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Bronchogenic Carcinoma in Patients Seropositive for Human Immunodeficiency Virus
Bronchogenic Carcinoma in Patients Seropositive for Human Immunodeficiency Virus* Michael F. Tenholder; M.D., F.C.C.P.; and Harold D. jackson, M.D. As the HIV epidemic continues and the patients are closely followed throughout the course of the illness from HIV seropositivity to depressed total CD4 counts, the natural history of lung cancer in this population is evolving. HIVinfected patients with lung cancer are in general younger men with significant smoking histories. Adenocarcinoma is the predominant cell type. There has been no correlation between stage of lung cancer and CD4 counts. The lung cancer stage at presentation has also not affected prognosis (no survivors beyond 1 year from diagnosis). While HIV
seropositivity has not yet been identified as a risk factor for bronchogenic carcinoma, the current literature suggests that lung neoplasms behave in an aggressive manner in HIV-positive patients. We present two cases to illustrate the value of transbronchial biopsy which should be performed in all patients with masses, nodules, or focal lesions that persist despite appropriate therapy for opportunistic organisms in HIV-positive patients.
epidemiologic studies suggest an increased incidence of malignancy in persons with human immunodeficiency virus (HIV) infection, the incidence of bronchogenic carcinoma has not increased in persons with HIV infection. 1 In this study, the registry risk for Kaposi's sarcoma increased 1 ,850-fold and for non-Hodgkin's lymphoma (especially Burkitt's and immunoblastic) it increased 6.2-fold. 1 Lung cancer incidence did not change, but nonsignificant increases in some other tumors, notably testicular, Hodgkin's disease, hepatoma, urinary tract, and acute lymphoblastic leukemia occurred. 1 In another study at a suburban New York hospital, the overall attack rate for malignancy in HIV-positive patients was 14.5 percent (29 of 200). The incidence of neoplastic disease in the patients with Centers for Disease Control (CDC)defined AIDS was 33 percent (25 of 75).2 Infection with HIV causes increased proliferation (hyperplasia) of epidermal cells. 3 This may account for the increase in squamous cell carcinomas of the oral cavity and anorectum observed in AIDS patients. It is also noteworthy that invasive cervical carcinoma has been added to the list of AIDS-defining illnesses. 4 While opportunistic pathogens account for the majority of intrathoracic abnormalities, pulmonary neoplasms are being encountered more often than would be expected for the age group under consideration. The 45 bronchogenic cancers in HIV-infected individuals reported to date indicate a different clinical behavior pattern from that seen in non-HIV-infected patients with lung cancer. 5 Clinicians need to be vigilant for the possibility of the early appearance of bronchogenic carcinoma in this subset of patients.
Since the earliest reported cases of patients with HIV and lung cancer,6 •7 it has been recognized that bronchogenic neoplasms would be difficult to separate clinically from HIV-related opportunistic infection, Kaposi's sarcoma, or non-Hodgkins lymphoma. 8 During the last 4 years, 226 patients have been enrolled for follow-up in our HIV clinic and 328 patients have been diagnosed or treated at our institution for lung cancer. We have identified two patients with bronchogenic carcinoma and HIV infection. Both had their conditions diagnosed by transbronchial lung biopsy specimens. We present these cases and the literature review to emphasize the rapid characteristic course of lung cancer in HIV infection and to stress the importance of early trans bronchial biopsy for this diagnosis.
~though
*From the Medical College of Georgia (Drs. Ten holder and Jackson) and the Pulmonary Disease Section, VA Medical Center (Dr. Tenholder), Augusta, Georgia. This work was supported by the Research Service of the Veterans Affairs Medical Center, Augusta, Georgia. Manuscript received December 4, 1992; revision accepted February 19, 1993.
