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Hodgkin's disease in patients with HIV infection and in the general population: Comparison of clinicopathological features and survival*
Annals of Oncology 5 (Suppl. 2): S37-S40, 1994. O 1994 Kluwer Academic Publishers. Printed in the Netherlands
Original article Hodgkin's disease in patients with HTV infection and in the general population: Comparison of clinicopathological features and survival* D. Errante,1 V. Zagonel,2 E. Vaccher,1 D. Serraino,3 D. Bernardi,1 R. Sorio,2 M. Trovo,4 A. Carbone,5 S. Monfardini2 & U. Tirelli1 'Division of Medical Oncology and AIDS, 2 Division of Medical Oncology, 3Epidemiology Unit, 4 Division of Radiotherapy, s Division of Pathology, Centro di Riferimento Oncologico, Aviano, Italy
in older patients than in the other two groups. HIV-infected patients are more likely to show advanced stages, B sympBackground: Hodgkin's disease (HD) has been described in toms, and extranodal involvement. Chemotherapy (CT) patients with HTV infection in association with unfavourable alone has been the most widely used (83%) treatment in prognostic factors. Similarly, HD in the older general popula- HIV-infected patients, while CT plus radiotherapy (RT) has been mostly employed in the general population. Twelve tion has a poorer prognosis than in younger patients. Patients and methods: With the aim of comparing the (14%) HIV-infected patients did not receive any treatment. clinicopathological features and survival of HD in HTV-in- Complete remission was achieved in 51% of the cases in the fected patients and in the general population, we analysed HIV-infected patients, and around 90% of the cases in the 176 patients with HD from 1986 to 1992. We divided the 84 general population. The estimated 4-year survival rate in the HTV-negative patients into two groups: group A included HIV-infected patients is much lower (33%) than in the other patients less than 55 years old, group B patients of 55 years two groups (100% in group A, and 88% in group B). or older. This division was made in order to compare HD Conclusion: While MC is the most common histological in HIV-infected patients with the less favourable group of subtype both in HIV-infected patients and in the older genpatients with HD in the general population, i.e., older pa- eral population, HD in HIV-infected patients has a worse tients. prognosis than in the older general population, not only beResults: Patients of the older group and HIV-infected pa- cause of underlying HIV infection, but also because of the tients had a significantly lower frequency (31% and 21%, more unfavourable clinicopathological features at presentarespectively) of nodular sclerosis subtype compared to the tion. younger group (85%). Mixed cellularity (MC) is significantly more frequent both in the older group and in HIV-infected Key words: age, general population, HIV infection, patients. Lymphocyte predominance is more frequent (16%) Hodgkin's disease Summary
era! population has been considered peculiar for its clinical and histological manifestations. In particular, it is associated with poor survival in older patients compared to younger patients [13,25]. Differences in histologic type, stage at diagnosis, frequency of B symptoms, delay in diagnosis, less aggressive staging procedures and treatment, or the inclusion of deaths due to other causes in survival estimates as sustained by Guinee and collegues [26], have all been claimed to explain the poorer survival of the older patients. A conclusive answer is not yet available, although it is clear that age is the most important prognostic factor in HD. The present study was undertaken to compare the clinicopathological features and survival of patients with HD and HTV infection (HTV-HD) with HD patients in the general population (HTV-negative HD) grouped by age <55 and ^55 years.
HD that is commonly observed in young men, irrespective of the HTV infection, has been described in patients with HTV infection both in the United States [1-4] and in Europe [5-7] in association with unfavourable prognostic factors, such as advanced-stage disease at presentation, unfavourable histological subtypes, aggressive clinical course, and an increased prevalence of associated opportunistic infections (OI). Whether HD should be included among the diseases diagnostic of the acquired immunodeficiency syndrome (AIDS) is still widely debated [6, 8, 9]. Recently Reynolds and coworkers found definitive increase in HD incidence in HIV-infected individuals in San Francisco [10]. Among the haematologic malignancies described in patients with HTV infection since the beginning of the HTV epidemic, high-grade B-cell non-Hodgkin's lymphomas (NHLs) has already been observed at an increased inciPatients and methods dence [11,12], and in association with peculiar clinicoThe Italian Cooperative Group on AIDS and Tumours (GICAT) has pathological features. Similarly, HD in the older gen* Supported in part by grants of AIRC '91 and grants of the V AIDS Project ISS '92.
