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AIDS and Malignant Mesothelioma—Is There a Connection?
AIDS and Malignant Mesothelioma-Is There a Connection?* Cynthia A Behling, M .D .; lbul L. Wolf, M.D .; and Ibrolz Haghlghl, M .D .
A 35-year-old male homosexual, a former intravenous drug abuser, was found to be human immunodeficiency virus (IDV) positive in 1984. He developed AIDS in 1987 and began treatment with zidovudine in 1989. One year later he developed left apical pleural blebs, a pneumothorax and an exudative pleural effusion. A malignant mesothelioma developed at the pleural blebs in the left apex. He was treated with adriamycin but rapid progression of the malignancy occurred and he died three months later. At autopsy, a malignant mesothelioma, causing respiratory failure and death, was found. The patient had DO exposure to asbestos and asbestosis was not present at autopsy. We postulate that the development of malignant mesothelioma was probably related to HIV immune suppression or HIV and/or cytomegalovirus or zidovudine and is a complication of AIDS similar to the development of other malignant neoplasms in patients with AIDS. (Chest 1993; 103:1268-69)
P
atients with human immunodeficiency virus (HIV) disease may develop various malignant neoplasms. The two most common malignancies are Kaposi's sarcoma and nonHodgkin's lymphoma. Two cases of malignant mesothelioma in HIV paitents have been cited in European reports. I.! We recently have observed a HIV-positive patient who died of a rapidly progressive malignant mesothelioma. He had no asbestos exposure and had a negative history for other nonasbestos-related etiologic factors causing malignant mesothelioma such as exposure to irradiation, nickel, silica, beryllium, erionite and organic chemicals? We postulate that his malignant mesothelioma developed as a consequence of HIV immune suppression, HIV, cytomegalovirus or zidovudine activation of promoter oncogenes or induction of loss of suppression genes. CASE REPORT
The patient was a 35-year-old homosexual white male, exintravenous drug abuser and alcoholic, who had been HIV-positive since 1984. The AIDS-related complex was diagnosed in 1987 and he was first referred here in November of 1989. At that time, CD4 count was 135; therapy with prophylactic zidovudine and trimethoprim and sulfamethoxazole (Septra), twice a day, began. He did well until September 1990, when he presented with chest pain and hemoptysis. At that time, he was found to have apical pleural blebs, a left apicalpneumothorax and a small left pleural exudative effusion. The air was evacuated twice, but eventually a chest tube was required. Sputum was nondiagnostic; pleural fluid was sterile and bloody (20,000 RBC; 650 WBC; glucose, 76 mg/dl, TP, 4.1gtdl; lactic dehydrogenase, 1,040 UII.., pH 7.37; and cytology on both was negative for malignancy. Bronchoscopyfor Pneumocystis carinU pneumonia (PCP), staining with acid-fast bacilli and coccidioidomycosis and Cryptococcus serologies were negative as well. Com·From the Department of Pathology, Veterans Administration Medical Center, and University of California, San Diego. Reprint requests: Dr. "blf, UC Medical Center; 225 DIckinson, San
Diego
1268
92103
puted tomography showed a round mass-like density with a bleb in the left upper lobe and a paratracheal nodule . Aspergilloma versus cavitary neoplasm were considered. After two weeks of a pers istent air leak, he underwent a thoracotomy with pleural abrasion and bullae-mass excision. Examination of a frozen section of the sample led the investigators to suspect malignancy with margins of the malignancyclose but clear. The llnal pathology report was malignant mesothelioma. A consultant suggested that the nodule represented reactive mesothelium in response to PCP although the patient did not have PCp, and specimens removed at bronchoscopy were negative for PCp. The patient returned in December with progressive dyspnea , recurrent hemoptysis, pleuritic chest pain and fever. A large left upper lobe mediastinal mass was noted and a transtracheal needle aspiration again showed malignant cells. The patient was readmitted for reevaluation. The physical examination revealed the patient to be thin , with a temperature of39.2"C; a pulse of 114 beats per minute; respirations, 20 breaths per minute; Bp, 120170 mm Hg, poor dentition; jugular venous pulse, 8. There were decreased hreath sounds in the left posterior area of the chest and dullness in the left side of the chest . Tachycardia was present. The liver span was 10cm below the coastal margin. Results of the extremities, neurologic and genitourinary examination were within normal limits. Laboratory studies included the following values: WBC count, 5,2OG'cu mm! hematocrit, 27.1 percent; hemoglobin, 9.3 gldl; platelets, 452,()()(Vcu mm; differential WBC count, 77 percent segmented neutrophils, 3 percent bands, 11 percent lymphocytes, 6 percent monocytes, 1 percent eosinophil and 2 percent basophils. HospUal Course