(Cheat 1993; 104:1049-53)
CASE REPORTS CASE
1
A 64·yea.r-old homosexual black man with an 80 pack-year history of tobacco use was hospitalized in November 1991 for evaluation of progressive dementia. He was confirmed HIV-positive in June 1989. In March 1991, he had a CD4 cell count of 77 without an AIDSdefining illness. His hospital admission CD4 cell count was 13 with a CDS cell count of 517 with a ratio of0.025. He had herpes zoster on the left Hank in a Tll-12 dermatome that was being treated with acyclovir (200 mg, three times a day). He also took azidothymidine (100 mg five times a day) for AIDS-related progressive dementia. The chest radiograph showed an enlarged cardiac silhouette and a 3.5-cm right lower lobe mass (Fig 1). His echocardiogram demonstrated mild left ventricular enlargement and moderate concentric left ventricular hypertrophy with an ejection fraction of 34 percent. Global hypokinesis was present along with calcified aortic and mitral valves. This aortic, mitral, and tricuspid valves were all moderately regurgitant. A computed tomographic (CI') examination of the head revealed diffuse cortical atrophy. Fiberoptic bronchoscopy showed no endobronchial abnormalities and transbronchial biopsy specimen under fluoroscopic guidance was positive for smallcell carcinoma. The patient received palliative radiation therapy for fever and postobstructive pneumonia (3,000 rad in ten fractions over 2 weeks). Systemic chemotherapy was considered but refused by the patient. He died of his malignancy 4 months after completing radiation therapy. CHEST I 104 I 4 I OCTOBER, 1993
1049
FIGURE 1. The chest radiograph shows an enlarged cardiac silhouette and a 3 5. -cm right lower lobe mass. CASE
2
A 56-year-old homosexual black man with a 30 pack-year history of tobacco use was hospitalized in March 1991 for pneumonia with associated hypoxemia. The chest radiograph revealed consolidative changes with air bronchograms in right middle and lower lobes, and an associated right pleural effusion (Fig 2). The mediastinum and hila were free of disease at this time. 1n view of his history of homosexual encounters, HIV-1 antibody serologic test was obtained; results were positive. His CD4 cell count was 613. Blood and sputum cultures grew Streptococcus pneumoniae. The patient responded favorably to intravenous penicillin G (2 million units ever 6 h). A follow-up radiograph showed the pneumonia had resolved but a new lesion was seen in the left upper lobe near the aortopulmonary window. A CT scan was ordered but he failed to keep follow-up appointments. The patient returned with a 3-week history of a nonproductive cough, progressive dyspnea on exertion, anorexia, and a 8.55-kg weight loss. The chest radiograph demonstrated a large lobulated mediastinal mass with bilateral reticulonodular inflltrates {Fig 3). Flexible fiberoptic bronchoscopy revealed multiple nodular, "pearly" lesions in the left upper lobar bronchus. Bronchial and transbronchial biopsy specimens showed metastatic adenocarcinoma with extensive lymphatic invasion by tumor (Fig 4). All cultures and bronchoalveolar lavage specimens were negative for infectious agents and malignancy. The CD4 cell count was 393 and the CDS cell count was 1,080 with a CD4/CD8 ratio of0.36. The patient received radiation therapy, 4,600 rad to the mediastinum over 4'/• weeks. Treatment with azidothymidine was started prior to hospital discharge. The patient died of widespread malignant disease 3 months after completing radiation therapy.
FIGURE 2. The chest radiograph shows right middle and lower lobe consolidation, air bronchograms, and an associated right pleural effusion.
percent) predominates as a histologic subtype. Sixteen of the patients (61 percent) are younger than 40 years old and only 2 are female. In contrast, non-HIV-
DISCUSSION
Prior to the study of Sridhar et al, 5 26 HIV-positive patients with bronchogenic neoplasms, including the 2 patients in this report, are described in the medical literature (Table 1). 6 •7 ·1H 4 Adenocarcinoma (14/26, 54 1050
FIGURE 3. The chest radiograph demonstrates bilateral and subcarinal mediastinal adenopathy with bilateral reticulonodular infiltrates most prominent in the left upper lobe. Bronchogenic Carcinoma in HIV-Seropositive Patients (Tenho/der. Jackson)
FIGURE 4. The histologic features of the transbronchial biopsy specimen (H and E, original magnification X 400) demonstrate malignant adenocarcinoma cells in dilated submucosal lymphatic channels.
