- Email: [email protected]
Lung cancer in patients with HIV-infection
ELSEVIER
Lung Cancer 15 (1996) 325-339
Lung cancer in patients with HIV-infection Rostislav Vyzula”‘, Scot C. Remick”ab,* aDivision of Medical Oncology, Albany Medical College, 47 New Scotland Ave., A-52, Albany, NY 12208, USA ‘Division of HIV Medicine, Albany Medical College, 47 New Scotland Ave., A-52, Albany, NY 12208, USA Received
19 March
1996; revised
I July
1996; accepted
9 July
1996
Abstract
Purpose: To identify and review the clinical characteristics and natural history of lung cancer in HIV-seropositive patients. A secondary objective was to compare the clinical features of HIV-seropositive and HIV-indeterminate lung cancer cases at our institution. Patients and methods: Sixteen patients with HIV infection and lung cancer were diagnosed between January 1988 and March 1995 at our institution and the clinical records were reviewed. HIV-indeterminate lung cancer cases were identified by the Albany Medical Center Hospital (AMCH) Tumor Registry. A Medline database search of HIV infection/AIDS and lung cancer was undertaken through December 1994. The New York State Department of Health (NYSDOH), Bureau of Cancer Epidemiology provided information on the incidence of lung cancer among residents of New York State by county of residence. Case reports and series regarding the clinical features of HIV-seropositive patients with lung cancer were reviewed. A more focused comparison between HIV-seropositive and HIV-indeterminate male lung cancer cases between 35 and 54 years of age at our institution was performed. The following clinical variables were identified in our 16 patients and 109 cases extracted from available clinical reports: sex, age, year and county of residence at time of lung cancer diagnosis, cigarette smoking history, HIV risk behavior, CD4 count at time of lung cancer diagnosis. CDC classification of HIV disease, interval in months from time of HIV
* Corresponding
author.
’ Current address: Department of Medicine, II Interna, University Hospital, Jihlavska 100, 639 00 Brno,
Czech
Republic.
0169-5002/96/$15.00
PZZ SO169-5002(95)00596-X
0 1996 Elsevier
Science
Ireland
Ltd.
All
rights
reserved
R. Vyzula,
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XC.
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seropositivity to lung cancer diagnosis, pathology and stage of lung cancer, performance status, treatment, response, and survival. Results: Lung cancer in HIV-seropositive patients is characterized by the following: a younger age at time of diagnosis when compared to HIV-indeterminate cases;the majority of casesoccur in a background of extensive cigarette smoking; over 80% of patients present with advanced stage of lung cancer (stage III and IV); up to 50% of cases have asymptomatic to mildly symptomatic HIV infection with a median CD4 lymphocyte count of 233 per ~1; there is a predominance of adenocarcinoma histopathology; and shortened survival when compared to HIV-indeterminate cases. Conclusion: Current reports of lung carcinoma in HIV-seropositive patients suggest that the natural history of this disease is different than in HIV-indeterminate cases. Lung cancer must be considered in the differential diagnosis of a solitary mass lesion on chest X-ray in HIV-seropositive patients. Keywords:
Lung cancer; HIV infection; Clinical characteristics
1. Introduction
It is apparent that as we approach the end of the second decade of the HIV epidemic solid tumors, other than AIDS-defining neoplasms, are increasingly recognized as causes of morbidity and mortality in this patient population [I]. The first case of lung,cancer in an HIV-infected patient was reported in 1984 [2]. A few case reports appeared thereafter [3,4]. In 1990 we reported six patients with concurrent HIV infection and lung cancer [5]. Several larger series of HIV-infected lung cancer patients have recently been published [6-81. Since our initial report, we have identified an additional ten cases of lung cancer from our HIV-infected population. This represents more than a doubling of cases at the midpoint of the second decade of the AIDS epidemic at our center. We are unaware of any detailed review of lung cancer cases in HIV-infected patients. A total of 109 coincident cases of lung cancer and HIV infection have been identified in the literature, and are the subject of this review. We have undertaken a preliminary epidemiological analysis of lung cancer in HIV-seropositive/AIDS cases in our medical center and referral region of New York State.
2. Patients and methods 2.1. Patients
HIV-infected patients with lung cancer were identified from referrals and clinical practices of the Divisions of HIV Medicine and Medical Oncology. Patients were also identified through participation in the multidisciplinary Chest Tumor Conference conducted at the Albany Medical Center and Hospital (AMCH). The Tumor Registry at AMCH was used to identify patients who were diagnosed as having
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327
lung cancer between January 1988 and December 1993. Data is incomplete for 1994 and 1995. The Tumor Registry does not track HIV-serostatus (HIV-indeterminate cases), but all HIV-infected patients with lung cancer were included in their records. A New York State Department of Health (NYSDOH) cancer registry search for all lung cancer cases diagnosed between 1981 and 1992 inclusive was also obtained. The NYSDOH cancer registry is incomplete for the years 1993-1995. Cases were identified by sex, age group (in the following ranges: O-14; 15-34; 35-54; 55-64; 65-74; and > 75 years), and county of residence. This permitted a more focused comparison of male lung cancer cases between the ages of 35 and 54. Pathologic diagnoses were establish in all patients by means of bronchoscopic biopsy (n = 6), mediastinoscopic biopsy (n = 3), cytologic examination of pleural fluid (n = l), and pathologic examination of a surgical specimen (n = 6). Patients were staged according to the revised International System for Staging Lung Cancer [9] adopted by the American Joint Committee on Cancer (AJCC) staging classification [lo]. In all patients, the pulmonary abnormality was initially suggested by plain chest radiographs and further defined by computed tomographic (CT) scans. Only one patient had coexisting intrathoracic disease (Pneumocystis carinii pneumonia). The remainder were free of concomitant opportunistic infections, lymphoma, or Kaposi sarcoma on basis of clinical, radiographic, and pathologic grounds. 2.2. Statistical analysis The following clinical characteristics were identified for all cases: sex, age, year and county of residence at the time of diagnosis of lung cancer, cigarette smoking history, HIV risk behavior, CD4 count at time of lung cancer diagnosis, Centers for Disease Control (CDC) classification of HIV disease by 1993 revised criteria [l 11, interval in months from time of HIV seropositivity to lung cancer diagnosis, pathology and stage of lung cancer by revised AJCC staging criteria [9,10], performance status (PS) by Eastern Cooperative Oncology Group (ECOG) criteria [12], treatment, response to treatment, and survival. Survival was plotted according to the method of Kaplan and Meier [ 131. The AMCH Tumor Registry was accessed to identify all cases of lung cancer between the years 1987 and 1993 and in males between 35 and 54 years of age. A total of 86 patients of whom 69 had non-small cell lung cancer (NSCLC) were identified. These patients were evaluated for histological type of lung cancer, stage of disease, and survival. These clinical features were compared to our HIVseropositive patients. The New York State Department of Health (NYSDOH) cancer registry tracks sex, age, county of residence at time of lung cancer diagnosis, and incidence of lung cancer by year of diagnosis [14]. The registry reports cancer incidence by decade, 198 1- 1990. We were able to obtain data for 1991 and 1992, the last years for which there is updated and complete data. Six HIV-seropositive patients with lung cancer
