign of bacterial pneumonia is fever, which occurs in virtually all patients who have bacterial pneumonia. Although rales and signs of consolidation occur inconsistently, the chest radiograph is abnormal in 93 percent to 97 percent of patients, usually showing localized infiltrates. The usefulness of sputum examination in the immunocompromised patient with pneumonia is controversial. If the patient has sputum and a suspected bacterial pneumonia, we usually send it for gram stain and routine culture. The results are used as a guide to antibiotic therapy if the patient is not improving on the initially prescribed regimen. Bacterial pneumonia in cancer patients can progress rapidly, and the incidence of bacteremia and mortality is high, particularly in patients with absolute neutrophil counts of less than 1,000 cells/mm3. Empiric broad-spectrum antibiotic coverage should be initiated immediately when the diagnosis of bacterial pneumonia is suspected or more commonly when the neutropenic patient presents with fever and no obvious source. An aminoglycoside with a third-generation cephalosporin or an extended-spectrum penicillin are favored combinations in neutropenic patients. In some studies monotherapy has been shown to be as effective and less toxic than combination antibiotic treatment. However, concern over the emergence of resistant organisms with one drug therapy remains.7 Although the optimal duration of antibiotic therapy for neutropenic patients is unknown, a two-week course is usually sufficient if there is rapid clinical improvement and white blood cell recovery. When prolonged neutropenia is present, longer courses might be considered even if the patient is clinically improving. If the neutropenic patient remains febrile or does not improve on broad-spectrum antibiotics, additional maneuvers that must be considered include reevaluation of antibiotic therapy, additional therapy to cover opportunistic infections (especially Aspergillus), and performance of an invasive procedure to make a specific diagnosis. When a cancer patient who is not neutropenic presents with suspected bacterial pneumonia and is clinically stable, the same guidelines for treatment are used as for the immunocompetent patient. Although most bacterial pneumonias in immunocompromised patients are thought to be acquired by the respiratory route or the blood, some pneumonias are caused by aspiration. Cancer patients at particular risk for aspiration pneumonia include those with head and neck tumors and those with mucositis due to infection, chemotherapy, and/or radiation therapy. Less common causes of bacterial pneumonia in cancer patients include Legionella pneumophila, Mycoplasma pneumoniae, Nocardia and Actinomyces species, and Moraxella catarrhalis. Legionnaires' disease in the immunocompromised host is often acquired from a nosocomial source. Fever, malaise, and a productive cough are common.8 Radiographically, the presence of bilateral infiltrates and cavitation is relatively frequent. Culture of the organism from respiratory secretions, blood, tissue, or pleural fluid is the mainstay for diagnosis. Direct fluorescent antibody tests are quicker but have limited sensitivity. Therapy of Legionella requires the use of antibiotics that can kill intracellular organisms. Although erythromycin is the antibiotic of choice, some experts recommend adding rifampin for the duration of therapy, which should be at least three weeks. Nocardia infection occurs primarily in patients with impairment of cell-mediated immunity, and its presence in respiratory secretions should always be considered diagnostic of disease.9 At least six to 12 months of therapy is indicated, and parenteral therapy should be continued for at least four to eight weeks. Sulfonamides are the mainstay of therapy. However, if patients cannot tolerate sulfa drugs or they fail treatment, minocycline alone or in combination with cefotaxime has been successful. Although protection against bacterial pneumonia by vaccination has not been demonstrated in the immunocompromised host, Pneumovax (Merck & co., Inc.) is recommended, and H. influenzae B vaccine should be considered in patients at risk for this infection (e.g., splenectomized patients, patients with globulin defects, etc). Prophylactic intravenous immune globulin in cancer patients with quantitative or qualitative hypogammaglobulinemia, such as patients with chronic lymphocytic leukemia or myeloma, has decreased the number of episodes of pneumonia and other