infected persons are older and adenocarcinoma is the histologic subtype in only 30 percent. The typical symptoms of lung cancer (cough, chest pain, hemoptysis, dyspnea) do not distinguish HIV-infected from noninfected patients. The dyspnea from the infectious diseases ofHIV-infected individuals may actually mask the presence of a simultaneous or underlying malignancy.7 All of the typical radiographic findings of lung cancer like mediastinal adenopathy, hilar masses, parenchymal pulmonary masses, and pleural effusions are also seen in the infections associated with AIDS (Table 1). In fact, we thought our second patient with a CD4 count >200 mm3 and a radiograph showing mediastinal adenopathy and interstitial lung disease was very likely to have widespread Mycobacterium tuberculosis infection. Even lymphoma or Kaposi's sarcoma was considered more likely than widespread lymphangitic adenocarcinoma. This presentation emphasizes the importance of considering lung cancer at this stage of HIV infection. During a 2-year study (1986 to 1988), the Italian Cooperative Group on AIDS-Related Tumors documented 49 HIV-related tumors other than malignant
lymphomas and Kaposi's sarcomas, predominantly among HIV-infected intravenous drug abusers. 14 In Italy, AIDS occurs predominantly (67 percent) in intravenous drug abusers, while only 18 percent are homosexual men. Lung cancer associated with HIV infection was observed in eight male patients, all but one of whom were smokers. Two of these eight were HIV-positive, two had progressed to the generalized lymphadenopathy stage, two had AIDS-related complex, and two had CDC-defined AIDS (cases 17 to 24, Table 1). Three patients were unable to receive treatment; four died while being treated because of progression of the neoplasia, and one died of an overdose. As we were compiling our data, an additional 19 patients with HIV infection and lung cancer were reported from the Sylvester Comprehensive Cancer Center at the University of Miami School of Medicine during a 5-year period 1986 to 1991.5 In this largest series of HIV-infected lung cancer patients reported to date, their patients were all male with significant smoking histories (median, 60 pack-years) and were young (median, 48 years). The authors found no correlation between the stage oflung cancer and CD4 counts. 5 Nine of their 19 HIV-seropositive patients had no HIV-related opportunistic infections and were essentially asymptomatic (CDC group 2 or 3 disease).5·15 It is worrisome that lung cancer may appear earlier in the course of HIV infection than other more commonly encountered neoplasms. 15 Only two patients had potentially resectable disease at presentation, but both died of metastatic disease (cases 7 and 13, Table 1). The available survival data suggest a very grim prognosis with no survivors beyond 1 year from diagnosis. In the study by Sridhar and colleagues, 5 the median survival was 3 months in the HIV-positive patients and there were no 1-year survivors.15 There has been no benefit demonstrated to date for the diagnosis oflimited as opposed to extensive small-cell carcinoma (Table 1). Even though patient 9 (Table 1) responded to chemotherapy and died of a drug overdose, no survival benefit can be attributed to radiation therapy or chemotherapy at this point. Another factor apparent from this review is the importance of a transbronchiallung biopsy specimen in establishing the presence of malignancy in HIVinfected patients. While bronchoalveolar lavage has a high diagnostic yield for opportunistic organisms, the cytologic examination of the lavage fluid and or bronchial washings has been disappointing in confirming malignancy and the biopsy specimen has been the sole diagnostic material in at least seven of these cases (Table 1). As we recommended earlier/ transbronchial lung biopsy should be performed in all patients with masses, nodules, or focal lesions that persist despite appropriate therapy for opportunistic organisms in patients who are HIV positive. CHEST I 104 I 4 I OCTOBER, 1993
1051
Table 1-Lung Cancer in HIV-Seropositive Patients* Reference No./ Case No./ Sex/Age, yr
Risk Factors
6/lJM/35
Homosexual
7121M/65 9131M/39 914/M/48
Transfusion IVDA, homosexual Homosexual
915/M/30
IVDA
916/M/38
Homosexual
917/M/37 QI8/M/46
Stage
Tumor
Radiographic Findings
NR
Adenosquamous
IV
None
3 84
30 15
Small cell Adenocarcinoma
Limited IIIB
PCP PCP, PPD+
16
50
Adenocarcinoma
IIIB
30
Small cell
Limited
Hepatitis B, ITP Hepatitis
15
Adenocarcinoma
IIIB
PCP
IVDA
20
Adenocarcinoma
IVDA
50
Hilar mass, mediastinal adenopathy Anterior mediastinal mass Cavitary right lower lobe mass
11110/M/45 311lfM/34
Homosexual
4
TB, asbestos exposure TB, hepatitis
1
NR
IV Squamous cell carcinoma Dysplastic carcinoid Extensive None
6
30
Small cell
None
Extensive Kaposi's sarcoma IV Candida oral plaques IV Toxoplasmosis
Adenocarcinoma
12/12/F/29
IVDA
24
25
Squamous cell
12/13/M/59
Homosexual
24
85
Adenocarcinoma
12/14/M/58
Prostitute
18
20
Adenocarcinoma
IIIF
131151M/28 13116/M/28 14/17-24/M 6<35, 1 (47) 1 (48}
Unknown IVDA NR
NR NR NR
10 25 7/8 Smokers
Homosexual Homosexual
29 14
80 30
Adenocarcinoma Squamous cell Adenocarcinoma (4) Small cell (2} Squamous cell (1} Mesothelioma Small cell Adenocarcinoma
IIIB IIIB III Limited III Limited Limited IIIB
T/25/M/64 T/26/M/56
Associated Diseases
4
Prostitution, IVDA Homosexual
1019/F/29
Tobacco Interval, Use , pack-years mo
Candida oral plaques Candida oral toxoplasmosis NR NR 518 positive type NR
Herpes zoster None
Right apical mass, mediastinal adenopathy, right scapula lytic lesion 2-cm lingular mass Lung mass, pleural effusion, mediastinal adenopathy Hilar mass, mediastinal adenopathy, pleural effusion Hilar mass, mediastinal adenopathy Lung mass, mediastinal adenopathy Lung mass
Right lower lobe consolidation, pleural effusion Right superior segment collapse, mediastinal adenopathy Right superior segment mass Left lower lobe mass, mediastinal adenopathy NR NR NR
Right lower lobe mass Mediastinal mass, interstitial disease
*NR =not reported; IVDA =intravenous drug abuse; Interval= time between HIV positivity and diagnosis oflung cancer; T=cases from this report; PCP= Pneumocystis carinli pneumonia; ITP =idiopathic thrombocytopenic purpura; TB =tuberculosis.