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1.5 (1996)
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were treated at our institution during this period. They resided in six different counties for which NYSDOH lung cancer incidence was retrieved. 2.3. Literature
review
The literature was reviewed for reports of HIV seropositivity, AIDS, and lung cancer through December 1994, employing a computer search of citations indexed in the National Library of Medicine’s and National Cancer Institute’s Medline, Cancerlit, and PDQ databases [2-815-371. Several cases were reported more than once [5,6,8,15,16,34]. For purposes of this review, cases were tabulated by year of the initial report or most complete clinical data. 3. Results
We report a series of 16 patients who developed HIV infection that preceded the development of lung cancer by a median interval of 9 months, range O-66 months. There were 15 males and 1 female with a median age of 44.5 years, range 30-61 years. All patients had a history of cigarette smoking, which was quantitated in 14 patients. Median duration of cigarette smoking was 30 pack-years, range 15-120 pack-years. Median CD4 lymphocyte at the time of lung cancer diagnosis in 13 patients was 184 per ~1, range 2-579 per ~1. CD4 lymphocyte count, at the time of lung cancer diagnosis was not available in three patients. CDC classification of HIV infection for all 16 patients was as follows: group A in two patients (13%); group A-2 in four patients (25%); group A-3 in three patients (19%); groups B-l,B-2, B-3 in one patient in each group (6% each); group C in one patient (6%); and group C-3 in three patients (19O/,). Note further subclassification by CD4 count was not available for three patients (two, group A, and one group C) as outlined above. The clinicopathological stage of lung cancer at time of presentation was as follows: stage I, three patients (19%); stage III B, in six patients (37%); stage IV, in seven patients (44%). Eight patients (50%) had adenocarcinoma; three patients (19%) squamous cell carcinoma; three patients (19%) large cell carcinoma; and two patients (12%) small cell carcinoma. Primary treatment consisted ofsurgical resection alone, three patients; systemic chemotherapy alone, five patients; radiation therapy alone, five patients; combined modality (chemotherapy and radiation), two patients; and supportive care/no therapy, two patient. Median survival was 21.5 weeks (range 2-56 weeks; n = 12 patients). Two patients remain alive at 15 and 77 weeks, respectively. Median survival for the 11 males between 35-54 years of age was 31 weeks. The clinical features of our 16 HIV-seropositive patients with lung cancer are summarized in Table 1. 3.1. HIV-seropositive
vs. HIV-indeterminate
males with lung cancer at AMCH
A total of 15 cases of HIV-seropositive males with lung cancer were seen at our center between January 1988 and March 1995. Of these 15 cases, eight patients were
1988 1988 1989 1989 1989 1989 1992 1992 1993 1993 1994 1994 1994 1995 1995 1995
1. 2. 3. 4. 5. 6. I. 8. 9. IO. 11. 12. 13. 14. 15. 16.
46 48 39 30 38 37 40 45 46 61 39 451 47 46 38 44
Age
50 50 15 30 15 20 >I0 30 1.5t 120 20 25 60 90 20 30
Tobacco IDU MSWM IDU/MSWM IDU MSWM IDU IDU IDU IDU MSWM MSWM IDU/HeS IDU/HeS MSWM HeS IDU
Risk 184 21 2 25 NA NA 160 304 NA 371 350 495 268 9 84 579
CD4 B-3 A-3 c-3 c-3 C A A-3 A-2 A A-2 B-2 A-2 A-2 c-3 A-3 B-l
-
CDC 2 16 10 1 4 1 0 8 24 41 0 38 66 19 8 64
HIV-CA Squamous, st.IV Adenocarcinoma, Adenocarcinoma, Small cell, st.IV Adenocarcinoma, Adenocarcinoma, Large cell, st.HIB Large cell, st.IIIB Adenocarcinoma, Squamous, St.1 Adenocarcinoma, Adenocarcinoma, Small cell, st.IIIB Squamous, st.IV Adenocarcinoma, Large cell, st.IV st.IV
st.IV st.IV
St.1
st.IlIB St.1
st.IIIB st.IIIB
Histology and Stage Branch S/bx PICY Branch Branch S/bx Branch Med S/bx Med S/bx Med Branch Branch S/bx S/bx
Dxb by 0 3 2 1 2 1 1 1 1 1 1 I 3 0 3 1
PS RT 0 CT CT CT s RT RT s s c RT c CT RT CT
Rx*
OS NA 3 12 32 56 NA 7 40 36 17-k 33 11 31 12 2 15+
Res NA PD PD PD NA NA PD PD NA CR PD PD PD PD PD NA
Notes: Risk: IDU, injection drug use; MSWM, men having sex with men; HeS, heterosexual; CDC, CDC clinical stage; HIV-CA, interval in mos. HIV to cancer diagnosis; Res, response: CR, Complete response; PD, Progressive disease; PS, Performance status (ECOG); Rx*, Treatment: S, surgery; CT, chemotherapy; C, combination therapy (CT+RT); RT, radiation therapy; $, Female; t, Pack/day; NA, not available; Dx by, diagnosis by: Branch, bronchoscopy; Med, mediastinoscopy; S/bx, surgical biopsy; P/cy, pleural effusion cytology; OS, survival in weeks.
Year
Pt
Table 1 Lung cancer in HIV seropositive patients at AMCH
R.
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diagnosed between 1987 and 1993 and were between 35 and 54 years of age. This permitted a comparison to the 86 HIV-indeterminate male lung cancer cases between 35 and 54 years of age identified in our tumor registry from 1987 to 1993. Two HIV-seropositive cases were excluded because of age: one case, age 30, diagnosed in 1989 and another case, age 61, diagnosed in 1994 and three were diagnosed in 1995. Of the 86 HIV-indeterminate cases, 69 (80.2%) had non-small cell lung cancer. Histological subtype of non-small cell lung cancer included: 29 patients (42%) squamous cell carcinoma, 24 patients (35%) adenocarcinoma, 12 patients (17%) large cell carcinoma, and four patients (6%) had epithelial cancer not otherwise specified. This compares with five cases (63%) adenocarcinoma, two cases (25%) large cell carcinoma, and one case (12%) squamous cell carcinoma in our eight HIV-seropositive patients. Clinical staging was recorded for 65 of the HIV-indeterminate cases: four patients (6%) were stage I, six patients (9%) stage II, 22 patients (33%) stage III, and 33 patients (51%) stage IV. Of the HIV-seropositive cases, two (25%) were stage I and six (75%) were stage III B (five cases) or IV (one case). Survival was known for 49 (71%) of HIV-indeterminate male non-small cell lung cancer cases between 35 and 54 years of age. Median survival for this group was 48 weeks, range l-227 weeks. Median survival for all 11 HIV-seropositive male patients between 35-54 years of age, including the five patients diagnosed in 1994 and 1995 was 31 weeks, range 2-56 weeks. The median survival durations of HIV-indeterminate and HIV-seropositive patients were compared (see Fig. 1) and the difference was judged to be significantly different [Kaplan Meier Log Rank test, P = 0.0035 (one HIV-seropositive patient alive at 15 weeks was censored from analysis)]. 100
0
IO
20
30
40
50
60
70
80
YO
100
weeks
Fig. 1. Kaplan-Meier males with non-small
survival cell lung
curves cancer
of HIV-seropostive (n = 11) versus between 35 and 54 years of age.
