Wegener s Granulomatosis

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1 Wegener s Granulomatosis Two Patients Presenting with Solitary Pulmonary Lesions and Review of Eleven Other Cases Roger W. Davis, M.D., Bernard F. Fetter, M.D., and W. Glenn Young, Jr., M.D. ABSTRACT The case histories are reported of 2 patients with Wegener s granulomatosis who presented with solitary lung lesions. Eleven additional cases of Wegener s granulomatosis diagnosed at this institution are reviewed. Five of the 13 patients have been classified as having a limited form of the disease with no evidence of renal involvement and a more benign and prolonged course. The age, sex, and race factors were essentially the same in patients with limited disease as they were in patients with renal involvement. Gastrointestinal bleeding was a prominent symptom in 4 patients. The bleeding was found to be due to vasculitis involving the large bowel with mucosal ulceration in 1 patient and was due to regional enteritis in another patient. The association of lower gastrointestinal bleeding with Wegener s granulomatosis has not heretofore been made. Steroid therapy has been beneficial in patients with disease limited to the respiratory tract. The patients with renal involvement had a rapid downhill course except for 1, who has survived more than two years on a combination of steroid and 6-mercaptopurine therapy. T he clinical manifestations of Wegener s granulomatosis are extremely variable, and the diagnosis often is difficult. Tissue biopsy of respiratory tract or kidney lesions, or both, is needed to make the definitive diagnosis. A diagnostic triad established by Godman and Churg [ll] consists of necrotizing granulomas of the upper or lower respiratory tract, panvasculitis, and focal glomerulonephritis. In 1966 Carrington and Liebow [5] introduced the concept of a so-called limited form of Wegener s granulomatosis with absence of renal involvement and prolonged survival. Since that time, other patients having this limited form of the disease have been reported [6, 71. Two forms of pulmonary disease are found in patients with Wegener s granulomatosis. The first and most common is a lesion, such as pneumonia, infarction, atelectasis, or edema, which is related only indirectly to the primary disease. The second type is a necrotizing granulomatous process which develops in the lung and usually presents as multiple nodular densities that vary in size and tend to coalesce [9, 151. Cavitation is common and presents From the Departments of Surgery and Pathology, Duke University Medical Center, Durham, N.C. Presented at the Eighteenth Annual Meeting of the Southern Thoracic Surgical Association, Tampa, Fla., Nov. 4-6, Address reprint requests to Dr. Davis, Department of Surgery, Duke University Medical Center, Durham, N.C VOL. 13, NO. 5, MAY,

2 DAVIS, FETTER, AND YOUNG as a comparatively small, irregular lucency [ 161. The differential diagnosis of such radiographic lesions usually rests between bronchial neoplasms, tuberculosis, lung abscess, and pulmonary infarction and rarely includes Wegener s granulomatosis. This communication reports 2 patients with Wegener s granulomatosis who presented with solitary pulmonary lesions for which they underwent exploratory thoracotomy. Their clinical courses have typified the two forms this disease can take. A review of 11 other patients diagnosed at this institution is included. PATIENT 1 This 46-year-old man was in good health until February of 1968, when he developed the abrupt onset of left lateral chest pain. The pain was pleuritic in nature and was not associated with fever, cough, sputum production, hemoptysis, or weight loss. His past history and a review of systems were unremarkable except that the patient had had intermittent episodes of bright red rectal bleeding for a period of 2 years. Repeated studies had failed to reveal the cause of this condition. Physical examination was normal except for some diffuse rhonchi in the right posterior lower lung field with accompanying dullness to percussion. Chest roentgenograms revealed a right middle lobe mass with some atelectasis of the right lower lobe (Fig. 1). The mass was round and smooth and measured approximately 2 cm. in diameter. Fungal skin tests and an intermediate purified protein derivative test were nonreactive. Pulmonary function tests revealed moderately severe restrictive lung disease with hypoxemia that could not be reversed by oxygen administration. Following a negative bronchoscopy, the patient underwent a right lateral thoracotomy. The mass was contained in toto in the right middle lobe, and a lobectomy was performed. There was no mediastinal lymph node in- FIG. 1. Chest roentgenogram revealing the right middle lobe mass (arrow) in Patient l, a 46-year-old man. The mass was found to be a necrotizing granuloma. 428 THE ANNALS OF THORACIC SURGERY