It remains difficult to predict during which stage of HIV infection that bronchogenic cancer will present. There are 16 cases in which the interval from diagnosis is reported and 9 of these cancers were found within 6 months of known HIV infection (Table 1). Like Sridhar and colleagues,5 we could find no predictive correlation to CD4 cell count with a range of 13/mm3 to 500/mm3 and a mean of 285 mm3 in the eight cases in which lymphocyte subtyping was reported (Table 1). A relationship may yet be discovered that would enable us to use the helper/suppressor lymphocyte ratio to choose appropriate therapeutic options. Whether increases in lung cancer will occur as specific therapies prolong survival in HIV-infected persons remains to be seen. Since an alteration in the immunologic system by immune-modulating treatment may have already changed the incidence of non-Hodgkin's lymphoma, 16 it certainly merits watching lung neo1052
plasm incidence in a prospective manner. REFERENCES
2
3
4
5
6
Biggar RJ, Burnett W, Mikl J, Nasca P. Can~-er among New York men at risk of acquired immunodeficiency syndrome. lnt J Cancer 1989; 43:979-85 Kaplan MH, Susin M, Pahwa SC, Fe lten J, Allen SL, Lichtman S. Neoplastic complications of HTLV-III infection. Am J Med 1987; 82:389-96 Nguyen VQ, Ossorio MA, Roy TM . Bronchogenic carcinoma and the acquired immunodeficiency syndrome. Ky Med Assoc J 1991; 89:322-24 CDC. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992; 41 (No. RR-17) Sridhar KS, Flores MR, Raub WA , Saldana M. Lung cancer in patients with human immunodeficiency virus infection compared with historic control subjects. Chest 1992; 102:1704-08 Irwin LE , Begandy MK, Moore TM . Adenosquamouscarcinoma of the lung in the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100:158 Bronchogenic Carcinoma in HIV-Seropositive Patients (Tenholder, Jackson)
7 Moser RJ, Tenholder MF, Ridenour R. Oat-cell carcinoma in transfusion associated acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:478 8 Northfelt DW, Jacobson MA. Is there an association between lung cancer and HIV infection? J Respir Dis 1991; 12:358 9 Braun MA, Killam DA, Remick SC, Ruckdeschel JC. Lung cancer in patients seropositive for human immunodeficiency virus. Radiology 1990; 175:341-43 10 Weitberg AB, Mayer K, Miller ME, Mikolich DJ. Dysplastic carcinoid tumor and AIDS-related complex. N Engl J Med 1986; 314:1455 11 Nusbaum NJ. Metastatic small-cell carcinoma of the lung in a patient with AIDS . N Engl J Med 1985; 312:1706 12 Francois T, Igual J, Cadranel J, Milleron B, Parquin F, Mayaud C, et al. Bronchial carcinoma in patients with human immuno-
13
14
15 16
deficiency virus (H1V) infection. Rev Pneumol Clin 1990; 46:99102 Broussier PM, Postal MJ, Gillet K, Antoun F, Dautzenherg B. Cancer bronchique au cours du sida. Rev Pneumol Clin 1989; 6:R189 Monfardini S, Vaccher E, Pizzocaro G, Stellini R. Sinicm A, Sabbatani S, et al. Unusual malignant tumours in 49 patients with HIV infection. AIDS 1989; 3:449-52 Remick SC. Lung cancer-an HIV-related neoplasm or a coincidental finding? Chest 1992; 102:1643-44 Pluda JM, Yarchoan R, Jaffe ES, Feuerstein IM. Solomon D, Steinberg SM, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990; 113:276-82
5th Paulista Congress on Pulmonary and Bronchial Medicine The Paulista Society of Pulmonary and Bronchial Medicine will present this congress at the Centro de Convencoes Reboucas, Sao Paulo, Brazil, November 7-10. For information, contact the Secretariat: Coordenacao de Eventos Reboucas, Av. Reboucas 600, 05402 Sao Paulo, SP, Brazil (fax: 55 11 881-1125).