HIV-indeterminate
(n = 49)
R. Vyzula, XC. Remick 1 Lung Cancer 15 (19961 3255339 Table 2 Lung cancer incidence in males ages 35-54 by county of HIV-infected NYSDOH
1981-1992
331
patients’ residence AMCH
Patients
County
Cumulative cases
Median/year
Range
1981-1992
1993-199s
Albany Columbia Dutchess Greene Ulster Warren Total
178 28 152 24 88 51 521
15 2 12 2 7 4
(12-18) (O-5) (9-22) (O-5) (3-11) (2-7)
2 1 1 1 1 1 7(1.3%)
5 0 0 0 1 0 6
3.2. Lung cancer in HIV-seropositive residence
vs. HIV-indeterminate
males by county of
Between 1981 and 1992 the NYSDOH cancer registry reported 521 cumulative cases of lung cancer in males (HIV-indeterminate) between 35 and 54 years of age in the six counties in which our HIV-seropositive patients in the corresponding age group and year of lung cancer diagnoses resided (Table 2). This means that at a minimum, 1.3% of male lung cancer patients in this age group and residing in these six counties of upstate New York are HIV-seropositive.
4. Discussion
It is estimated that there will be 170000 new cases of lung cancer diagnosed in 1995 [38]. Lung cancer is the second most common cancer in men and women but is the most common cause of cancer mortality for both sexes [38]. A recent report of cancer trends in the United States confirmed a small increase in the incidence of lung cancer among white males from periods 1975-1979 to 1987-1991 [39]. Overall the incidence of lung cancer among white males in 1987- 1991 was 82.2 cases per 100000 person years [39]. The peak age incidence of lung cancer in the white male population is 77 years per SEER program data from 1984 to 1988 [40]. For white males older than 75 years of age, the incidence rate of lung cancer is 579.5 cases per 100 000 person years from 1987 to 1991 [39]. The corresponding incidence of lung cancer for males between the ages of 35 and 54 years is 39.7 cases per 100000 person years [39]. Another study of never-married men between 25 and 54 years of age who resided in San Francisco, of whom an estimated 20000 (24%) were HIV-infected as of late 1984, identified a small increased trend in lung cancer incidence [41]. In this study the ratio of observed to expected cases of lung cancer rose from 1.5 in 1973-1979 to 1.9 in 1988-1990, which was judged to be statistically significant [41]. The authors commented however, that this did not appear to be temporally related to the HIV epidemic. It is possible that unrelated
332
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Cancer 15 (1996) 32.5-339
risk factors such as cigarette smoking may be more common in the never married male population [41,42]. Nonetheless, an increase in lung cancer incidence was observed in this study, which was small, inclusive of men not HIV-infected, and coincident with the onset of the AIDS epidemic. The incidence of epithelial cancers in patients under 30 years of age is rare [43]. We have identified 16 cases of lung cancer between 1988 and 1995 from among our HIV-infected patients between January 1988 and March 1995. Of these cases, 15 occurred in males. We estimate that since the AIDS epidemic began we have provided care to 2700 male patients with HIV infection at our institution. This represents 520 cases per 100000 population, and would correspond to a 6-fold increased risk when compared with an overall risk for white male persons of 82 cases per 100 000 population. Of the 15 males with HIV infection and lung cancer, 13 cases were between 35-54 years of age. Table 3 summarizes the clinical features of lung cancer in 109 HIV-infected patients identified upon review of the medical literature and our 16 patients. There are several important observations about lung cancer in this setting which deserve further comment. Adenocarcinoma, 60% of HIV-seropositive cases, is the predominant histopathological type of lung cancer, which is in keeping with the 50% occurrence rate observed in our patients. One study failed to identify a significant difference in the histopathology of lung cancer in HIV-seropositive patients when compared to HIV-indeterminate controls [7]. On the other hand there appears to be a genuine paucity of small (oat) cell carcinoma, which is seen in approximately 10% of HIV-infected lung cancer patients. Up to 25% of all lung cancer patients will have small-cell histology [44]. This might argue that the biological features of HIV-associated lung cancer are different [45]. It has been suggested that HIV-infected patients may be more prone to the development of adenocarcinoma from pulmonary scarring because of the increased incidence of pulmonary infections, and tuberculosis in particular, in this patient population [46]. Over 80% of HIV-infected patients present with advanced stage or inoperable disease (stage III or IV), including two-thirds with metastases at time of diagnosis. This may account for the shorter survival of HIV-infected patients when compared to HIV-indeterminate lung cancer cases. One study, however, did not identify a difference in clinical stage between HIV-seropositive and HIV-indeterminate control subjects [7]. Of the 170000 cases of lung cancer diagnosed annually, 70000 (41%) have disease confined to the thorax [47]. Of these cases, approximately 80% are resectable, including 28% with stage I (TlNO) disease [47]. It is this latter group of patients in whom a substantial chance for cure exists after surgical resection. Approximately 80 and 70% of patients with TlNO squamous cell carcinoma and adenocarcinoma respectively, survive 5 years [9,48,49]. This is in contrast to the postoperative survival for HIV-seropositive patients with stage I lung cancer, with survival durations of 1 + , 3 and 5 months reported by Sridhar and colleagues and 9 and 19 + months seen in our two patients [7]. In future studies it will be useful clinical information to report the survival of HIV-seropositive lung cancer patients undergoing curative resection and to note whether the predominant cause of death was attributable to lung cancer, progressive HIV infection/AIDS, or both.
PI
Irwin (USA) Moser (USA) Nusbaum (USA) Weitberg (USA)
Karp (USA)
[6,161
8
Pll
Francois(F)
1371 WI
PO1
Fineberg(USA)
Lacut (F) Abouya (West Africa)
1191
Broussier (F)
40
49 NA
(29-59)
41 (35-47) 48.6
28
(30-48)
38.5
PI
35 65 45 29
Age
NA
1 2
#C
[I81
1984 1985 1985 1986
Year
Lake-Lewin (USA) Braun (USA)
1171
[31 141
Ref.
Author
NAxl Adenocarcinoma, st.IV x 7 Squamous, st.IV x 1
Small cell, extensive Adenocarcinoma x 1
Adenocarcinoma Epidermoid, st.IV Squamous cell Small cell Adenocarcinoma, st.II111x 2 Epidermoid, St.111x 1
Adenocarcinoma, st.IIII x 4 Squamous, st.IV x 1 Small cell, limited x 1
Adenosquamous, st.IV Small cell Small cell-extensive SC variant dysplastic carcinoid Adenocarcinoma
Histology and stage
Table 3 Lung cancer in HIV seropositive patients in the literature
CTx2 RTx4 No.x2
(20-45)
Sxl NAxl NA NA
Cxl
NA
RTxl CTx3 NAxl CTx2
No.xl
NA
NA No No C
Rx
22
heavy NA
(20-85)
20 (15-25) Smokers NA 67.5
(15-50)
25
NA
NAS
NA 30 heavy
Tobacco
NA
24 NA
NA
48x I NA NA
(1-16)
3
NA
HIV-CA
NA
NA NA
(176-500)
309.3
241.5 (128-355) NA
(2-184) ?l=4
23
NA
390 NA NA NA
CD4
AIDS x 8
SYM x 1 AIDS x 1 AIDS NA
ASYM x 1 AIDS x 1 ASYM x 1
NA
AIDS x 5
ASYM x 1
NA
NA AIDS AIDS SYM
HIV class
2.8 mo
(40-44) n=2 NA NA
42
;6-12) NA
(3-56) n=4
22
NA
NA days days alive
Survival
v31 ~241 WI
Lacoste (F) Nguyen (USA) Bagheri (USA) Cowan (UK) Fraire (USA) Gachupin-Garcia (USA)
[71
[311
~321
[331 [8,151
Chan (USA)
Gruden (USA)
Repetto (I) Vaccher (I)
1291 1301
Hajjar (F) Lichtman (USA) Sridhar (USA)
(271 [28]
WI
Ref.