infections in these patients. The administration of growth factors (specifically granulocyte colony-stimulating factor) to cancer patients who are at risk for morbidity from febrile neutropenia seems to be of greatest benefit if given before neutropenia develops.10 The prevalence of TB is higher in some immunocompromised patients, particularly those with lung cancer, head and neck cancer, and lymphophroliferative disorders,11 but its overall incidence in non-HIV-positive cancer patients still remains low. In patients with lung and head and neck cancers, TB typically develops early in the course of the neoplastic disease, while in patients with lymphoproliferative disorders, the infection develops when the underlying malignancy is advanced.12 In most cancer patients with TB, the disease results from reactivation of a latent infection. However, the severe malnutrition and weight loss that accompany advanced cancer increase the susceptibility to active infection from exogenous sources as well. Diagnosis of TB is often delayed because fever and constitutional symptoms are commonly attributed to the underlying neoplasm. Chest radiographs can show typical upper lobe cavities, but lower lobe infiltrates, masses, nodules, and a miliary pattern occur more frequently in immunosuppressed patients. Sputum examination should always be attempted although it is less often positive in these patients.13 When sputum smears are negative for the tubercle bacillus, bronchoscopy should be performed. Therapy for sensitive TB is similar and as effective in immunocompromised patients as it is in the general population. Because of the increasing incidence of isoniazid-resistant TB, initially a four-drug regimen is recommended: isoniazid, rifampin, ethambutol, and pyrazinamide (for the first two months of therapy). If the organism is sensitive to isoniazid and rifampin, the ethambutol can be stopped and double therapy should be continued for an additional seven to ten months.14 If there is microbial resistance to isoniazid or rifampin, treatment with the sensitive drug (i.e., isoniazid or rifampin) and ethambutol should be extended to at least 18 months including 12 months after sputum conversion. Many authorities recommend continuing pyrazinamide as well. There are no good studies on effectiveness of drugs for multiresistant TB. Four or five drugs to which the organism is sensitive should be given.15 The appropriate duration of treatment is unknown but probably should be continued for two years or more. Whether surgical resection of localized disease has benefit is unknown. Immunocompromised patients with positive tuberculin reactions should receive 12 months of prophylaxis with isoniazid (300 mg/day). To increase the sensitivity of the tuberculin skin test in cancer patients, it should be performed before immunosuppresive therapy is instituted, and a reaction size of 5 mm of induration is used to define a positive reaction. Bacille Camette-Guérin, an attenuated strain of Mycobacterium bovis that is given as a live vaccine, is not recommended for TB prophylaxis because disseminated disease and deaths have been reported in immunocompromised patients. Pulmonary infections with non-tuberculous mycobacteria, which are widely distributed in nature, clinically and often radiographically are indistinguishable from TB, but are not contagious. Mycobacterim avium complex (MAC) and Mycobacterium kansasii are the most frequently isolated organisms and occur commonly in patients with lung cancer, head and neck cancer, and hairy cell leukemia. A non-tuberculous mycobacterium called Mycobacterium haemophilum has recently been identified as a pathogen in immunocompromised patients.16 The organism causes pulmonary and extrapulmonary disease (especially in the skin, lymph nodes, and joints) and has been reported mostly in bone marrow transplant patients and the HIV infected. Eradication of atypical mycobacteria is often difficult and usually requires four to five drugs to which the organism is sensitive for 18 months or longer. A useful way to consider pulmonary fungal infections in the immunocompromised patient is to separate them on the basis of the patient's underlying immunologic defects. Patients with neutropenia more commonly develop infections with Aspergillus, Mucor, and Candida species. These organisms are called “opportunistic fungi” because they usually infect only patients with abnormal host defenses. Patients with T-cell defects more often develop infections with Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitides. These organisms are called “pathogenic fungi” because they also infect immunologically normal persons. Because Aspergillus and Cryptococcus are major causes of pneumonia in patients with cancer, they will be discussed here. Immunosuppressed patients at risk for invasive pulmonary aspergillosis include those with prolonged neutropenia; those receiving chronic corticosteroids, antibiotic therapy, and/or chemotherapy; and those with a prior history of Aspergillus pneumonia. The clinical features of pulmonary aspergillosis include fever, dyspnea, nonproductive cough, and pleuritic chest pain with or more frequently without a friction rub. Often the only evidence of Aspergillus pneumonia is fever with pulmonary infiltrates that do not respond to antibiotics. Massive hemoptysis is a rare complication and tends to occur during the stage of bone marrow recovery and cavity formation. Tracheobronchitis is another form of pulmonary Aspergillus infection that occurs in immunocompromised patients. Patients present with wheezing and/or dyspnea, and the chest radiograph can be normal or show lobar atelectasis.17 Aspergillus pneumonia may or may not accompany the airway disease. Early in the course of Aspergillus infection, the chest radiograph may be normal, or it may show a single nodule; multiple nodules; or a large, wedge-shaped, pleural-based lesion that mimics pulmonary infarction. A computed tomographic scan of the chest can show abnormalities weeks before the chest radiograph becomes abnormal.18 Because Aspergillus infections are difficult to diagnose before death and because they are an important cause of mortality in neutropenic patients, empiric therapy for aspergillosis in the proper setting has become commonplace.19 Amphotericin B is the drug of choice for invasive aspergillosis. Surgical resection should be considered in leukemic patients and bone marrow transplant recipients who, after therapy, have residual disease especially with mycetomas. Liposomal amphotericin B, which can allow higher doses of drug with potentially reduced toxicity, and itraconazole appear to be promising drugs for the treatment of Aspergillus infection in immunocompromised patients.20, 21 Other strategies for treatment of aspergillosis include adding fungus-specific antibodies to liposomes to increase the efficiency of drug targeting and optimize drug delivery to sites most likely to be infected (e.g., aerosol to the lungs).20 The clearest correlation with survival in patients with invasive aspergillosis is remission of the underlying malignancy and recovery of functioning neutrophils. The role of granulocyte colony-stimulating factors remains uncertain. Disseminated cryptococcosis is manifested by the occurrence of meningitis and pulmonary involvement, which occurs in up to 50 percent of patients with disseminated infection. Isolated cryptococcal pneumonia is much less frequent.22 Radiographically, pneumonia usually presents as a single, well-defined mass that ranges from 2 to 10 cm in diameter and mimics primary lung cancer. Cavitation, intrathoracic adenopathy, and pleural effusions are rare in cancer patients. However, they are common in HIV-infected patients. Because the disease is commonly disseminated when it becomes clinically obvious, cerebrospinal fluid, blood, and urine cultures provide excellent sources for diagnosis. Conversely, when the organism is retrieved from respiratory secretions, the patient should be evaluated for disseminated infection, including a lumbar puncture. The latex agglutination test for cryptococcal polysaccharide antigen is useful for diagnosis and should be followed to measure the efficacy of therapy.23 Amphotericin B is the recommended therapy for cryptococcal infection, and flucytosine is synergistic. This combination should be considered in patients with cryptococcal meningitis. In patients with pulmonary cryptococcosis alone, amphotericin B may be adequate, but there is no agreement as to the dose and duration of therapy. Although its role in the non-AIDS immunocompromised patient is undefined, fluconazole is a promising azole for the treatment of pulmonary cryptococcosis. In patients who are immunocompromised, particularly with deficiencies of cellular immunity, severe morbidity and death can occur during primary infection or reactivation of certain viruses. Cytomegalovirus (CMV) is a major cause of morbidity and mortality in allogeneic bone marrow transplant (Allo-BMT) recipients.24 