The Heme/Oncology consultant felt that given the rapid growth, the mass was malignant and suggested bimodal therapy (radiation and chemotherapy). Irradiation was initiated the next day. It was believed that chemotherapy was of unlikely benefit, but since the patient requested all possible therapy, low-dose weelcly treatment with adriamycin was begun . Lactic dehydrogenase level rose to 2,010 UII... By January 1991, there had been marked progression of the malignant mesothelioma along with cachexia, pain, dysphagia and severe dyspnea. The patient died on February 5, 1991.
Results of the Autopsy The most significant llnding at autopsy was the nearly complete replacement of the left lung by a necrotic, hemorrhagic, malignant neoplasm (Fig 1). The malignancy was densely adherent to the parietal pleura over all surfaces of the lung; no normal pleural surfaces could be identified . It invaded the mediastinum and the
FIGURE 1. Gross photograph of the left lung demonstrating the malignant mesothelioma originating from the pleural surface and invading and nearly completely replacing the left lung. AIDS and MalIgnant MesoIheIloma (Behling, WOlf, Heghlghl)
FIGURE 2. Histologic section demonstrating the malignant mesothelioma (hematoxylin and eosin, original magnification x 4(0) . pericardium. Microscopically, the neoplasm was largely necrotic. Viable areas showed sheets and cords of poorly differentiated malignant cells with scant cytoplasm and large nuclei with nucleoli (Fig 2). The individual malignant cells were separated by a fine network of mucopolysaccharides and hyaluronic acid. Mucicarmine stains were negative and alcian blue stains were positive; alcian blue was removed by pretreatment with hyaluronidase. Immunocytochemical stains demonstrated that the malignant cells were positive for cytokemtin and vimentin and negative for carcinoembryonic antigen. Thus, this malignant neoplasm was consistent with a malignant mesothelioma. Metastatic malignant mesothelioma was found on the surface of the dum over the left cerebral hemisphere, abdominal, bronchial and hilar lymph nodes, epicardium and right kidney. DISCUSSION
The development of a malignant mesothelioma in a patient with AIDS may be purely fortuitous. However, since a number of malignant neoplasms have developed in AIDS patients, it would be appropriate to perhaps suspect that there may be a connection . A number of investigations certainly have demonstrated a connection with the development of Kaposi's sarcoma or non-Hodgkins lymphoma in AIDS patients. The patient presented clinically with signs and symptoms of a malignant mesothelioma. The patient had chest pain and an exudative pleural effusion. He developed pleural blebs with a subsequent pneumothorax. The malignant mesothelioma developed at the site of the apical pleural blebs in the left lung. Differential diagnosis of the pleural lesion included a reactive pleuritis which may follow a spontaneous pneumothorax. Subpleural blebs may occur in chronic pcp. The blebs may rupture spontaneously leading to one or more episodes of pneumothorax, interstitial pulmonary 6brosis, pulmonary septal cell reactive hyperplasia and occasional deposition of calcific salts which may be related to therapy with aerosolized pentamidine..... However, the patient was not infected with PCP and had never been treated with pentamidine. There was no evidence ofasbestos exposure in the patient, nor was there evidence of asbestos in the surgical or autopsy specimens. However, it should be noted that one third of mesothelioma cases are not associated with a history of asbestos exposure. We found no other etiologic factors responsible for non-asbestos-related malignant mesothelioma. We could not implicate previous irradiation or exposure to nickel, silica, beryllium, erionite or organic chemicals. Carcinoma of the lung associated with HIV infection was reported in eight patients by Monfardini et al.· Four had an
