tj I CLINICAL CONFERENCE IN PULMONARY DISEASE

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1 tj I CLINICAL CONFERENCE IN PULMONARY DISEASE A Perplexing Case of Hilar Adenopathy Clinical Conference in Pulmonary Disease from the Ohio State University College of Medicine Robert A. Shaw, M.D., F.C.C.P.; Steven A. Schonfeld, M.D.; and Michael E. Whitcomb, M.D., F.C.C.P. The diagnosis of sarcoidosis is so highly likely in an asymptomatic patient who is discovered to have bilateral hilar adenopathy that tissue confirmation of the disease is generally considered unnecessary.1 Although sarcoidosis is also the most likely diagnosis in a patient with bilateral hilar adenopathy who is symptomatic or has abnormal findings on physical examination, other diagnoses must be considered. A vigorous diagnostic evaluation, frequently including pathologic examination of tissue obtained by invasive biopsy procedures, must be undertaken in such patients to ensure an accurate diagnosis. The case presented here illustrates the importance of this principle and provides an opportunity to discuss an unusual disease that causes both intrathoracic lymph node enlargement and parenchymal lung disease. CASE REPORT A 44-year-old woman was admitted to The Ohio State University Hospital for evaluation of peripheral lymph node enlar~ement and bilateral hilar adenopathy. The patient described a three-week history of dyspnea on exertion and a nonproductive cough. She denied having had rash, fever, or wei~ht loss, and was taking no medication. Her past medical history was unremarkable. On physical examination the patient was noted to be obese and in no distress. Her vital signs were normal. Slight periorbital edema was present, and numerous 1- to 2-cm tender lymph nodes were palpable in the cervical, axillary, and inguinal regions. Inspiratory rales were audible at both bases. The remainder of the examination findings were normal. Laboratory studies disclosed the following values: hemoglobin g/dl; and WBCs. 8,500/mma, with 69 percent neutrophils, 13 percent lymphocytes, 4 percent monocytes, and 13 percent eosinophils. Serum protein electrophoresis showed a marked increase in the gamma region, shown by immunoelectrophoresis to represent a polyclonal increase in IgG. Computerized axial tomography of the abdomen demonstrated enlargement of the retroperitoneal lymph nodes. Skin test reactions were positive for mumps and PHA but 736 SHAW, SCHONFELD, WHITCOMB negative for intermediate PPD. A chest roentgenogram revealed bilateral hilar adenopathy and a diffuse reticulonodular infiltrate (Fig 1). Pulmonary function test results disclosed a mild restrictive ventilatory defect (total lung capacity 72 percent of predicted) and diminished DLcosb ( 65 percent predicted). DISCUSSION Dr. Michael E. Whitcomb: Dr. Shaw, will you discuss the differential diagnosis of bilateral hilar adenopathy? Dr. Robert A. Shaw: When confronted with a patient whose chest roentgenogram demonstrates bilateral hilar adenopathy, the major disease processes to be considered are sarcoidosis, neoplasm, and infection. In Winterbauer's series 1 of 85 patients with bilateral hilar adenopathy alone or in conjunction with roentgenographic abnormalities that FIGURE 1. Bilateral hilar adenopathy and diffuse reticulanodular infiltrate.