3 Wegener's Granulomatosis volvement. The mass was firm, well demarcated, and granular in consistency with no apparent capsule and no cavitation. Microscopical examination revealed an area of destructive necrosis involving the alveolar structures, bronchioles, and blood vessels (Fig. 2). The surrounding vessels were involved with a necrotizing vasculitis characterized by a cellular intimal proliferation, medial fibrinoid necrosis, and an inflammatory cell infiltrate in all layers (Fig. 3). A striking feature of the necrotizing parenchymal process was the presence of multinucleated giant cells with no caseous necrosis. During the subsequent 3 years this patient has had intermittent episodes of shortness of breath and gastrointestinal bleeding. He has been maintained on prednisone, 20 mg. daily. The chest roentgenogram has remained unchanged. More recently the patient has been troubled with repeated upper respiratory tract infections and chronic sinusitis. His urinalysis, blood urea nitrogen, and serum creatinine have remained normal. PATIENT 2 This 66-year-old man was well until a mild, nonproductive cough developed in December, The patient was treated with tetracycline, and the symptoms subsided. One month later he experienced an exacerbation which was accompanied by fever, chills, and right-sided pleuritic chest pain. The patient had no weight loss, hemoptysis, or sputum production. Past history, review of systems, and family history were unremarkable. Physical examination demonstrated diminished breath sounds over the right FIG. 2. Microphotograph demonstrating an area of destructive necrosis of lung parenchyma in Patient 1, with granulonzatosis and panuasculitis. (H 6. E; X 110.) VOL. 13, NO. 5, MAY,

4 DAVIS, FETTER, AND YOUNG FIG. 3. Microscopical section of a pulmonary arteriole involved with a diffuse uasculitis characteristic of that seen in Wegener s granulomatosis. (Patient 1.) (H 6. E; X 110.) middle and right lower lung fields with dullness to percussion. The right maxillary sinus illuminated poorly, and the nasal mucosa was hyperemic. The usual studies, including skin tests, sputum cultures, sputum cytology, pulmonary function tests, and bronchoscopy, were all normal. Serum creatinine, blood urea nitrogen, hemogram, and urinalysis were within normal limits. Chest roentgenograms and planograms revealed a mass in the posterior segment of the right lower lobe (Fig. 4). He underwent exploratory thoracotomy in February, 1970, and a large FIG. 4. Roentgenogram demonstrating a right lower lobe mass in Patient 2, who was found postoperatively to have Wegen er s granuloma t osis. 430 THE ANNALS OF THORACIC SURGERY

5 Wegener's Granulomatosis mass was found in the right lower lobe. A lobectomy was performed. There was no evidence of involvement of the other two lobes or of any mediastinal structure. The mass was round, firm, and well demarcated. It was filled with a dense, yellow, necrotic material which grew no pathogens. Microscopical examination showed a necrotic lesion surrounded by chronic inflammatory cell infiltrates, multinucleated giant cells, and fibrosis. There was a prominent vasculitis of the surrounding vessels with fibrinoid degeneration, diffuse chronic inflammatory infiltrate, and multinucleated giant cells. Postoperatively the patient's shortness of breath, fever, and malaise persisted. He had occasional hemoptysis, and his upper respiratory tract symptoms became more severe. Three weeks after operation he experienced the onset of severe rectal bleeding accompanied by abdominal cramps and diarrhea. Two months after operation an infiltrate appeared in the left lower lobe. One week later he was admitted to the hospital with massive hemoptysis, a fever of 39"C., and persistent heavy rectal bleeding. The patient was found to have gross hematuria, proteinuria, and a serum creatinine of 3.0 mg. per 100 ml. Chest roentgenograms revealed patchy infiltrates in both lower lung fields. Arterial PO, was 35 mm. Hg, and the pc02 was 36 mm. Hg. The hematocrit was 19%, and the white blood cell count was 12,800 with a normal differential. A latex agglutination test was 4+ positive. Sputum cultures and sputum cytologies were again normal. Cultures of the stool and microscopical examinations for parasites revealed no pathogens. The patient was intubated and maintained on positive-pressure respiration with 100% oxygen. The PO, never rose above 35 mm. Hg. Two days later the patient died. Postmortem examination revealed a generalized vasculitis involving virtually all organ systems. There was consolidation of the lungs with intraalveolar hemorrhage and numerous areas of necrosis throughout both lungs. Necrotic areas were surrounded with a granulomatous inflammation and multinucleated giant cells. There was extensive hyaline membrane formation in both lungs. Inflammation with giant cells was also seen in the paranasal sinuses. The kidneys showed focal glomerulonephritis with degeneration of the glomerular tufts and fibrin accumulation within the glomerular capillaries. Immunofluorescent staining revealed immunoglobulin G and M and fibrin deposition on the basement membrane of the glomerular capillaries. The colonic mucosa was edematous throughout, and sections revealed focal necrotizing vasculitis with mucosal ulceration. The final anatomical diagnosis was Wegener's granulomatosis. Comment The clinical features and duration of illness in Wegener's granulomatosis can be protean. The terminal events, however, are usually characterized by severe necrosis of the respiratory tract and renal failure [14, 18, 231. In VOL. 13, NO. 5, MAY,