adenocarcinoma; two were small cell, one was a squamous cell and one was a mesothelioma. The median age was low, occurring in young adults of whom all but one were smokers. Braun et all O described the clinical and radiographic 6ndings in six patients seropositive with HIY. The patients were in a younger age group than is commonly associated with lung cancer. Radiographs demonstrated mediastinal adenopathy, hilar masses, parenchymal masses and pleural effusions. Other reports of lung cancer associated with AIDS include those of Nguyen et al," Nusbaum," Moser et al'3and Irwin et al." Thus, we still believe it is appropriate to suggest that the malignant mesothelioma in this patient has an AIDS connection. The causes for the development and increasing incidence of malignant neoplasms in AIDS patients has not been determined. However, various theories have been published . Immunode6ciency results in loss of immunologic surveillance with the propensity for proliferation of malignant cells." REFERENCES
1 Monfardini S, Vaccher E, Pizzocaro G, Stellini R, Siniceo A, Sabbatani S, et al, Unusual malignant tumors in 49 patients with HIV infection. Aids 1989; 7:449-52 2 Quilichini R, Pommier De Santi P, Marqueste L, DurandGasselin J, Aubert L, Chaffanjon P. Pleural mesothelioma in a HIV seropositive patient. Presse Medicale 1989; 18:495-6 3 Peterson ]T, Greenberg SO, BufBer PA. Non-asbestos-related malignant mesothelioma: a review. Cancer 1984; 54:951-60 4 Whitcomb ME, Schwarz MI, Charles MA. Interstitial fibrosis after Pneumocystis carinii pneumonia . Ann Intern Med 1970; 73:761-5 5 Eng RHK, Bishburg E, Smith SM. Evidence for destruction of lung tissues during Pneumocystis carinU infection. Arch Intern Med 1987; 147:746-9 6 Martinez CM, Romanelli A, Mullen Mp, Lee M. Spontaneous pneumothomces in AIDS patients receiving aerosolized pentamidine . Chest 1989; 94:1317-8 7 Feuerstein 1M, Archer A, Pluda J, Francis P, Falloon J, Masur H , et al. Thin-walled cavities and pneumothorax in patients with Pneumocystis carinll pneumonia CT demonstration. Radiology 1990; 174:697-702 8 Tmvis WD, Pitta1uga S, Lipschik GY, Ognibene F, Suffredini A, Masur H, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am J Surg Patholl990; 14:615-25 9 Monfardini S, Vaccher E, Pizzocaro G. Rare HIV related tumors in intravenous drug abusers consist mainly in testicular, cervical and pulmonary rather than oral and anorectal carcinomas [abstract) . Proc Am Soc Clin Oncoll989; 8:5 10 Bmun MA, Killam DA, Remick SC, Ruckdescehl JC. Lung cancer in patients seropositive for human immunodeficiency virus. Radiology 1990; 175:341-3 11 Nguyen VQ, Ossorio MA, Roy TM. Bronchogenic carcinoma and the acquired immunodeficiency syndrome . J Ky Med Assoc 1991: 89:322-4 12 Nusbaum MJ. Metastatic small cell carcinoma of the lung in a patient with AIDS. N Eng! J Med 1985: 312:1706 13 Moser RJ, Tenholder MF, Rideour R. Oat cell carcinoma in transfusion associated acquired immunodeficiency syndrome . Ann Intern Med 1985; 103:478 14 Irwin LE , Begandy MK, MooreTM . Adenosquarnouscarcinoma of the lung in the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100:158 15 Penn I. The occurrence of malignant tumors in immunosuppressed states. Prog Allergy 1986; 37:254-300 CHEST I 103 I 4 I APRIL, 1993
1289
A 35-year-old male homosexual, a former intravenous drug abuser, was found to be human immunodeficiency virus (IDV) positive in 1984. He developed AIDS in 1987 and began treatment with zidovudine in 1989. One year later he developed left apical pleural blebs, a pneumothorax and an exudative pleural effusion. A malignant mesothelioma developed at the pleural blebs in the left apex. He was treated with adriamycin but rapid progression of the malignancy occurred and he died three months later. At autopsy, a malignant mesothelioma, causing respiratory failure and death, was found. The patient had DO exposure to asbestos and asbestosis was not present at autopsy. We postulate that the development of malignant mesothelioma was probably related to HIV immune suppression or HIV and/or cytomegalovirus or zidovudine and is a complication of AIDS similar to the development of other malignant neoplasms in patients with AIDS. (Chest 1993; 103:1268-69)