Author
Table 3 (continued)
1993 1993
1993
1993
1992 1992
1991 1991 1992 1992 1992 1992
Year
Large cell, st.IV Small cell NA Adenocarcinoma x 8 Squamous m x 6 Large cell x 2 Small cell x 1 Adenosquamous x 1 Mixed small and large x 1 st.1 x 3; st.11x I; St.111x 5; st.IV x 10 Adenocarcinoma x 3 Small cell x 1 Adenocarcinoma x 2 squamous cell x 2 Large cell x 1 Small cell x 1 Adenosquamous x 1 NA Adenocarcinoma, st.III-IV x 10
(40-41) 50 NA 42 (36-66)
42
NA 31
2 18
38
NA Adenocarcinoma, st.IV Epidermoid, st.IV Adenocarcinoma Adenocarcinoma, st.IV Adenocarcinoma, st.IV
Histology and stage
NA 34 37 32 34 40.5
Age
7
4
1 2 19
2 1 1 1 1 2
#C
NA Sx16
smokers
smokers
(20-50) NA NA 60 n= 16 No.xl Nax2
NA Insignif No 0.5-17 l-1.5? 35
Tobacco
NA RTx3
NA
NA
No.xl NA NA RTx7 CTxl sx3 Cxl No.x7
NA No NA C RT RTxl
Rx
NA NA
NA
NA
24 NA NA
NA 0 24 84 0 NA
HIV-CA
NA 241
103 (7-468)
NA
NAxl 15 NA 121 (13-628) n= 17
NA NA NA 386 429 >2oox 1
CD4
NA ASYMx3
AIDSx7
NA
AIDS NA ASYM x 5 SYMx9 AIDS x 5
NA SYM AIDS SYM AIDS SYMx2
HIV class
NA 8
NA
NA
;4-40) n= 14 alive x 2
n=2 32 NA
NA 4 NA
Survival
[361
Belani (USA) 1995
1994
1993
Year
125
10
23
2’
#C
(38861)
45
41 (32-61)
(56-64)
60 (7.5540)
i3sO-80)
Adenocarcinoma, 30 st.I,IV x 4 Squamous cell, St.1x 2 (2&120) Large cell, st.III,IV x 3 n = 8 Small cell, St.111x 1
Adenocarcinoma Small cell Adenocarcinoma x 20 Squamous cell x 3
Epidermoid,st.IV x 2 NS x 3 Large cell, st.111x 1 NA Small cell, LD x 2; EDxl Mesothelioma, St.1x 2
(28-55)
Tobacco
Histology and stage
Age
cx2 sx2
RT x4 CTx2
cx4 No.x7
RTx12
!tx”:
Sxl No.x9
CT x 4 S+CTx
Rx 1
n= 10
(O-66)
21.5
f:4-24) (O-60)
HIV-CA
(9-579) n=9
203 (13-393) 213 (71-380) n= 13 304
(13-617) n= 14
CD4
AIDS x 3
SYMx2
ASYM x 5
SYMxl NAx 1 NA
SYMx9 AIDS x 6
HIV class
alive x 2
n=lO
;;-77)
5s
$
6
t3 9
2 0 9 3 G 2
F
_, 3
17(16-18)
; P
B 3 E F
20
(O-48) n=ll alive x 1
Survival
Notes: #C, number of cases; HIV-CA, interval in mos. between HIV and cancer diagnosis; Rx *, treatment; S, surgery; RT, radiation therapy; CT, chemotherapy; C, combination (CT + RT); CD4, lymphocyte count per ~1; HIV Class., a/sym, a/symptomatic or AIDS; Survival, in weeks; median (range), t Pk/day; 1 Not available.
Total
This report
[35]
]341
Ref.
Tenholder (USA)
Author
Table 3 (continued)
336
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1 Lung
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15 (1996)
325-339
Another striking feature is the development of lung cancer in approximately one-half of HIV-seropositive patients in whom their underlaying infection is either asymptomatic or mildly symptomatic. We observed lung cancer in six patients (38%) in whom their HIV infection was asymptomatic and another two patients (12%) with mildly symptomatic HIV infection. This may be explained by the median CD4 lymphocyte count of 233 per ~1 observed for 49 patients identified in the literature and the median CD4 count of 184 per ~1 in 13 of our patients at time of lung cancer diagnosis. This suggests that pronounced immunodeficiency and symptomatic HIV infection may not be significant cofactors in the pathogenesis of lung cancer in these patients. It is worrisome that lung cancer may appear earlier in the course of HIV infection than other more commonly encountered neoplasms. HIV-seropositive patients with lung cancer are younger, median age 45 years, when compared to HIV-indeterminate cases [7]. As previously stated the peak age incidence for lung cancer in the white male population is 77 years. Of interest, adenocarcinoma (32-54%) tends to predominate in HIV-indeterminate lung cancer patients less than 40 years of age as well [50-551. Reported series of lung cancer patients in this age group tend to be male (approximately 2:l male-to-female ratio) and approximately 80% of patients have an extensive history of cigarette smoking [50-551. The outcome of surgical treatment in these younger patients with limited disease confined to the hemithorax does not differ from the general experience in patients of all ages [51]. It is unclear whether HIV-seropositive patients will obtain the same disease-free survival following curative resection as HIV-indeterminate cases especially those with early stage disease (e.g. TlNO). As the AIDS epidemic evolves, more recent epidemiological surveys are finding an increased incidence of malignancy other than AIDS-defining neoplasms in HIV-infected patients across all transmission categories [56-581. These neoplasms include basal cell carcinoma, Hodgkin disease, and seminoma [1,56-581. At present it is not apparent that there is a true increased incidence of lung cancer in HIV-infected patients. Current cancer epidemiological and surveillance programs still include periods of cancer incidence prior to or at the start of the HIV epidemic [40]. Existing cancer surveillance databases are just beginning to be linked to AIDS registries [56]. In a short time the true incidence of lung cancer in HIV-infected patients will be known. Until then it is clear that lung cancer that develops in this setting is characterized by the following: a younger age at time of diagnosis when compared to HIV-indeterminate cases; the majority of cases occur in a background of extensive cigarette smoking; over 80% of patients present with advanced stage of lung cancer (stage III and IV); up to 50% of cases have asymptomatic to mildly symptomatic HIV infection with a median CD4 lymphocyte count of 233 per ~1; there is a predominance of adenocarcinoma histopathology; and shortened survival when compared to HIV-indeterminate cases. Close surveillance following surgical resection of early stage (TlNO) disease is warranted to define the therapeutic outcome from this approach. Cigarette smoking appears to be as prevalent among HIV-seropositive lung cancer patients as in the general population, and cessation would be a key component of prevention. Injecting drug use is a common risk behavior in HIV-infected lung cancer patients. Current reports of lung carcinoma in
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HIV-seropositive patients suggests that the natural history of this disease is different than that in HIV-indeterminate cases. Lastly, for primary practitioners and internists taking care of HIV-seropositive patients, lung carcinoma must be considered in the differential diagnosis of an abnormal chest radiograph, especially a solitary mass lesion. For the clinical and basic science investigator, it will be important to track the epidemiologic, biologic features, and pathogenesis of this neoplasm in this setting.
Acknowledgements
We extend our appreciation to Patricia Brooks, Jan Orlowski, and Barbara Whitten of the AMCH Tumor Registry. We also want to thank Patricia Wolfgang, research scientist, at the NYSDOH Bureau of Cancer Epidemiology for providing information on the incidence of lung cancer among residents of New York State and the counties within the northeastern health system area. We also want to thank Mikhail Torosoff, post doctoral fellow for helping with statistical analysis. Supported in part by N.I.H. Grant Nos. AI 32760-03.