6 DAVIS, FETTER, AND YOUNG both patients reported here, the diagnosis was proved histologically only after exploratory thoracotomy had been performed for lesions thought preoperatively to be tumor. Both patients eventually had upper respiratory tract involvement; however, only Patient 2 developed renal involvement. This second patient s history was characteristic of the fulminating downhill course seen in widespread Wegener s granulomatosis. The first patient has no evidence of renal involvement and has had a protracted course of steroid therapy, with good response. He is representative of the more limited form of the disease as originally described by Carrington and Liebow [5]. Eleven other cases of Wegener s granulomatosis have been diagnosed at the Duke University Medical Center. All patients had histological diagnoses and had evidence of a necrotizing granulomatous process in the upper or lower respiratory tract, or both, with an accompanying vasculitis. Eight of the 13 patients had evidence of renal involvement, which was confirmed in 6 by renal biopsy or postmortem examination. In the remaining 5 patients, who had the limited form of the disease, the average duration of illness has been 6.8 years, ranging from 1 to 15 years. All 5 are still living. The 8 patients with renal involvement had an average course of 1.1 years from the time of the initial onset of symptoms, and all but 1 has died. The duration of their illness ranged from two weeks to twenty-six months. The 1 living patient is being maintained on 50 mg. daily of 6-mercaptopurine and steroids. All patients with limited Wegener s granulomatosis are on prednisone ranging from 20 to 60 mg. daily. The average age of the 13 patients at the time of onset of symptoms was 45.2 years, with no difference between those with limited and those with extensive disease. All were white except for 1 patient, who was black, and the group included 4 women, 2 with each form of the disease. Eight patients in our series presented with symptoms referable to the upper respiratory tract. The 2 patients reported here had solitary lung lesions, and 1 asymptomatic patient was found to have a cavitary pulmonary lesion on a routine chest roentgenogram. In 1958 Walton [241 noted that ulceration of the respiratory tract is primary and that the widespread lesions occur later in the natural history of the disease. There was only 1 patient in this series who failed to develop any pulmonary lesion. It is generally thought that the progression of the disease is accelerated once renal involvement has become apparent. Our experience would support the concept that renal involvement need not invariably follow the development of respiratory lesions and that those patients with no renal disease tend to have prolonged survival and an excellent response to steroid therapy. Fahey and associates [8] first suggested that Wegener s granulomatosis was a disease of hypersensitivity. Immunological studies in patients with Wegener s granulomatosis and the development of certain animal models confirm this [lo, 121. Latex agglutination tests were strongly positive in all patients, although none were troubled with arthralgia. No patient had a 432 THE ANNALS OF THORACIC SURGERY