P
atients with human immunodeficiency virus (HIV) disease may develop various malignant neoplasms. The two most common malignancies are Kaposi's sarcoma and nonHodgkin's lymphoma. Two cases of malignant mesothelioma in HIV paitents have been cited in European reports. I.! We recently have observed a HIV-positive patient who died of a rapidly progressive malignant mesothelioma. He had no asbestos exposure and had a negative history for other nonasbestos-related etiologic factors causing malignant mesothelioma such as exposure to irradiation, nickel, silica, beryllium, erionite and organic chemicals? We postulate that his malignant mesothelioma developed as a consequence of HIV immune suppression, HIV, cytomegalovirus or zidovudine activation of promoter oncogenes or induction of loss of suppression genes. CASE REPORT
The patient was a 35-year-old homosexual white male, exintravenous drug abuser and alcoholic, who had been HIV-positive since 1984. The AIDS-related complex was diagnosed in 1987 and he was first referred here in November of 1989. At that time, CD4 count was 135; therapy with prophylactic zidovudine and trimethoprim and sulfamethoxazole (Septra), twice a day, began. He did well until September 1990, when he presented with chest pain and hemoptysis. At that time, he was found to have apical pleural blebs, a left apicalpneumothorax and a small left pleural exudative effusion. The air was evacuated twice, but eventually a chest tube was required. Sputum was nondiagnostic; pleural fluid was sterile and bloody (20,000 RBC; 650 WBC; glucose, 76 mg/dl, TP, 4.1gtdl; lactic dehydrogenase, 1,040 UII.., pH 7.37; and cytology on both was negative for malignancy. Bronchoscopyfor Pneumocystis carinU pneumonia (PCP), staining with acid-fast bacilli and coccidioidomycosis and Cryptococcus serologies were negative as well. Com·From the Department of Pathology, Veterans Administration Medical Center, and University of California, San Diego. Reprint requests: Dr. "blf, UC Medical Center; 225 DIckinson, San
Diego
1268
92103
puted tomography showed a round mass-like density with a bleb in the left upper lobe and a paratracheal nodule . Aspergilloma versus cavitary neoplasm were considered. After two weeks of a pers istent air leak, he underwent a thoracotomy with pleural abrasion and bullae-mass excision. Examination of a frozen section of the sample led the investigators to suspect malignancy with margins of the malignancyclose but clear. The llnal pathology report was malignant mesothelioma. A consultant suggested that the nodule represented reactive mesothelium in response to PCP although the patient did not have PCp, and specimens removed at bronchoscopy were negative for PCp. The patient returned in December with progressive dyspnea , recurrent hemoptysis, pleuritic chest pain and fever. A large left upper lobe mediastinal mass was noted and a transtracheal needle aspiration again showed malignant cells. The patient was readmitted for reevaluation. The physical examination revealed the patient to be thin , with a temperature of39.2"C; a pulse of 114 beats per minute; respirations, 20 breaths per minute; Bp, 120170 mm Hg, poor dentition; jugular venous pulse, 8. There were decreased hreath sounds in the left posterior area of the chest and dullness in the left side of the chest . Tachycardia was present. The liver span was 10cm below the coastal margin. Results of the extremities, neurologic and genitourinary examination were within normal limits. Laboratory studies included the following values: WBC count, 5,2OG'cu mm! hematocrit, 27.1 percent; hemoglobin, 9.3 gldl; platelets, 452,()()(Vcu mm; differential WBC count, 77 percent segmented neutrophils, 3 percent bands, 11 percent lymphocytes, 6 percent monocytes, 1 percent eosinophil and 2 percent basophils. HospUal Course
The Heme/Oncology consultant felt that given the rapid growth, the mass was malignant and suggested bimodal therapy (radiation and chemotherapy). Irradiation was initiated the next day. It was believed that chemotherapy was of unlikely benefit, but since the patient requested all possible therapy, low-dose weelcly treatment with adriamycin was begun . Lactic dehydrogenase level rose to 2,010 UII... By January 1991, there had been marked progression of the malignant mesothelioma along with cachexia, pain, dysphagia and severe dyspnea. The patient died on February 5, 1991.