References [l]
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Lung Cancer 15 (1996) 325-339
Lung cancer in patients with HIV-infection Rostislav Vyzula”‘, Scot C. Remick”ab,* aDivision of Medical Oncology, Albany Medical College, 47 New Scotland Ave., A-52, Albany, NY 12208, USA ‘Division of HIV Medicine, Albany Medical College, 47 New Scotland Ave., A-52, Albany, NY 12208, USA Received
19 March
1996; revised
I July
1996; accepted
9 July
1996
Abstract
Purpose: To identify and review the clinical characteristics and natural history of lung cancer in HIV-seropositive patients. A secondary objective was to compare the clinical features of HIV-seropositive and HIV-indeterminate lung cancer cases at our institution. Patients and methods: Sixteen patients with HIV infection and lung cancer were diagnosed between January 1988 and March 1995 at our institution and the clinical records were reviewed. HIV-indeterminate lung cancer cases were identified by the Albany Medical Center Hospital (AMCH) Tumor Registry. A Medline database search of HIV infection/AIDS and lung cancer was undertaken through December 1994. The New York State Department of Health (NYSDOH), Bureau of Cancer Epidemiology provided information on the incidence of lung cancer among residents of New York State by county of residence. Case reports and series regarding the clinical features of HIV-seropositive patients with lung cancer were reviewed. A more focused comparison between HIV-seropositive and HIV-indeterminate male lung cancer cases between 35 and 54 years of age at our institution was performed. The following clinical variables were identified in our 16 patients and 109 cases extracted from available clinical reports: sex, age, year and county of residence at time of lung cancer diagnosis, cigarette smoking history, HIV risk behavior, CD4 count at time of lung cancer diagnosis. CDC classification of HIV disease, interval in months from time of HIV
* Corresponding
author.
’ Current address: Department of Medicine, II Interna, University Hospital, Jihlavska 100, 639 00 Brno,
Czech
Republic.
0169-5002/96/$15.00
PZZ SO169-5002(95)00596-X
0 1996 Elsevier
Science
Ireland
Ltd.
All
rights
reserved
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seropositivity to lung cancer diagnosis, pathology and stage of lung cancer, performance status, treatment, response, and survival. Results: Lung cancer in HIV-seropositive patients is characterized by the following: a younger age at time of diagnosis when compared to HIV-indeterminate cases;the majority of casesoccur in a background of extensive cigarette smoking; over 80% of patients present with advanced stage of lung cancer (stage III and IV); up to 50% of cases have asymptomatic to mildly symptomatic HIV infection with a median CD4 lymphocyte count of 233 per ~1; there is a predominance of adenocarcinoma histopathology; and shortened survival when compared to HIV-indeterminate cases. Conclusion: Current reports of lung carcinoma in HIV-seropositive patients suggest that the natural history of this disease is different than in HIV-indeterminate cases. Lung cancer must be considered in the differential diagnosis of a solitary mass lesion on chest X-ray in HIV-seropositive patients. Keywords:
Lung cancer; HIV infection; Clinical characteristics
1. Introduction
It is apparent that as we approach the end of the second decade of the HIV epidemic solid tumors, other than AIDS-defining neoplasms, are increasingly recognized as causes of morbidity and mortality in this patient population [I]. The first case of lung,cancer in an HIV-infected patient was reported in 1984 [2]. A few case reports appeared thereafter [3,4]. In 1990 we reported six patients with concurrent HIV infection and lung cancer [5]. Several larger series of HIV-infected lung cancer patients have recently been published [6-81. Since our initial report, we have identified an additional ten cases of lung cancer from our HIV-infected population. This represents more than a doubling of cases at the midpoint of the second decade of the AIDS epidemic at our center. We are unaware of any detailed review of lung cancer cases in HIV-infected patients. A total of 109 coincident cases of lung cancer and HIV infection have been identified in the literature, and are the subject of this review. We have undertaken a preliminary epidemiological analysis of lung cancer in HIV-seropositive/AIDS cases in our medical center and referral region of New York State.
2. Patients and methods 2.1. Patients
HIV-infected patients with lung cancer were identified from referrals and clinical practices of the Divisions of HIV Medicine and Medical Oncology. Patients were also identified through participation in the multidisciplinary Chest Tumor Conference conducted at the Albany Medical Center and Hospital (AMCH). The Tumor Registry at AMCH was used to identify patients who were diagnosed as having
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327
lung cancer between January 1988 and December 1993. Data is incomplete for 1994 and 1995. The Tumor Registry does not track HIV-serostatus (HIV-indeterminate cases), but all HIV-infected patients with lung cancer were included in their records. A New York State Department of Health (NYSDOH) cancer registry search for all lung cancer cases diagnosed between 1981 and 1992 inclusive was also obtained. The NYSDOH cancer registry is incomplete for the years 1993-1995. Cases were identified by sex, age group (in the following ranges: O-14; 15-34; 35-54; 55-64; 65-74; and > 75 years), and county of residence. This permitted a more focused comparison of male lung cancer cases between the ages of 35 and 54. Pathologic diagnoses were establish in all patients by means of bronchoscopic biopsy (n = 6), mediastinoscopic biopsy (n = 3), cytologic examination of pleural fluid (n = l), and pathologic examination of a surgical specimen (n = 6). Patients were staged according to the revised International System for Staging Lung Cancer [9] adopted by the American Joint Committee on Cancer (AJCC) staging classification [lo]. In all patients, the pulmonary abnormality was initially suggested by plain chest radiographs and further defined by computed tomographic (CT) scans. Only one patient had coexisting intrathoracic disease (Pneumocystis carinii pneumonia). The remainder were free of concomitant opportunistic infections, lymphoma, or Kaposi sarcoma on basis of clinical, radiographic, and pathologic grounds. 2.2. Statistical analysis The following clinical characteristics were identified for all cases: sex, age, year and county of residence at the time of diagnosis of lung cancer, cigarette smoking history, HIV risk behavior, CD4 count at time of lung cancer diagnosis, Centers for Disease Control (CDC) classification of HIV disease by 1993 revised criteria [l 11, interval in months from time of HIV seropositivity to lung cancer diagnosis, pathology and stage of lung cancer by revised AJCC staging criteria [9,10], performance status (PS) by Eastern Cooperative Oncology Group (ECOG) criteria [12], treatment, response to treatment, and survival. Survival was plotted according to the method of Kaplan and Meier [ 131. The AMCH Tumor Registry was accessed to identify all cases of lung cancer between the years 1987 and 1993 and in males between 35 and 54 years of age. A total of 86 patients of whom 69 had non-small cell lung cancer (NSCLC) were identified. These patients were evaluated for histological type of lung cancer, stage of disease, and survival. These clinical features were compared to our HIVseropositive patients. The New York State Department of Health (NYSDOH) cancer registry tracks sex, age, county of residence at time of lung cancer diagnosis, and incidence of lung cancer by year of diagnosis [14]. The registry reports cancer incidence by decade, 198 1- 1990. We were able to obtain data for 1991 and 1992, the last years for which there is updated and complete data. Six HIV-seropositive patients with lung cancer