CHEST I 104 I 4 I OCTOBER. 1993
1053
seropositivity has not yet been identified as a risk factor for bronchogenic carcinoma, the current literature suggests that lung neoplasms behave in an aggressive manner in HIV-positive patients. We present two cases to illustrate the value of transbronchial biopsy which should be performed in all patients with masses, nodules, or focal lesions that persist despite appropriate therapy for opportunistic organisms in HIV-positive patients.
epidemiologic studies suggest an increased incidence of malignancy in persons with human immunodeficiency virus (HIV) infection, the incidence of bronchogenic carcinoma has not increased in persons with HIV infection. 1 In this study, the registry risk for Kaposi's sarcoma increased 1 ,850-fold and for non-Hodgkin's lymphoma (especially Burkitt's and immunoblastic) it increased 6.2-fold. 1 Lung cancer incidence did not change, but nonsignificant increases in some other tumors, notably testicular, Hodgkin's disease, hepatoma, urinary tract, and acute lymphoblastic leukemia occurred. 1 In another study at a suburban New York hospital, the overall attack rate for malignancy in HIV-positive patients was 14.5 percent (29 of 200). The incidence of neoplastic disease in the patients with Centers for Disease Control (CDC)defined AIDS was 33 percent (25 of 75).2 Infection with HIV causes increased proliferation (hyperplasia) of epidermal cells. 3 This may account for the increase in squamous cell carcinomas of the oral cavity and anorectum observed in AIDS patients. It is also noteworthy that invasive cervical carcinoma has been added to the list of AIDS-defining illnesses. 4 While opportunistic pathogens account for the majority of intrathoracic abnormalities, pulmonary neoplasms are being encountered more often than would be expected for the age group under consideration. The 45 bronchogenic cancers in HIV-infected individuals reported to date indicate a different clinical behavior pattern from that seen in non-HIV-infected patients with lung cancer. 5 Clinicians need to be vigilant for the possibility of the early appearance of bronchogenic carcinoma in this subset of patients.
Since the earliest reported cases of patients with HIV and lung cancer,6 •7 it has been recognized that bronchogenic neoplasms would be difficult to separate clinically from HIV-related opportunistic infection, Kaposi's sarcoma, or non-Hodgkins lymphoma. 8 During the last 4 years, 226 patients have been enrolled for follow-up in our HIV clinic and 328 patients have been diagnosed or treated at our institution for lung cancer. We have identified two patients with bronchogenic carcinoma and HIV infection. Both had their conditions diagnosed by transbronchial lung biopsy specimens. We present these cases and the literature review to emphasize the rapid characteristic course of lung cancer in HIV infection and to stress the importance of early trans bronchial biopsy for this diagnosis.
~though
*From the Medical College of Georgia (Drs. Ten holder and Jackson) and the Pulmonary Disease Section, VA Medical Center (Dr. Tenholder), Augusta, Georgia. This work was supported by the Research Service of the Veterans Affairs Medical Center, Augusta, Georgia. Manuscript received December 4, 1992; revision accepted February 19, 1993.