2 were consistent with either sarcoidosis or tumor, 87 percent were ultimately shown to have sarcoidosis. All of the 29 patients who were asymptomatic were subsequently shown to have sarcoidosis.. In contrast, 11 of 56 patients ( 20 percent) who were symptomatic or had an abnormal physical examination had a disease other than sarcoidosis. Thus, it is apparent that while the overwhelming majority of patients with bilateral hilar adenopathy have sarcoidosis, other diseases must be considered in patients who have symptoms or abnormal physical findings. In adults, neoplastic diseases are the most important alternatives to sarcoidosis that must be considered Hilar enlargement associated with neoplasm is usually unilateral, occurring bilaterally in less than 5 percent of affected patients. 1 This latter group comprises primarily the lymphoproliferative disorders and is most commonly seen with Hodgkin's disease. 2 Approximately 10 percent of patients with leukemia manifest hilar adenopathy. Lymphocytic leukemia is the most common in this group. 3 Since sarcoidosis rarely causes anterior mediastinal adenopathy, such a roentgenographic finding should strongly suggest neoplasm. Bilateral hilar adenopathy has been reported to occur during the course of a number of infectious diseases, including tuberculosis, brucellosis, anthrax, tularemia, plague, Mycoplasma pneumonia, rubella, echovirus pneumonia, varicella pneumonia, psitticosis, toxoplasmosis, E-B virus mononucleosis, histoplasmosis, coccidioidomycosis, blastomycosis, and several parasitic infections. However, it should be emphasized that hilar adenopathy is usually unilateral in these cases and is associated with ipsilateral parenchymal infiltrates.4 In addition, other manifestations of these infections tend to distinguish them clearly from sarcoidosis. Infectious hilar adenopathy in adults is usually associated with tuberculosis or fungal diseases. Hilar lymph node enlargement also occurs in several uncommon diseases, such as amyloidosis, berylliosis, and silicosis. Other features of these diseases usually make the diagnosis relatively straightforward. Dr. Whitcomb: In considering the diagnostic approach to be undertaken in evaluating bilateral hilar adenopathy, it is important to keep two points clearly in mind. First, the majority of such patients, even those with symptoms or abnormal physical findings, have sarcoidosis, and, second, the main category of disease that must be differentiated from sarcoidosis is malignancy-primarily, lymphoproliferative malignancy. Although it is true, as Dr. Shaw summarized, that certain infections chracterized by granulomatous inflammation may produce bilateral hilar adenopathy, other clinical and laboratory features of these diseases easily distinguish them from sarcoidosis. Thus, for practical purposes, tissue confirmation of a granulomatous process in a patient who is not thought to have infection on clinical grounds is virtually diagnostic of sarcoidosis. Nevertheless, all biopsy specimens should be cultured to definitely exclude all of these infectious diseases. Occasionally, noncaseating granulomatous lesions can be found in lymph nodes draining malignant lesions, but only in the exceptional case would other indicators of malignancy be absent. Extranodal tissue biopsy in such cases may be necessary for histopathologic confirmation. The initial diagnostic evaluation depends to a great extent on the clinical impression that the patient has either sarcoidosis or a lymphoproliferative disorder. The presence of fever, anemia, substantial weight loss, peripheral adenopathy, anterior mediastinal adenopathy, hepatosplenomegaly, all of which may be seen in sarcoidosis, nonetheless should raise the suspicion that the patient has a lymphoproliferative disease. In all such cases, a prompt, thorough, and aggressive workup is indi4 cated. Regardless of the clinical impression, any easily accessible site of disease should be examined by biopsy first, eg, skin lesions or enlarged peripheral lymph nodes. As in the case presented for discussion, these sites will frequently yield the diagnosis. If easily accessible sites of disease either are not available for biopsy examination or yield nondiagnostic materia~ then conjunctival or minor salivary gland lip biopsies are probably the most benign procedures, and in more than one-half of patients with sarcoidosis, will yield tissue confirmation of the disease. If these biopsy results are negative, then fiberoptic bronchoscopy with bronchial mucosal and transbronchial lung biopsy should be undertaken. Tissue confirmation of sarcoidosis will be obtained in at least 75 percent of patients with these combined biopsy procedures. Bronchoalveolar lavage may also be performed at the time of fiberoptic bronchoscopy. The presence of an increased percentage of lymphocytes in the bronchoalveolar cell population certainly would be consistent with, but never diagnostic of sarcoidosis. A note of caution is in order, since our experience suggests that similar findings may be observed in some patients with lymphoproliferative diseases. Should these less invasive approaches be nondiagnostic, then it is reasonable to proceed directly to mediastinal lymph node biopsy. Mediastinoscopy or anterior mediastinotomy are excellent procedures A PERPLEXING CASE OF HILAR ADENOPATHY 737