Interestingly, in recipients of autologous bone marrow and other cancer patients, it rarely causes active disease. The clinical signs, symptoms, and radiographic findings of CMV pneumonia are nonspecific and often indistinguishable from other common pneumonias. If the organism is cultured from bronchoalveolar lavage, blood, or urine in Allo-BMT recipients, even if asymptomatic, treatment for CMV is usually given. The combination of ganciclovir and intravenous gammaglobulin has been shown in two small, uncontrolled studies of Allo-BMT patients to significantly decrease the mortality from this disease. In our institution with this regimen,25 the death rate from CMV pneumonia has decreased from 90 percent to 30 percent. Although ganciclovir prophylaxis appears to prevent CMV pneumonia in Allo-BMT recipients, few studies have shown a survival advantage associated with its use. Varicella-zoster, herpes simplex, respiratory syncytial virus, adenovirus, and influenza virus can occasionally cause pneumonia in patients with cancer.26 prevention of influenza A and B involves the use of an inactivated influenza vaccine, and although the immune response in immunocompromised patients is variable, it is recommended that such patients receive vaccination.27 P. carinii pneumonia (pCp) rarely if ever occurs in patients who have normal immune function. In cancer patients, PCP occurs most commonly in patients who have underlying malignancies associated with defects in cell-mediated immunity; who have undergone organ transplantation; or who are receiving immunosuppressive drugs, especially cyclosporine or corticosteroids. A retrospective, 12-year review at Memorial Hospital showed that of the 142 PCP cases found, 47 percent were in patients with hematologic malignancies, 31 percent were in patients with solid tumors, and 18 percent were in bone marrow transplant patients.28 Amphotericin B is the drug of choice for invasive aspergillosis. Nonproductive cough, shortness of breath, and fever are the typical symptoms of Pneumocystis pneumonia. The natural history of untreated PCP is a rapidly progressive involvement of the lungs culminating in death. The typical radiographic appearance of PCP is one of diffuse bilateral symmetric, mixed interstitial, and alveolar infiltrates. Lobar or asymmetric bilateral infiltrates, solitary and multiple nodules, a miliary pattern, upper lobe infiltrates, pneumothoraces, and normal chest radiographs have also been reported.29 The diagnosis of PCP is made only by finding the organism in respiratory secretions or body tissues. Although induced sputum has had a high yield in HIV-infected patients, its sensitivity in cancer patients with PCP appears to be low. Under most circumstances, bron-choscopy is the procedure of choice to provide the diagnosis in cancer patients. There are two drugs that are highly effective in the treatment of Pneumocys-tis pneumonia: trimethoprim-sulfamethoxazole (TMP-SMX) and parenteral pentamidine.30 If a patient does not respond to initial anti-PCP therapy, there are no controlled studies indicating the best approach. However, most clinicians switch from TMP-SMX to intravenous pentamidine and vice versa. Other agents, such as trimetrexate and difluoromethylornithine, have some efficacy against Pneumocystis pneumonia, but major toxicity, especially bone marrow suppression, limits their usefulness in cancer patients. Atovaquone shows some promise in the treatment of HIV-associated PCP with less toxicity but higher relapse rates when compared with conventional agents. Pulmonary edema is a frequent complication of cancer treatment and may be of cardiogenic or noncardiogenic origin. Controlled, randomized trials in HIV-infected patients have shown that the addition of corticosteroids to conventional agents in patients with moderate to severe PCP (defined as an arterial oxygen tension of <70 mm Hg or an alveolar to arterial gradient of >35 mm Hg while on room air) is beneficial. There are no similar trials in cancer patients, and there are no specific criteria for initiating steroid therapy or for dosing. It has been our experience that adding corticosteroids or increasing the dose in cancer patients already receiving chronic steroid therapy may be beneficial, particularly in patients with moderate to severe PCP. Effective prophylaxis against PCP can be achieved by administering low, intermittent doses of TMP-SMX. One double-strength tablet of TMP-SMX twice a day for three consecutive days a week has a high degree of