(Cheat 1993; 104:1049-53)
CASE REPORTS CASE
1
A 64·yea.r-old homosexual black man with an 80 pack-year history of tobacco use was hospitalized in November 1991 for evaluation of progressive dementia. He was confirmed HIV-positive in June 1989. In March 1991, he had a CD4 cell count of 77 without an AIDSdefining illness. His hospital admission CD4 cell count was 13 with a CDS cell count of 517 with a ratio of0.025. He had herpes zoster on the left Hank in a Tll-12 dermatome that was being treated with acyclovir (200 mg, three times a day). He also took azidothymidine (100 mg five times a day) for AIDS-related progressive dementia. The chest radiograph showed an enlarged cardiac silhouette and a 3.5-cm right lower lobe mass (Fig 1). His echocardiogram demonstrated mild left ventricular enlargement and moderate concentric left ventricular hypertrophy with an ejection fraction of 34 percent. Global hypokinesis was present along with calcified aortic and mitral valves. This aortic, mitral, and tricuspid valves were all moderately regurgitant. A computed tomographic (CI') examination of the head revealed diffuse cortical atrophy. Fiberoptic bronchoscopy showed no endobronchial abnormalities and transbronchial biopsy specimen under fluoroscopic guidance was positive for smallcell carcinoma. The patient received palliative radiation therapy for fever and postobstructive pneumonia (3,000 rad in ten fractions over 2 weeks). Systemic chemotherapy was considered but refused by the patient. He died of his malignancy 4 months after completing radiation therapy. CHEST I 104 I 4 I OCTOBER, 1993
1049
FIGURE 1. The chest radiograph shows an enlarged cardiac silhouette and a 3 5. -cm right lower lobe mass. CASE
2
A 56-year-old homosexual black man with a 30 pack-year history of tobacco use was hospitalized in March 1991 for pneumonia with associated hypoxemia. The chest radiograph revealed consolidative changes with air bronchograms in right middle and lower lobes, and an associated right pleural effusion (Fig 2). The mediastinum and hila were free of disease at this time. 1n view of his history of homosexual encounters, HIV-1 antibody serologic test was obtained; results were positive. His CD4 cell count was 613. Blood and sputum cultures grew Streptococcus pneumoniae. The patient responded favorably to intravenous penicillin G (2 million units ever 6 h). A follow-up radiograph showed the pneumonia had resolved but a new lesion was seen in the left upper lobe near the aortopulmonary window. A CT scan was ordered but he failed to keep follow-up appointments. The patient returned with a 3-week history of a nonproductive cough, progressive dyspnea on exertion, anorexia, and a 8.55-kg weight loss. The chest radiograph demonstrated a large lobulated mediastinal mass with bilateral reticulonodular inflltrates {Fig 3). Flexible fiberoptic bronchoscopy revealed multiple nodular, "pearly" lesions in the left upper lobar bronchus. Bronchial and transbronchial biopsy specimens showed metastatic adenocarcinoma with extensive lymphatic invasion by tumor (Fig 4). All cultures and bronchoalveolar lavage specimens were negative for infectious agents and malignancy. The CD4 cell count was 393 and the CDS cell count was 1,080 with a CD4/CD8 ratio of0.36. The patient received radiation therapy, 4,600 rad to the mediastinum over 4'/• weeks. Treatment with azidothymidine was started prior to hospital discharge. The patient died of widespread malignant disease 3 months after completing radiation therapy.
FIGURE 2. The chest radiograph shows right middle and lower lobe consolidation, air bronchograms, and an associated right pleural effusion.
percent) predominates as a histologic subtype. Sixteen of the patients (61 percent) are younger than 40 years old and only 2 are female. In contrast, non-HIV-
DISCUSSION
Prior to the study of Sridhar et al, 5 26 HIV-positive patients with bronchogenic neoplasms, including the 2 patients in this report, are described in the medical literature (Table 1). 6 •7 ·1H 4 Adenocarcinoma (14/26, 54 1050
FIGURE 3. The chest radiograph demonstrates bilateral and subcarinal mediastinal adenopathy with bilateral reticulonodular infiltrates most prominent in the left upper lobe. Bronchogenic Carcinoma in HIV-Seropositive Patients (Tenho/der. Jackson)
FIGURE 4. The histologic features of the transbronchial biopsy specimen (H and E, original magnification X 400) demonstrate malignant adenocarcinoma cells in dilated submucosal lymphatic channels.