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were treated at our institution during this period. They resided in six different counties for which NYSDOH lung cancer incidence was retrieved. 2.3. Literature
review
The literature was reviewed for reports of HIV seropositivity, AIDS, and lung cancer through December 1994, employing a computer search of citations indexed in the National Library of Medicine’s and National Cancer Institute’s Medline, Cancerlit, and PDQ databases [2-815-371. Several cases were reported more than once [5,6,8,15,16,34]. For purposes of this review, cases were tabulated by year of the initial report or most complete clinical data. 3. Results
We report a series of 16 patients who developed HIV infection that preceded the development of lung cancer by a median interval of 9 months, range O-66 months. There were 15 males and 1 female with a median age of 44.5 years, range 30-61 years. All patients had a history of cigarette smoking, which was quantitated in 14 patients. Median duration of cigarette smoking was 30 pack-years, range 15-120 pack-years. Median CD4 lymphocyte at the time of lung cancer diagnosis in 13 patients was 184 per ~1, range 2-579 per ~1. CD4 lymphocyte count, at the time of lung cancer diagnosis was not available in three patients. CDC classification of HIV infection for all 16 patients was as follows: group A in two patients (13%); group A-2 in four patients (25%); group A-3 in three patients (19%); groups B-l,B-2, B-3 in one patient in each group (6% each); group C in one patient (6%); and group C-3 in three patients (19O/,). Note further subclassification by CD4 count was not available for three patients (two, group A, and one group C) as outlined above. The clinicopathological stage of lung cancer at time of presentation was as follows: stage I, three patients (19%); stage III B, in six patients (37%); stage IV, in seven patients (44%). Eight patients (50%) had adenocarcinoma; three patients (19%) squamous cell carcinoma; three patients (19%) large cell carcinoma; and two patients (12%) small cell carcinoma. Primary treatment consisted ofsurgical resection alone, three patients; systemic chemotherapy alone, five patients; radiation therapy alone, five patients; combined modality (chemotherapy and radiation), two patients; and supportive care/no therapy, two patient. Median survival was 21.5 weeks (range 2-56 weeks; n = 12 patients). Two patients remain alive at 15 and 77 weeks, respectively. Median survival for the 11 males between 35-54 years of age was 31 weeks. The clinical features of our 16 HIV-seropositive patients with lung cancer are summarized in Table 1. 3.1. HIV-seropositive
vs. HIV-indeterminate
males with lung cancer at AMCH
A total of 15 cases of HIV-seropositive males with lung cancer were seen at our center between January 1988 and March 1995. Of these 15 cases, eight patients were
1988 1988 1989 1989 1989 1989 1992 1992 1993 1993 1994 1994 1994 1995 1995 1995
1. 2. 3. 4. 5. 6. I. 8. 9. IO. 11. 12. 13. 14. 15. 16.
46 48 39 30 38 37 40 45 46 61 39 451 47 46 38 44
Age
50 50 15 30 15 20 >I0 30 1.5t 120 20 25 60 90 20 30
Tobacco IDU MSWM IDU/MSWM IDU MSWM IDU IDU IDU IDU MSWM MSWM IDU/HeS IDU/HeS MSWM HeS IDU
Risk 184 21 2 25 NA NA 160 304 NA 371 350 495 268 9 84 579
CD4 B-3 A-3 c-3 c-3 C A A-3 A-2 A A-2 B-2 A-2 A-2 c-3 A-3 B-l
-
CDC 2 16 10 1 4 1 0 8 24 41 0 38 66 19 8 64
HIV-CA Squamous, st.IV Adenocarcinoma, Adenocarcinoma, Small cell, st.IV Adenocarcinoma, Adenocarcinoma, Large cell, st.HIB Large cell, st.IIIB Adenocarcinoma, Squamous, St.1 Adenocarcinoma, Adenocarcinoma, Small cell, st.IIIB Squamous, st.IV Adenocarcinoma, Large cell, st.IV st.IV
st.IV st.IV
St.1
st.IlIB St.1
st.IIIB st.IIIB
Histology and Stage Branch S/bx PICY Branch Branch S/bx Branch Med S/bx Med S/bx Med Branch Branch S/bx S/bx
Dxb by 0 3 2 1 2 1 1 1 1 1 1 I 3 0 3 1
PS RT 0 CT CT CT s RT RT s s c RT c CT RT CT
Rx*
OS NA 3 12 32 56 NA 7 40 36 17-k 33 11 31 12 2 15+
Res NA PD PD PD NA NA PD PD NA CR PD PD PD PD PD NA
Notes: Risk: IDU, injection drug use; MSWM, men having sex with men; HeS, heterosexual; CDC, CDC clinical stage; HIV-CA, interval in mos. HIV to cancer diagnosis; Res, response: CR, Complete response; PD, Progressive disease; PS, Performance status (ECOG); Rx*, Treatment: S, surgery; CT, chemotherapy; C, combination therapy (CT+RT); RT, radiation therapy; $, Female; t, Pack/day; NA, not available; Dx by, diagnosis by: Branch, bronchoscopy; Med, mediastinoscopy; S/bx, surgical biopsy; P/cy, pleural effusion cytology; OS, survival in weeks.
Year
Pt
Table 1 Lung cancer in HIV seropositive patients at AMCH
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diagnosed between 1987 and 1993 and were between 35 and 54 years of age. This permitted a comparison to the 86 HIV-indeterminate male lung cancer cases between 35 and 54 years of age identified in our tumor registry from 1987 to 1993. Two HIV-seropositive cases were excluded because of age: one case, age 30, diagnosed in 1989 and another case, age 61, diagnosed in 1994 and three were diagnosed in 1995. Of the 86 HIV-indeterminate cases, 69 (80.2%) had non-small cell lung cancer. Histological subtype of non-small cell lung cancer included: 29 patients (42%) squamous cell carcinoma, 24 patients (35%) adenocarcinoma, 12 patients (17%) large cell carcinoma, and four patients (6%) had epithelial cancer not otherwise specified. This compares with five cases (63%) adenocarcinoma, two cases (25%) large cell carcinoma, and one case (12%) squamous cell carcinoma in our eight HIV-seropositive patients. Clinical staging was recorded for 65 of the HIV-indeterminate cases: four patients (6%) were stage I, six patients (9%) stage II, 22 patients (33%) stage III, and 33 patients (51%) stage IV. Of the HIV-seropositive cases, two (25%) were stage I and six (75%) were stage III B (five cases) or IV (one case). Survival was known for 49 (71%) of HIV-indeterminate male non-small cell lung cancer cases between 35 and 54 years of age. Median survival for this group was 48 weeks, range l-227 weeks. Median survival for all 11 HIV-seropositive male patients between 35-54 years of age, including the five patients diagnosed in 1994 and 1995 was 31 weeks, range 2-56 weeks. The median survival durations of HIV-indeterminate and HIV-seropositive patients were compared (see Fig. 1) and the difference was judged to be significantly different [Kaplan Meier Log Rank test, P = 0.0035 (one HIV-seropositive patient alive at 15 weeks was censored from analysis)]. 100
0
IO
20
30
40
50
60
70
80
YO
100
weeks
Fig. 1. Kaplan-Meier males with non-small
survival cell lung
curves cancer
of HIV-seropostive (n = 11) versus between 35 and 54 years of age.
HIV-indeterminate
(n = 49)
R. Vyzula, XC. Remick 1 Lung Cancer 15 (19961 3255339 Table 2 Lung cancer incidence in males ages 35-54 by county of HIV-infected NYSDOH
1981-1992
331
patients’ residence AMCH
Patients
County
Cumulative cases
Median/year
Range
1981-1992
1993-199s
Albany Columbia Dutchess Greene Ulster Warren Total
178 28 152 24 88 51 521
15 2 12 2 7 4
(12-18) (O-5) (9-22) (O-5) (3-11) (2-7)
2 1 1 1 1 1 7(1.3%)
5 0 0 0 1 0 6
3.2. Lung cancer in HIV-seropositive residence
vs. HIV-indeterminate
males by county of
Between 1981 and 1992 the NYSDOH cancer registry reported 521 cumulative cases of lung cancer in males (HIV-indeterminate) between 35 and 54 years of age in the six counties in which our HIV-seropositive patients in the corresponding age group and year of lung cancer diagnoses resided (Table 2). This means that at a minimum, 1.3% of male lung cancer patients in this age group and residing in these six counties of upstate New York are HIV-seropositive.