3 FIGURE 2. Submandibular lymph node biopsy specimen showing proliferation of small blood vessels and infiltration with plasma cells and immunoblasts. Table I-Pre.entin1 Feature. in AILD for specifically identifying the cause of bilateral hilar adenopathy. Several studies have shown that mediastinoscopy provides tissue confirmation of the diagnosis of sarcoidosis in virtually all patients with this disease. Since mediastinal nodes accessible during mediastinoscopy are usually involved by the same disease involving hilar nodes, an extremely high percentage of lymphoproliferative diseases or bilateral hilar adenopathies caused by a solid tumor metastasis also will be diagnosed by this procedure. If there is clear evidence of anterior mediastinal adenopathy on the chest roentgenogram, anterior mediastinotomy is probably the preferred technique for exploring the mediastinum, since nodes in this area may not be accessible at the mediastinoscopy. On occasion, an exploratory thoracotomy may be required to make an absolute diagnosis. This should be necessary in a very small percentage of patients. Since tissue confirmation of the diagnosis is critically important, other laboratory studies that merely tend to support a diagnosis of one disease or another are usually of little value. In the patient described, a lymphoproliferative disorder was initially suspected because of her symptoms and extensive lymphadenopathy. The initial approach was a biopsy evaluation of the enlarged supraclavicular nodes. The specimens revealed sheets of immature cells with plasmocytoid features, amorphous interstitial material, and vascular proliferation consistent with a diagnosis of angioimmunoblastic lymphadenopathy (Fig 2). This is an interesting disease that has only recently been recognized as a cause of bilateral hilar adenopathy. Dr. Schonfeld will discuss the important features of this disease. Dr. Steven A. Schonfeld: Immunoblastic or angioimmunoblastic lymphadenopathy ( AILD) was first described as a clinical-pathologic entity by Lukes and Tindle5 and Frizzera et al6 less than a decade ago. Well over 200 cases have now been described in the literature. This disease is characterized by distinctive lymph node histopathology. General nodal effacement is produced by pronounced proliferation of immune reactive cells ( immunoblasts, plasma cells, and lymphocytes}, an abundant proliferation of small blood vessels, and an amorphous acidophilic interstitial material. This morphologic triad serves to distinguish AILD from other lymphoproliferative disorders with similar clinical manifestations, such as Hodgkin's disease. Although similar histologic changes can be found in extranodal sites, including skin, muscle, bone marrow, spleen, liver, kidney, lungs, peripancreatic tissues, Clinical Features Representative Incidence,* % Laboratory Results Representative Incidence.* % Age (mean) ~~ ~~ n Sex Positive Coomb's test 52 Male 53 Eosinophilia 38 Female 47 Leukocytosis 39 Lymphadenopathy Thrombocytopenia 13 Regional 26 Lymphopenia 45 Generalized 84 Hypergammaglobulinemia (polyclonal) 83 Hepatosplenomegaly 54 Pulmonary infiltrates 15 Hepatomegaly 46 Pleural effusion 12 Splenomegaly 41 Mediastinal and/or hilar adenopathy 18 Skin rash Fever Skin rash Fever Pruritus Sweats Wei~ht loss 64 *Summarized from References 5, 6, and SHAW, SCHONFELD, WHITCOMB

4 and pericardium, these changes do not have the same diagnostic significance as the presence of the lesion in nodal tissue. 5 6 Clinically, AILD presents in middle-aged or older patients with fever, sweats, generalized lymphadenopathy, weight loss, occasionally a rash, and hepatosplenomegaly (Table 1). Nonproductive cough, dyspnea, and pleuritic chest pain also occur frequently. Hypergammaglobulinemia is a consistent finding, and anemia, eosinophilia, leukocytosis, thrombocytopenia, and lymphopenia may occur. Abnormal thyroid function tests, the appearance of various autoantibodies, and Bence-Jones proteinuria occur much less commonly. The frequent occurrence of roentgenographically significant pulmonary involvement, as exemplified by our case, is noteworthy. Hilar and paratracheal adenopathy, both unilateral and bilateral, although infrequently symmetric, is common and may wax and wane throughout the course of the disease. Parenchymal disease usually produces an interstitial pattern of diffuse linear and small nodular densities. Confluence of these densities can produce an alveolar-appearing pattern, with fluffy, patchy infiltrates throughout the lungs. s.9 There is a suggestion in the literature of basilar predominance, but this does not appear to be of any diagnostic or prognostic significance. Lung biopsy material obtained before therapy has shown interstitial infiltration by a process with both cellular and organizational features similar to those seen in the nodal specimens. Immunofluorescent stains have shown a nonspecific pattern of intracellular IgG and IgM deposition throughout the alveolar walls without complement present. 