infected persons are older and adenocarcinoma is the histologic subtype in only 30 percent. The typical symptoms of lung cancer (cough, chest pain, hemoptysis, dyspnea) do not distinguish HIV-infected from noninfected patients. The dyspnea from the infectious diseases ofHIV-infected individuals may actually mask the presence of a simultaneous or underlying malignancy.7 All of the typical radiographic findings of lung cancer like mediastinal adenopathy, hilar masses, parenchymal pulmonary masses, and pleural effusions are also seen in the infections associated with AIDS (Table 1). In fact, we thought our second patient with a CD4 count >200 mm3 and a radiograph showing mediastinal adenopathy and interstitial lung disease was very likely to have widespread Mycobacterium tuberculosis infection. Even lymphoma or Kaposi's sarcoma was considered more likely than widespread lymphangitic adenocarcinoma. This presentation emphasizes the importance of considering lung cancer at this stage of HIV infection. During a 2-year study (1986 to 1988), the Italian Cooperative Group on AIDS-Related Tumors documented 49 HIV-related tumors other than malignant
lymphomas and Kaposi's sarcomas, predominantly among HIV-infected intravenous drug abusers. 14 In Italy, AIDS occurs predominantly (67 percent) in intravenous drug abusers, while only 18 percent are homosexual men. Lung cancer associated with HIV infection was observed in eight male patients, all but one of whom were smokers. Two of these eight were HIV-positive, two had progressed to the generalized lymphadenopathy stage, two had AIDS-related complex, and two had CDC-defined AIDS (cases 17 to 24, Table 1). Three patients were unable to receive treatment; four died while being treated because of progression of the neoplasia, and one died of an overdose. As we were compiling our data, an additional 19 patients with HIV infection and lung cancer were reported from the Sylvester Comprehensive Cancer Center at the University of Miami School of Medicine during a 5-year period 1986 to 1991.5 In this largest series of HIV-infected lung cancer patients reported to date, their patients were all male with significant smoking histories (median, 60 pack-years) and were young (median, 48 years). The authors found no correlation between the stage oflung cancer and CD4 counts. 5 Nine of their 19 HIV-seropositive patients had no HIV-related opportunistic infections and were essentially asymptomatic (CDC group 2 or 3 disease).5·15 It is worrisome that lung cancer may appear earlier in the course of HIV infection than other more commonly encountered neoplasms. 15 Only two patients had potentially resectable disease at presentation, but both died of metastatic disease (cases 7 and 13, Table 1). The available survival data suggest a very grim prognosis with no survivors beyond 1 year from diagnosis. In the study by Sridhar and colleagues, 5 the median survival was 3 months in the HIV-positive patients and there were no 1-year survivors.15 There has been no benefit demonstrated to date for the diagnosis oflimited as opposed to extensive small-cell carcinoma (Table 1). Even though patient 9 (Table 1) responded to chemotherapy and died of a drug overdose, no survival benefit can be attributed to radiation therapy or chemotherapy at this point. Another factor apparent from this review is the importance of a transbronchiallung biopsy specimen in establishing the presence of malignancy in HIVinfected patients. While bronchoalveolar lavage has a high diagnostic yield for opportunistic organisms, the cytologic examination of the lavage fluid and or bronchial washings has been disappointing in confirming malignancy and the biopsy specimen has been the sole diagnostic material in at least seven of these cases (Table 1). As we recommended earlier/ transbronchial lung biopsy should be performed in all patients with masses, nodules, or focal lesions that persist despite appropriate therapy for opportunistic organisms in patients who are HIV positive. CHEST I 104 I 4 I OCTOBER, 1993
1051
Table 1-Lung Cancer in HIV-Seropositive Patients* Reference No./ Case No./ Sex/Age, yr
Risk Factors
6/lJM/35
Homosexual
7121M/65 9131M/39 914/M/48
Transfusion IVDA, homosexual Homosexual
915/M/30
IVDA
916/M/38
Homosexual
917/M/37 QI8/M/46
Stage
Tumor
Radiographic Findings
NR
Adenosquamous
IV
None
3 84
30 15
Small cell Adenocarcinoma
Limited IIIB
PCP PCP, PPD+
16
50
Adenocarcinoma
IIIB
30
Small cell
Limited
Hepatitis B, ITP Hepatitis
15
Adenocarcinoma
IIIB
PCP
IVDA
20
Adenocarcinoma
IVDA
50