4. Discussion
It is estimated that there will be 170000 new cases of lung cancer diagnosed in 1995 [38]. Lung cancer is the second most common cancer in men and women but is the most common cause of cancer mortality for both sexes [38]. A recent report of cancer trends in the United States confirmed a small increase in the incidence of lung cancer among white males from periods 1975-1979 to 1987-1991 [39]. Overall the incidence of lung cancer among white males in 1987- 1991 was 82.2 cases per 100000 person years [39]. The peak age incidence of lung cancer in the white male population is 77 years per SEER program data from 1984 to 1988 [40]. For white males older than 75 years of age, the incidence rate of lung cancer is 579.5 cases per 100 000 person years from 1987 to 1991 [39]. The corresponding incidence of lung cancer for males between the ages of 35 and 54 years is 39.7 cases per 100000 person years [39]. Another study of never-married men between 25 and 54 years of age who resided in San Francisco, of whom an estimated 20000 (24%) were HIV-infected as of late 1984, identified a small increased trend in lung cancer incidence [41]. In this study the ratio of observed to expected cases of lung cancer rose from 1.5 in 1973-1979 to 1.9 in 1988-1990, which was judged to be statistically significant [41]. The authors commented however, that this did not appear to be temporally related to the HIV epidemic. It is possible that unrelated
332
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Cancer 15 (1996) 32.5-339
risk factors such as cigarette smoking may be more common in the never married male population [41,42]. Nonetheless, an increase in lung cancer incidence was observed in this study, which was small, inclusive of men not HIV-infected, and coincident with the onset of the AIDS epidemic. The incidence of epithelial cancers in patients under 30 years of age is rare [43]. We have identified 16 cases of lung cancer between 1988 and 1995 from among our HIV-infected patients between January 1988 and March 1995. Of these cases, 15 occurred in males. We estimate that since the AIDS epidemic began we have provided care to 2700 male patients with HIV infection at our institution. This represents 520 cases per 100000 population, and would correspond to a 6-fold increased risk when compared with an overall risk for white male persons of 82 cases per 100 000 population. Of the 15 males with HIV infection and lung cancer, 13 cases were between 35-54 years of age. Table 3 summarizes the clinical features of lung cancer in 109 HIV-infected patients identified upon review of the medical literature and our 16 patients. There are several important observations about lung cancer in this setting which deserve further comment. Adenocarcinoma, 60% of HIV-seropositive cases, is the predominant histopathological type of lung cancer, which is in keeping with the 50% occurrence rate observed in our patients. One study failed to identify a significant difference in the histopathology of lung cancer in HIV-seropositive patients when compared to HIV-indeterminate controls [7]. On the other hand there appears to be a genuine paucity of small (oat) cell carcinoma, which is seen in approximately 10% of HIV-infected lung cancer patients. Up to 25% of all lung cancer patients will have small-cell histology [44]. This might argue that the biological features of HIV-associated lung cancer are different [45]. It has been suggested that HIV-infected patients may be more prone to the development of adenocarcinoma from pulmonary scarring because of the increased incidence of pulmonary infections, and tuberculosis in particular, in this patient population [46]. Over 80% of HIV-infected patients present with advanced stage or inoperable disease (stage III or IV), including two-thirds with metastases at time of diagnosis. This may account for the shorter survival of HIV-infected patients when compared to HIV-indeterminate lung cancer cases. One study, however, did not identify a difference in clinical stage between HIV-seropositive and HIV-indeterminate control subjects [7]. Of the 170000 cases of lung cancer diagnosed annually, 70000 (41%) have disease confined to the thorax [47]. Of these cases, approximately 80% are resectable, including 28% with stage I (TlNO) disease [47]. It is this latter group of patients in whom a substantial chance for cure exists after surgical resection. Approximately 80 and 70% of patients with TlNO squamous cell carcinoma and adenocarcinoma respectively, survive 5 years [9,48,49]. This is in contrast to the postoperative survival for HIV-seropositive patients with stage I lung cancer, with survival durations of 1 + , 3 and 5 months reported by Sridhar and colleagues and 9 and 19 + months seen in our two patients [7]. In future studies it will be useful clinical information to report the survival of HIV-seropositive lung cancer patients undergoing curative resection and to note whether the predominant cause of death was attributable to lung cancer, progressive HIV infection/AIDS, or both.
PI
Irwin (USA) Moser (USA) Nusbaum (USA) Weitberg (USA)
Karp (USA)
[6,161
8
Pll
Francois(F)
1371 WI
PO1
Fineberg(USA)
Lacut (F) Abouya (West Africa)
1191
Broussier (F)
40
49 NA
(29-59)
41 (35-47) 48.6
28
(30-48)
38.5
PI
35 65 45 29
Age
NA
1 2
#C
[I81
1984 1985 1985 1986
Year
Lake-Lewin (USA) Braun (USA)
1171
[31 141
Ref.
Author
NAxl Adenocarcinoma, st.IV x 7 Squamous, st.IV x 1
Small cell, extensive Adenocarcinoma x 1
Adenocarcinoma Epidermoid, st.IV Squamous cell Small cell Adenocarcinoma, st.II111x 2 Epidermoid, St.111x 1
Adenocarcinoma, st.IIII x 4 Squamous, st.IV x 1 Small cell, limited x 1
Adenosquamous, st.IV Small cell Small cell-extensive SC variant dysplastic carcinoid Adenocarcinoma
Histology and stage
Table 3 Lung cancer in HIV seropositive patients in the literature
CTx2 RTx4 No.x2
(20-45)
Sxl NAxl NA NA
Cxl
NA
RTxl CTx3 NAxl CTx2
No.xl
NA
NA No No C
Rx
22
heavy NA
(20-85)
20 (15-25) Smokers NA 67.5
(15-50)
25
NA
NAS
NA 30 heavy
Tobacco
NA
24 NA
NA
48x I NA NA
(1-16)
3
NA
HIV-CA
NA
NA NA
(176-500)
309.3
241.5 (128-355) NA
(2-184) ?l=4
23
NA
390 NA NA NA
CD4
AIDS x 8
SYM x 1 AIDS x 1 AIDS NA
ASYM x 1 AIDS x 1 ASYM x 1
NA
AIDS x 5
ASYM x 1
NA
NA AIDS AIDS SYM
HIV class
2.8 mo
(40-44) n=2 NA NA
42
;6-12) NA
(3-56) n=4
22
NA
NA days days alive
Survival
v31 ~241 WI
Lacoste (F) Nguyen (USA) Bagheri (USA) Cowan (UK) Fraire (USA) Gachupin-Garcia (USA)
[71
[311
~321
[331 [8,151
Chan (USA)
Gruden (USA)
Repetto (I) Vaccher (I)
1291 1301
Hajjar (F) Lichtman (USA) Sridhar (USA)
(271 [28]
WI
Ref.