Results of the Autopsy The most significant llnding at autopsy was the nearly complete replacement of the left lung by a necrotic, hemorrhagic, malignant neoplasm (Fig 1). The malignancy was densely adherent to the parietal pleura over all surfaces of the lung; no normal pleural surfaces could be identified . It invaded the mediastinum and the
FIGURE 1. Gross photograph of the left lung demonstrating the malignant mesothelioma originating from the pleural surface and invading and nearly completely replacing the left lung. AIDS and MalIgnant MesoIheIloma (Behling, WOlf, Heghlghl)
FIGURE 2. Histologic section demonstrating the malignant mesothelioma (hematoxylin and eosin, original magnification x 4(0) . pericardium. Microscopically, the neoplasm was largely necrotic. Viable areas showed sheets and cords of poorly differentiated malignant cells with scant cytoplasm and large nuclei with nucleoli (Fig 2). The individual malignant cells were separated by a fine network of mucopolysaccharides and hyaluronic acid. Mucicarmine stains were negative and alcian blue stains were positive; alcian blue was removed by pretreatment with hyaluronidase. Immunocytochemical stains demonstrated that the malignant cells were positive for cytokemtin and vimentin and negative for carcinoembryonic antigen. Thus, this malignant neoplasm was consistent with a malignant mesothelioma. Metastatic malignant mesothelioma was found on the surface of the dum over the left cerebral hemisphere, abdominal, bronchial and hilar lymph nodes, epicardium and right kidney. DISCUSSION
The development of a malignant mesothelioma in a patient with AIDS may be purely fortuitous. However, since a number of malignant neoplasms have developed in AIDS patients, it would be appropriate to perhaps suspect that there may be a connection . A number of investigations certainly have demonstrated a connection with the development of Kaposi's sarcoma or non-Hodgkins lymphoma in AIDS patients. The patient presented clinically with signs and symptoms of a malignant mesothelioma. The patient had chest pain and an exudative pleural effusion. He developed pleural blebs with a subsequent pneumothorax. The malignant mesothelioma developed at the site of the apical pleural blebs in the left lung. Differential diagnosis of the pleural lesion included a reactive pleuritis which may follow a spontaneous pneumothorax. Subpleural blebs may occur in chronic pcp. The blebs may rupture spontaneously leading to one or more episodes of pneumothorax, interstitial pulmonary 6brosis, pulmonary septal cell reactive hyperplasia and occasional deposition of calcific salts which may be related to therapy with aerosolized pentamidine..... However, the patient was not infected with PCP and had never been treated with pentamidine. There was no evidence ofasbestos exposure in the patient, nor was there evidence of asbestos in the surgical or autopsy specimens. However, it should be noted that one third of mesothelioma cases are not associated with a history of asbestos exposure. We found no other etiologic factors responsible for non-asbestos-related malignant mesothelioma. We could not implicate previous irradiation or exposure to nickel, silica, beryllium, erionite or organic chemicals. Carcinoma of the lung associated with HIV infection was reported in eight patients by Monfardini et al.· Four had an