Hilar mass, mediastinal adenopathy Anterior mediastinal mass Cavitary right lower lobe mass
11110/M/45 311lfM/34
Homosexual
4
TB, asbestos exposure TB, hepatitis
1
NR
IV Squamous cell carcinoma Dysplastic carcinoid Extensive None
6
30
Small cell
None
Extensive Kaposi's sarcoma IV Candida oral plaques IV Toxoplasmosis
Adenocarcinoma
12/12/F/29
IVDA
24
25
Squamous cell
12/13/M/59
Homosexual
24
85
Adenocarcinoma
12/14/M/58
Prostitute
18
20
Adenocarcinoma
IIIF
131151M/28 13116/M/28 14/17-24/M 6<35, 1 (47) 1 (48}
Unknown IVDA NR
NR NR NR
10 25 7/8 Smokers
Homosexual Homosexual
29 14
80 30
Adenocarcinoma Squamous cell Adenocarcinoma (4) Small cell (2} Squamous cell (1} Mesothelioma Small cell Adenocarcinoma
IIIB IIIB III Limited III Limited Limited IIIB
T/25/M/64 T/26/M/56
Associated Diseases
4
Prostitution, IVDA Homosexual
1019/F/29
Tobacco Interval, Use , pack-years mo
Candida oral plaques Candida oral toxoplasmosis NR NR 518 positive type NR
Herpes zoster None
Right apical mass, mediastinal adenopathy, right scapula lytic lesion 2-cm lingular mass Lung mass, pleural effusion, mediastinal adenopathy Hilar mass, mediastinal adenopathy, pleural effusion Hilar mass, mediastinal adenopathy Lung mass, mediastinal adenopathy Lung mass
Right lower lobe consolidation, pleural effusion Right superior segment collapse, mediastinal adenopathy Right superior segment mass Left lower lobe mass, mediastinal adenopathy NR NR NR
Right lower lobe mass Mediastinal mass, interstitial disease
*NR =not reported; IVDA =intravenous drug abuse; Interval= time between HIV positivity and diagnosis oflung cancer; T=cases from this report; PCP= Pneumocystis carinli pneumonia; ITP =idiopathic thrombocytopenic purpura; TB =tuberculosis.
It remains difficult to predict during which stage of HIV infection that bronchogenic cancer will present. There are 16 cases in which the interval from diagnosis is reported and 9 of these cancers were found within 6 months of known HIV infection (Table 1). Like Sridhar and colleagues,5 we could find no predictive correlation to CD4 cell count with a range of 13/mm3 to 500/mm3 and a mean of 285 mm3 in the eight cases in which lymphocyte subtyping was reported (Table 1). A relationship may yet be discovered that would enable us to use the helper/suppressor lymphocyte ratio to choose appropriate therapeutic options. Whether increases in lung cancer will occur as specific therapies prolong survival in HIV-infected persons remains to be seen. Since an alteration in the immunologic system by immune-modulating treatment may have already changed the incidence of non-Hodgkin's lymphoma, 16 it certainly merits watching lung neo1052
plasm incidence in a prospective manner. REFERENCES
2
3
4
5
6
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7 Moser RJ, Tenholder MF, Ridenour R. Oat-cell carcinoma in transfusion associated acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:478 8 Northfelt DW, Jacobson MA. Is there an association between lung cancer and HIV infection? J Respir Dis 1991; 12:358 9 Braun MA, Killam DA, Remick SC, Ruckdeschel JC. Lung cancer in patients seropositive for human immunodeficiency virus. Radiology 1990; 175:341-43 10 Weitberg AB, Mayer K, Miller ME, Mikolich DJ. Dysplastic carcinoid tumor and AIDS-related complex. N Engl J Med 1986; 314:1455 11 Nusbaum NJ. Metastatic small-cell carcinoma of the lung in a patient with AIDS . N Engl J Med 1985; 312:1706 12 Francois T, Igual J, Cadranel J, Milleron B, Parquin F, Mayaud C, et al. Bronchial carcinoma in patients with human immuno-
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deficiency virus (H1V) infection. Rev Pneumol Clin 1990; 46:99102 Broussier PM, Postal MJ, Gillet K, Antoun F, Dautzenherg B. Cancer bronchique au cours du sida. Rev Pneumol Clin 1989; 6:R189 Monfardini S, Vaccher E, Pizzocaro G, Stellini R. Sinicm A, Sabbatani S, et al. Unusual malignant tumours in 49 patients with HIV infection. AIDS 1989; 3:449-52 Remick SC. Lung cancer-an HIV-related neoplasm or a coincidental finding? Chest 1992; 102:1643-44 Pluda JM, Yarchoan R, Jaffe ES, Feuerstein IM. Solomon D, Steinberg SM, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990; 113:276-82
5th Paulista Congress on Pulmonary and Bronchial Medicine The Paulista Society of Pulmonary and Bronchial Medicine will present this congress at the Centro de Convencoes Reboucas, Sao Paulo, Brazil, November 7-10. For information, contact the Secretariat: Coordenacao de Eventos Reboucas, Av. Reboucas 600, 05402 Sao Paulo, SP, Brazil (fax: 55 11 881-1125).
CHEST I 104 I 4 I OCTOBER. 1993
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