Author
Table 3 (continued)
1993 1993
1993
1993
1992 1992
1991 1991 1992 1992 1992 1992
Year
Large cell, st.IV Small cell NA Adenocarcinoma x 8 Squamous m x 6 Large cell x 2 Small cell x 1 Adenosquamous x 1 Mixed small and large x 1 st.1 x 3; st.11x I; St.111x 5; st.IV x 10 Adenocarcinoma x 3 Small cell x 1 Adenocarcinoma x 2 squamous cell x 2 Large cell x 1 Small cell x 1 Adenosquamous x 1 NA Adenocarcinoma, st.III-IV x 10
(40-41) 50 NA 42 (36-66)
42
NA 31
2 18
38
NA Adenocarcinoma, st.IV Epidermoid, st.IV Adenocarcinoma Adenocarcinoma, st.IV Adenocarcinoma, st.IV
Histology and stage
NA 34 37 32 34 40.5
Age
7
4
1 2 19
2 1 1 1 1 2
#C
NA Sx16
smokers
smokers
(20-50) NA NA 60 n= 16 No.xl Nax2
NA Insignif No 0.5-17 l-1.5? 35
Tobacco
NA RTx3
NA
NA
No.xl NA NA RTx7 CTxl sx3 Cxl No.x7
NA No NA C RT RTxl
Rx
NA NA
NA
NA
24 NA NA
NA 0 24 84 0 NA
HIV-CA
NA 241
103 (7-468)
NA
NAxl 15 NA 121 (13-628) n= 17
NA NA NA 386 429 >2oox 1
CD4
NA ASYMx3
AIDSx7
NA
AIDS NA ASYM x 5 SYMx9 AIDS x 5
NA SYM AIDS SYM AIDS SYMx2
HIV class
NA 8
NA
NA
;4-40) n= 14 alive x 2
n=2 32 NA
NA 4 NA
Survival
[361
Belani (USA) 1995
1994
1993
Year
125
10
23
2’
#C
(38861)
45
41 (32-61)
(56-64)
60 (7.5540)
i3sO-80)
Adenocarcinoma, 30 st.I,IV x 4 Squamous cell, St.1x 2 (2&120) Large cell, st.III,IV x 3 n = 8 Small cell, St.111x 1
Adenocarcinoma Small cell Adenocarcinoma x 20 Squamous cell x 3
Epidermoid,st.IV x 2 NS x 3 Large cell, st.111x 1 NA Small cell, LD x 2; EDxl Mesothelioma, St.1x 2
(28-55)
Tobacco
Histology and stage
Age
cx2 sx2
RT x4 CTx2
cx4 No.x7
RTx12
!tx”:
Sxl No.x9
CT x 4 S+CTx
Rx 1
n= 10
(O-66)
21.5
f:4-24) (O-60)
HIV-CA
(9-579) n=9
203 (13-393) 213 (71-380) n= 13 304
(13-617) n= 14
CD4
AIDS x 3
SYMx2
ASYM x 5
SYMxl NAx 1 NA
SYMx9 AIDS x 6
HIV class
alive x 2
n=lO
;;-77)
5s
$
6
t3 9
2 0 9 3 G 2
F
_, 3
17(16-18)
; P
B 3 E F
20
(O-48) n=ll alive x 1
Survival
Notes: #C, number of cases; HIV-CA, interval in mos. between HIV and cancer diagnosis; Rx *, treatment; S, surgery; RT, radiation therapy; CT, chemotherapy; C, combination (CT + RT); CD4, lymphocyte count per ~1; HIV Class., a/sym, a/symptomatic or AIDS; Survival, in weeks; median (range), t Pk/day; 1 Not available.
Total
This report
[35]
]341
Ref.
Tenholder (USA)
Author
Table 3 (continued)
336
R. Vyzula,
S.C.
Remick
1 Lung
Cancer
15 (1996)
325-339
Another striking feature is the development of lung cancer in approximately one-half of HIV-seropositive patients in whom their underlaying infection is either asymptomatic or mildly symptomatic. We observed lung cancer in six patients (38%) in whom their HIV infection was asymptomatic and another two patients (12%) with mildly symptomatic HIV infection. This may be explained by the median CD4 lymphocyte count of 233 per ~1 observed for 49 patients identified in the literature and the median CD4 count of 184 per ~1 in 13 of our patients at time of lung cancer diagnosis. This suggests that pronounced immunodeficiency and symptomatic HIV infection may not be significant cofactors in the pathogenesis of lung cancer in these patients. It is worrisome that lung cancer may appear earlier in the course of HIV infection than other more commonly encountered neoplasms. HIV-seropositive patients with lung cancer are younger, median age 45 years, when compared to HIV-indeterminate cases [7]. As previously stated the peak age incidence for lung cancer in the white male population is 77 years. Of interest, adenocarcinoma (32-54%) tends to predominate in HIV-indeterminate lung cancer patients less than 40 years of age as well [50-551. Reported series of lung cancer patients in this age group tend to be male (approximately 2:l male-to-female ratio) and approximately 80% of patients have an extensive history of cigarette smoking [50-551. The outcome of surgical treatment in these younger patients with limited disease confined to the hemithorax does not differ from the general experience in patients of all ages [51]. It is unclear whether HIV-seropositive patients will obtain the same disease-free survival following curative resection as HIV-indeterminate cases especially those with early stage disease (e.g. TlNO). As the AIDS epidemic evolves, more recent epidemiological surveys are finding an increased incidence of malignancy other than AIDS-defining neoplasms in HIV-infected patients across all transmission categories [56-581. These neoplasms include basal cell carcinoma, Hodgkin disease, and seminoma [1,56-581. At present it is not apparent that there is a true increased incidence of lung cancer in HIV-infected patients. Current cancer epidemiological and surveillance programs still include periods of cancer incidence prior to or at the start of the HIV epidemic [40]. Existing cancer surveillance databases are just beginning to be linked to AIDS registries [56]. In a short time the true incidence of lung cancer in HIV-infected patients will be known. Until then it is clear that lung cancer that develops in this setting is characterized by the following: a younger age at time of diagnosis when compared to HIV-indeterminate cases; the majority of cases occur in a background of extensive cigarette smoking; over 80% of patients present with advanced stage of lung cancer (stage III and IV); up to 50% of cases have asymptomatic to mildly symptomatic HIV infection with a median CD4 lymphocyte count of 233 per ~1; there is a predominance of adenocarcinoma histopathology; and shortened survival when compared to HIV-indeterminate cases. Close surveillance following surgical resection of early stage (TlNO) disease is warranted to define the therapeutic outcome from this approach. Cigarette smoking appears to be as prevalent among HIV-seropositive lung cancer patients as in the general population, and cessation would be a key component of prevention. Injecting drug use is a common risk behavior in HIV-infected lung cancer patients. Current reports of lung carcinoma in
R.
Vyzula,
XC.
Remick
/Lung
Cancer
15 (1996)
325-339
337
HIV-seropositive patients suggests that the natural history of this disease is different than that in HIV-indeterminate cases. Lastly, for primary practitioners and internists taking care of HIV-seropositive patients, lung carcinoma must be considered in the differential diagnosis of an abnormal chest radiograph, especially a solitary mass lesion. For the clinical and basic science investigator, it will be important to track the epidemiologic, biologic features, and pathogenesis of this neoplasm in this setting.
Acknowledgements
We extend our appreciation to Patricia Brooks, Jan Orlowski, and Barbara Whitten of the AMCH Tumor Registry. We also want to thank Patricia Wolfgang, research scientist, at the NYSDOH Bureau of Cancer Epidemiology for providing information on the incidence of lung cancer among residents of New York State and the counties within the northeastern health system area. We also want to thank Mikhail Torosoff, post doctoral fellow for helping with statistical analysis. Supported in part by N.I.H. Grant Nos. AI 32760-03.
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