been collecting data on malignant tumours in patients with HIV infection since 1986. Among 870 malignancies observed in HIV setting, 92 patients with HD have been reported [7] and constitute the HIV-HD patient group of this study. The HIV-negative HD
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Introduction
38
Results Table 1 shows patient characteristics and histologic type by group. More males were present in the HTVHD group in comparison with HTV-negative HD. No
IVDU was present among HTV-negative HD. With respect to the histologic type, patients of the older group (B) and HTV-infected patients (C) had a significantly lower frequency (31% and 21%, respectively) of nodular sclerosis (NS) subtype compared to the younger group (A) (85%). Mixed cellularity (MC) subtype is significantly more frequent both in patients of the older group and in HTV-infected patients. Lymphocyte depletion (LD), is much more frequently detected in HTVinfected patients as well. Lymphocyte predominance (LP) subtype is observed at a higher rate (16%) in older patients in comparison to the other two groups. Table 2 reports stage and B symptoms by group. A significantly higher proportion of advanced stages and B symptoms is present in patients of the HTV-infected group than in the other two groups. An involvement only of the lymph nodal sites is seen in about one-third of the HTV-infected patients (around 70% in the other two groups). Treatment of patients is shown in Table 3. Chemotherapy (CT) alone has been the most widely used (83%) treatment in HTV-infected patients, while in the two groups of the general population the chemotherapy plus radiotherapy (RT) association has been more frequently employed (63%). A remarkable point is that 12 HTV-infected patients (14%) did not receive any treatment Response evaluation and survival are reported in Table 4. The CR rate (51%) obtained in HTVinfected patients is significantly lower than that observed in the general population (around 90%). The overall 4-yr survival in the HTV-infected patients is much lower (33%) in comparison to that observed in both the groups of the general population (100% in younger, and 88% in older HTV-negative HD).
Table 1. Patient characteristics and histologic type by group.
No. patients Median age (range) Sex Male Female Histology LP NS MC LD Unclassifiable
Younger patients (A) <55 years
Older patients (B) >55yrs
HTV patients (C)
52 26 yrs (15-51)
32 63.5 yrs (55-76)
92 28 yrs (19-57)
30 22
17 15
84 8
2 (4%) 44 (85%) 5 (10%) 1 (2%)
5 (16%) 10 (31%) 15 (47%) 2 (6%) -
Younger patients (A) <55 years 31/52(60%) 21/52(40%) 18/52 (35%) 38/52 (73%)
P value A vs. B
A vs. C
Bvs. C
1 (1%) 19 (21%) 49 (55%) 20 (23%) 3/92 (3%)
N.S. <0.001 <0.001 N.S.
N.S. <0.001 <0.001 <0.001
0.005 N.S. N.S. 0.06
Older patients (B) >55 years
HTV patients (C)
P value A vs. B
A.vsC
Bvs. C
16/32 (50%) 16/32 (50%) 11/32(34%) 22/32 (69%)
18/89 71/89 65/79 32/87
N.S. N.S. N.S. N.S.
<0.001 <0.001 <0.001 <0.001
0.003 0.003 <0.001 0.004
Table 2. Clinical features by group.
Stage
i-n m-iv
B symptoms Only lymph nodal involvement
(20%) (80%) (82%) (37%)
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group is constituted by a series of 84 patients histologically diagnosed and treated at our institution, Centre di Riferimento Oncologico, Aviano, Italy, between 1986 and 1992. This single-institution series was chosen for comparison with the HIV-HD group because 22 out of 92 patients collected by the GICAT were initially diagnosed or histologically classified after the review by the Pathology Division of the Centro di Riferimento Oncologico. Only patients with histological confirmation of HD were admitted into this study. For this study, in the HTV-negative HD group, we have identified those patients 15 to 55 years of age as the 'younger' group (median age, 26 years) and those patients >55 years of age as the 'older* group (median age, 64 years). Criteria for this division and the median age of the two groups were similar to those used in a previous study on survival of older patients with HD by Walker and colleagues [25J. The medical records were reviewed with special attention to age, sex, histology, sites affected by HD, clinical stage, type of treatment, response, and survival. The clinical stage at presentation was established according to the Ann Arbor system [27]. Complete response (CR) was defined as complete disappearance of all measurable diseases lasting at least 4 weeks. Partial response (PR) was defined as a 50% reduction in the sum of the products of the cross-sectional diameters of known lesions. No response (NR) was defined as less than a PR or as the occurrence of progression. Survival was calculated from the date of diagnosis to death or to patient's latest contact Survival distributions were estimated according to the product-limit method of Kaplan-Meier [28]. The chisquare test was used to test differences between proportion [29]. Owing to the fact that the majority of patients in the HIV-HD group were intravenous drug users (IVDUs), in accordance with the epidemiology of HIV infection in Italy, frequent changes of address, of treating physicians, and of other economic and logistic problems connected with such IVDU group were present Therefore, complete information was not available from all cases.
39 Table 3. Treatment of patients by group.
RT RT + CT CT No treatment Unknown
Younger patients (A) <55 years
Older patients (B) >55 years
HIV patients (C)
10 (19%) 33 (63%) 9 (17%)
2 (6%) 20 (63%) 10 (31%)
Younger patients (A) <55 years
P value A vs. B
A vs. C
B vs. C
7 (9%) 6 (8%) 62 (83%) 12 (14%) 5 (5%)
N.S. N.S. N.S.