7 Wegener s Granulomatosis positive lupus erythematosus preparation, and none of 5 patients tested had antinuclear antibodies in their serum. All patients had elevated gamma globulin, and 2 had mild elevations of the beta globulins. Serum albumin levels were mildly depressed in all but 3 patients. Immunoelectrophoresis was performed in 3 patients, and all demonstrated elevation of the IgM fraction with the other immunoglobulin fractions being normal. Four of these 13 patients were troubled with persistent lower gastrointestinal bleeding. One patient developed a bowel obstruction and at operation was found to have regional enteritis. This illness presented six years after his initial upper respiratory tract symptoms. His regional enteritis has been quiescent since operation and the institution of steroid therapy. It is interesting that the 2 patients reported in this communication both had lower gastrointestinal bleeding. The second patient was found at postmortem examination to have focal necrotizing vasculitis of the colon with numerous small mucosal ulcerations. Many studies and case reports have attempted to evaluate the optimal treatment for these patients [ll. Bouroncle, Smith, and Cuppage [3] and Peermohamed and Shafar [21] have reported on the use of azathioprine; McIlvanie [ 171 used chlorambucil; Kaplan and associates [ 131 have reported on the beneficial use of a new agent, duazomycin-a, in conjunction with azathioprine; Capizzi and Bertino [4] advocated methotrexate; Novack and Pearson [20] have alluded to the beneficial use of steroids alone or in combination with other drugs. The problems in evaluating drug therapy are numerous and are especially complicated in this disease because of the natural variability in the duration of the illness. In those having a limited form of the disease, steroids may constitute adequate therapy. Several investigators have reported that those with the widespread form of Wegener s granulomatosis as originally described may be benefited by immunosuppressive therapy. References 1. Aldo, M. A., Benson, M. D., Comerford, F. R., and Cohen, A. S. Treatment of Wegener s granulomatosis with immunosuppressive agents. Arch. Intern. Med. 126:298, Beidleman, B. Wegener s granulomatosis: Prolonged therapy with large doses of steroids. J.A.M.A. 186:827, Bouroncle, B. A., Smith, E. J., and Cuppage, F. E. Treatment of Wegener s granulomatosis with Imuran. Am. J. Med. 42:314, Capizzi, R. L., and Bertino, J. R. Methotrexate therapy of Wegener s granulomatosis. Ann. Intern. Med. 74:74, Carrington, C. B., and Liebow, A. A. Limited forms of angiitis and granulomatosis of Wegener s type. Am. J. Med. 41:497, Cassan, S. M., Coles, D. T., and Harrison, E. G., Jr. The concept of limited forms of Wegener s granulomatosis. Am. J. Med. 49:366, Cassan, S. M., Divertie, M. B., Hollenhorst, R. W., and Harrison, E. G., Jr. Pseudotumor of the orbit and limited Wegener s granulomatosis. Ann. Zntern. Med. 72:687, 1970.

8 DAVIS, FETTER, AND YOUNG Fahey, J. L., Leonard, E., Churg, J., and Godman, G. C. Wegener s granulomatosis. Am. J. Med. 17:168, Felson, B. Less familiar roentgen patterns of pulmonary granulomas: Sarcoidosis, histoplasmosis, and noninfectious necrotizing granulomatosis (Wegener s syndrome). Am. J. Roentgenol. Radium Ther. Nucl. Med. 81:211, Germuth, F. G., Jr., and Pollack, A. D. Immune complex disease: 111. The granulomatous manifestations. Johns Hopkins Med. J. 121:254, Godman, G. C., and Churg, J. Wegener s granulomatosis-pathology and review of the literature. Arch. Pathol. 58:533, Gorrin, H. D. Wegener s granulomatosis: Its significance in understanding the hypersensitive mechanisms of disease. South. Med. J. 63: 189, Kaplan, S. R., Hayslett, J. P., and Calabresi, P. Treatment of advanced Wegener s granulomatosis with azathioprine and duazomycin-a. N. Engl. J. Med. 278:239, Leak, D., and Clein, G. P. Acute Wegener s granulomatosis. Thorax 22:437, Levin, D. C. Pulmonary ahnormalities in the necrotizing vasculitides and their rapid response to steroids. Radiology 97:521, Lynch, E. C., Fred, H. L., and Greenberg, S. D. Pulmonary cavitation in Wegener s granulomatosis. Am. J. Roentgenol. Radium Ther. Nucl. Med. 92:521, McIlvanie, S. K. Wegener s granulomatosis: Successful treatment with chlorambucil. J.A.M.A. 197:130, Nielsen, K., Christiansen, I., and Jensen, E. Wegener s granulomatosis: A survey and three cases. Acta Med. Scand. 181:577, Norton, W. L., Suki, W., and Strunk, S. Combined corticosteroid and azathioprine therapy in two patients with Wepener s granulomatosis. Arch. Intern. Med. 121:554, Novack, S. N., and Pearson, C. M. Cyclophosphamide therapy in Wegener s granulomatosis. N. Engl. J. Med. 284:938, Peermohamed, A. R., and Shafar, J. Sustained azathioprine-induced remission in Wegener s granulomatosis. Br. Med. J. 4:600, Raitt, J. W. Wegener s granulomatosis: Treatment with cytotoxic agents and adrenocorticoids. Ann. Intern. Med. 74:344, Shuman, H. W. Hemorrhage in Wegener s granulomatosis. N. Engl. J. Med. 282:513, Walton, E. W. Giant-cell granuloma of the respiratory tract (Wegener s granulomatosis). Br. Med. J. 2:265, THE ANNALS OF THORACIC SURGERY