efficacy in preventing PCP.31 PCP has a mortality rate of up to 50 percent in cancer patients, reinforcing the need for prophylaxis.28 Cancer patients who require prophylaxis include those with defects in cell-mediated immunity and those undergoing Allo-BMT. Consideration of prophylaxis for cancer patients receiving high-dose corticosteroids should also be given.28 Although TMP-SMX is the drug of choice for PCP prophylaxis, the use of aerosolized pentamidine is an effective alternative in cancer patients who are intolerant to TMP-SMX.32 Other alternatives include intravenous pentamidine every two to four weeks or oral daily dapsone. Because efficacy of these alternative agents has been shown in HIV patients, it is assumed they are effective in other immunocompromised patients as well. Occasionally, other protozoans can cause serious pulmonary disease in cancer patients. Strongyloides stercoralis should be anticipated in patients who have been exposed to Strongyloides infection any time in their lifetime and then develop illness or receive treatment that affects helper T-cell function.33 The diagnosis should be considered in any immunosuppressed patient who comes from an endemic area and develops vague abdominal symptoms of pain, diffuse tenderness, or distention and then develops pneumonia. Although blood cultures may be positive for one or more bacteria from the gut flora, the diagnosis is made by demonstrating the filariform larvae in sputum or other respiratory tract specimens, especially bronchoalveolar lavage fluid. The larvae may also be found in feces or in cerebrospinal fluid if meningitis occurs. Standard therapy for strongyloidi-asis is thiabendazole. The duration of therapy is usually between 10 and 14 days. However, the optimal treatment time is unknown. If latent or active infection with Strongyloides is proven or highly suspected, treatment with thiabendazole should be given before immunosuppression and active disease occurs. Toxoplasmosis is an uncommon cause of pulmonary infiltrates in immunocompromised patients. The usual setting of toxoplasmosis is cerebrospinal fluid involvement with meningitis. When pulmonary disease occurs, it is usually in patients with HIV infection or organ transplantation. Patients under treatment for cancer are at risk for a wide variety of pulmonary complications. The pulmonologist is frequently called on to evaluate dyspnea in this setting. The differential diagnosis is broad. Besides pulmonary infection the most frequent causes considered are anemia, exacerbation of obstructive airways disease, cancer progression in the lungs, atelectasis from endobroncheal tumor or extrinsic compression, pulmonary edema of cardiac or noncardiac origin, pleural effusion, pulmonary emboli, and drug- and radiation-induced pulmonary toxicity. Leukostasis and leukoagglutinin reactions are less common. Preexisting lung diseases, such as idiopathic pulmonary fibrosis, must also be distinguished from new acute problems. Review of prior radiographs in this setting is mandatory for a full understanding of the patient's problem. Unrelated diseases, such as hypersensitivity pneumonitis, can occur in cancer patients as well as any other individual. Patients who have anemia due to their cancer or the effects of chemotherapy will frequently complain of exertional dyspnea as the initial symptom. In some cases, erythropoetin therapy can be highly effective in ameliorating these symptoms. Diagnostic evaluations for noninfectious pulmonary problems often arise as a result of the identification of radiographic abnormalities. Cancer presents in the chest in several characteristic patterns. Metastatic disease most often presents as single or multiple nodules, in a lymphangitic pattern, and/or as a pleural effusion. Certain types of cancer can form metastatic endobronchial lesions and present with lobar atelectasis or volume loss on the chest radiograph. Breast and colon cancer most frequently form these endobronchial lesions. Renal cell cancer and melanoma can also metastasize endobronchially. Tumor emboli, though rare, can cause dyspnea and hypoxemia with or without infiltrates. Lymphomas usually present in the chest as mediastinal lymphadenopathy, but parenchymal nodules, infiltrates often with air bronchograms, and/or pleural effusions may also be present. Sarcoidlike granulomas can be associated with lymphoma or other malignancies, such as germ cell tumors, and radiographically can mimic these malignancies. Chemotherapy for germ cell tumo