adenocarcinoma; two were small cell, one was a squamous cell and one was a mesothelioma. The median age was low, occurring in young adults of whom all but one were smokers. Braun et all O described the clinical and radiographic 6ndings in six patients seropositive with HIY. The patients were in a younger age group than is commonly associated with lung cancer. Radiographs demonstrated mediastinal adenopathy, hilar masses, parenchymal masses and pleural effusions. Other reports of lung cancer associated with AIDS include those of Nguyen et al," Nusbaum," Moser et al'3and Irwin et al." Thus, we still believe it is appropriate to suggest that the malignant mesothelioma in this patient has an AIDS connection. The causes for the development and increasing incidence of malignant neoplasms in AIDS patients has not been determined. However, various theories have been published . Immunode6ciency results in loss of immunologic surveillance with the propensity for proliferation of malignant cells." REFERENCES
1 Monfardini S, Vaccher E, Pizzocaro G, Stellini R, Siniceo A, Sabbatani S, et al, Unusual malignant tumors in 49 patients with HIV infection. Aids 1989; 7:449-52 2 Quilichini R, Pommier De Santi P, Marqueste L, DurandGasselin J, Aubert L, Chaffanjon P. Pleural mesothelioma in a HIV seropositive patient. Presse Medicale 1989; 18:495-6 3 Peterson ]T, Greenberg SO, BufBer PA. Non-asbestos-related malignant mesothelioma: a review. Cancer 1984; 54:951-60 4 Whitcomb ME, Schwarz MI, Charles MA. Interstitial fibrosis after Pneumocystis carinii pneumonia . Ann Intern Med 1970; 73:761-5 5 Eng RHK, Bishburg E, Smith SM. Evidence for destruction of lung tissues during Pneumocystis carinU infection. Arch Intern Med 1987; 147:746-9 6 Martinez CM, Romanelli A, Mullen Mp, Lee M. Spontaneous pneumothomces in AIDS patients receiving aerosolized pentamidine . Chest 1989; 94:1317-8 7 Feuerstein 1M, Archer A, Pluda J, Francis P, Falloon J, Masur H , et al. Thin-walled cavities and pneumothorax in patients with Pneumocystis carinll pneumonia CT demonstration. Radiology 1990; 174:697-702 8 Tmvis WD, Pitta1uga S, Lipschik GY, Ognibene F, Suffredini A, Masur H, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am J Surg Patholl990; 14:615-25 9 Monfardini S, Vaccher E, Pizzocaro G. Rare HIV related tumors in intravenous drug abusers consist mainly in testicular, cervical and pulmonary rather than oral and anorectal carcinomas [abstract) . Proc Am Soc Clin Oncoll989; 8:5 10 Bmun MA, Killam DA, Remick SC, Ruckdescehl JC. Lung cancer in patients seropositive for human immunodeficiency virus. Radiology 1990; 175:341-3 11 Nguyen VQ, Ossorio MA, Roy TM. Bronchogenic carcinoma and the acquired immunodeficiency syndrome . J Ky Med Assoc 1991: 89:322-4 12 Nusbaum MJ. Metastatic small cell carcinoma of the lung in a patient with AIDS. N Eng! J Med 1985: 312:1706 13 Moser RJ, Tenholder MF, Rideour R. Oat cell carcinoma in transfusion associated acquired immunodeficiency syndrome . Ann Intern Med 1985; 103:478 14 Irwin LE , Begandy MK, MooreTM . Adenosquarnouscarcinoma of the lung in the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100:158 15 Penn I. The occurrence of malignant tumors in immunosuppressed states. Prog Allergy 1986; 37:254-300 CHEST I 103 I 4 I APRIL, 1993
1289