10 Unilateral and bilateral pleural effusions may occur. The effusions are exudative with a preponderance of mononuclear cells, but no other particular characteristic findings The etiology of AILD is not well understood. The basic lesion appears to be a nonneoplastic hyperimmune proliferation of the B-cell line, with an exaggerated lymphocyte transformation to immunoblasts and plasma cells, suggesting a hypersensitivity reaction. 5 6 In fact, in one-third of the cases reported in the first two major series, 5 6 a drug exposure (penicillin, sulfonamides, aspirin, diphenylhydantoin, and griseofulvin) preceded the first symptoms. Despite its benign histologic appearance, the disease tends to be progressive. Lukes and Tindle5 reported a median survival of 15 months in 18 fatal cases and Cullen et al 11 a 90 percent mortality within one year of the onset of disease if it failed to achieve a complete remission. Three of the initial cases in Lukes and Tindle's report evolved into an immunoblastic sarcoma, 5 and a number of other reports of malignant transformation have appeared. 12 This phenomenon has occurred both with and without prior chemotherapy and may, as Lukes and Tindle suggest, represent the potential of frank neoplasia to develop in AILD or any other disease characterized by chronic immune reaction. Therapy for AILD remains controversial. Supportive treatment with moderate doses of corticosteroids, as for a hyperimmune syndrome, seems to be the safest therapeutic approach 6 11 and may achieve a 40 percent rate of remission. This may improve somewhat with more intensive cytotoxic chemotherapy, but the latter approach carries the risk of immunosuppression and the increased morbidity and mortality of opportunistic infection. Secondary tumorigenesis might also be taken into consideration and must be balanced against the potential benignity of the basic lesion. Cullen et al11 cite several reports of partial remissions following levamisol therapy. Dr. Whitcomb: Dr. Shaw, will you discuss management of the case discussed? Fl:cURE 3. Slight reduction in hilar adenopathy has occurred. Dr. Shaw: As Dr. Whitcomb mentioned, the lymph node biopsy specimens were diagnostic of AILD. Eosinophilia and hypergammaglobulinemia gave further support to the diagnosis. Fever developed during the hospitalization, although no source of infection could be found. Since her symptoms were quite debilitating, our hematology consultants recommended that treatment with cyclophosphamide, vincristine (On covin), and prednisone be started This regimen was chosen because it is usually well A PERPLEXING CASE OF HILAR ADENOPATHY 739

5 tolerated and is effective in treating lymphoproliferative disorders, although its efbcacy in treating AILD is unknown. The patient's cough, fever, and fatigue resolved promptly after the first course of treatment. Slight reduction in the hilar adenopathy also occurred (Fig 3). Three months later, however, the patient returned with painful axillary adenopathy, and another lymph node biopsy was performed to determine if malignant transformation had occurred. The pathologic findings were identical with those seen on her initial biopsy examinations. Chemotherapy was changed to nitrogen mustard, Oncovin, procarbazine, and prednisone in the hope of arresting the process. After two courses of this treatment she continues to have painful adenopathy without significant improvement. 1 Winterbauer RH, Belie N, Moores KD. A clinical interpretation of bilateral hilar adenopathy. Ann Intern Med 1973; 78: Martin JJ. The Nisbet Symposium: Hodgkin's disease. Radiological aspects of the disease. Australas Radio) 1967; 11: Klatte E, Yardley J, Smith E, Rohn R, Campbell J. The pulmonary manifestations and complications of leukemia. Am J Roentgenol 1963; 89:598 4 Fraser RG, Pare JA. Diagnosis of diseases of the chest IV. Philadelphia: WB Saunders, 1970: Lukes RJ, Tindle BH. Immunoblastic lymphadenopathy: a hyperimmune entity resembling Hodgkin's disease. N Engl J Med 1975; 282:1-8 6 Frizzera G, Moran EM, Rappaport H. Angio-immunoblastic lymphadenopathy: diagnosis and clinical course. Am J Med 1975; 59: Seman MD, Schwarz MI. Stanford RE. Interstitial pneumonia in angioimmunoblastic lymphadenopathy with dysproteinemia: a case report with special histopathologic studies. Ann Intern Med 1976; 85: Zylak CJ, Banerjee R, Galbraith P A, McCarthy DS. Lung involvement in angioimmunoblastic lymphadenopathy. Radiology 1976; 121: Schultz DR, Yuris AA. Immunoblastic lymphadenopathy with mixed cryoblobulinemia. N Eng) J Med 1975; 292: Weisenburger D, Armitage J, Dick F. Immunoblastic lymphadenopathy with pulmonary infiltrates, hypocomplementemia and vasculitis: a hyperimmune syndrome. Am J Med 1977; 63: Cullen MH, Stansfeld AG, Oliver RID, Lister TA, Malpas JS. Angioimmunoblastic lymphadenopathy: report of ten cases and review of the literature. Q J Med 1979; 48: F"JSher Rl, JafFe ES, Brayeau RC, Anderson JC, Tarr HK. Immunoblastic lymphadenopathy: evolution into a malignant lymphoma with plasmacytoid features. Am J Med 1976; 61: Postgraduate Courses: Clinical Management and Control of Tuberculosis The National Jewish Hospital and Research Center, National Asthma Center, will present Postgraduate Courses on Clinical Management and Control of Tuberculosis at the NJHRC, 3800 East Colfax Avenue, Denver on February 1-5 and March 29-April 2. For information, write to Dr. Thomas S. Moulding, Course Director, 3800 East Colfax Avenue, Denver SHAW, SCHONFELD, WHITCOMB