N.S. <0.001 <0.001
N.S. <0.001 <0.001
Older patients (B) >55 years
HTV patients (C)
P value A vs. B
A vs. C
B vs. C
48/52
31/32
51V75
44 (92%) 3 (6%) 1 (2%) 100%
29 (93%) 1 (3%) 1 (3%) 88%
26(51%) 22 (43%) 3 (6%) 33%
N.S. N.S. N.S. N.S.
<0.001 <0.001 N.S. <0.001
<0.001 <0.001 N.S. <0.001
Table 4. Response to treatment and survival by group.
24 patients were not evaluable for response because of incomplete information available (see text).
Discussion
25] have reported an increased rate of advanced stages in the older general population. Our data do not conMany studies have reported a higher incidence of HD firm this feature, but this may be due to the low number among HTV-infected patients [30,31], even if there is of patients. up to now only one epidemiological study demonstratAlthough a significantly higher rate of B symptoms ing a statistical link between HD and HTV infection is registered in the HTV-infected group than in the other [10]. Therefore, HD is not yet accepted as an ATDS- two groups, it is difficult in the first group to evaluate defining pathology. Serraino and colleagues [32] docu- whether fever, night sweats, and weight loss are related mented for the first time a significant difference in the either to malignancy or to HTV status. Another peculiar distribution of HD histologic subtypes in HTV-infected feature observed in our study within the HTV-infected patients as compared to HD in the general population. group, often reported in the literature [2-6], is the low In particular, they registered a 4-fold high frequency of incidence of only lymph nodal involvement of HD at MC and approximately 12-fold higher frequency of LD onset [7]. among HTV-infected patients. In our study, we found a Some difficulties have been encountered by many very similar MC subtype rate between HTV-infected authors in the treatment of HD both in elderly patients patients and elderly patients. A higher incidence of MC [15, 25, 26] and in HTV-infected patients [6, 7, 35]. Pain elderly HD patients has been previously described tients of the general population were more likely to [14, 19, 21, 25], without clear evidence that the poor receive RT after CT than the HTV-infected patients. prognosis of these patients is merely influenced by the This may be due, first, to the fact that the HTV-negative histologic subtype [21]. On the other hand, there is a HD patients of our study were in most cases included lack of NS in elderly patients and HTV patients; this in prospective studies employing RT after CT, whereas feature has been found also among other groups of HD treatment of HIV-positive HD was dependent on indipatients with naturally occurring immunodeficiency, in vidual patient and physician choice. In fact the use of particular among pediatric patients [33]. The evidence RT after CT in an immunocompromised patient might of a high rate of LP in the older general population has play a negative role by increasing immunosuppression. been reported by other previous studies [13,25]. More- Even though the objective response rate obtained does over, variations of HD risk patterns according to histo- not differ within the three groups, the CR rate in the logic subtype have been shown in the general popula- HIV-positive patients is significantly lower. Probably tion, suggesting that the histologic subtypes of HD this unsatisfactory result is linked to the limited posrepresent distinct entities with at least partially differ- sibility of an adequate treatment in these patients, ent etiologies [34]. The rate of advanced stages in HTV- owing to the frequent occurrence of opportunistic and infected patients is significantly higher in comparison nonopportunistic infections and the reduced bone marto both older and younger HD groups, while in our row tolerance. The recent availability of bone marrow study there is no statistical difference within the two growth factors could significantly ameliorate the bone groups of the general population. Other studies [13,18, marrow tolerance after CT and could probably permit
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Eval. patients/total patients Response CR PR NR Actuarial overall survival at 4 years;
40
an association of antineoplastic and antiretroviral drugs in this setting. Beside the unfavourable clinicopathological features of HD at presentation, the underlying HTV infection, together with the low CR rate, accounts for the significantly lower 4-year crude survival rate in these patients. Only by controlling HIV infection will it be possible to improve the survival of HIV-positive HD patients significantly. References
Correspondence to: Umberto Tirelli Division of Medical Oncology and AIDS Centra di Riferimento Oncologico 33081 Aviano Italy
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1. Ames ED, Conjalka MS, Goldberg AF et al. Hodgkin's disease and AIDS: Twenty-three new cases and a review of the literature. Hematol/Oncol Clin North Am 1991; 5: 343-56. 2. Ree HJ, Strauchen JA, Khan AA et al. Human immunodeficiency virus associated Hodgkin's disease: Clinico-pathologic studies of 24 cases and preponderance of mixed cellularity type characterized by the occurrence of fibrohistiocytoid stromal cells. Cancer 1991; 67:1614-21. 3. Knowles DM, Chamulak GA, Subar M et al. Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS): The New York Medical Center experience with 105 patients (1981-1986). Ann Inter Med 1988; 108: 744-53. 4. Lowenthal DA, Straus DJ, Campbell SW et al. AlDS-related lymphoid neoplasia: The Memorial Hospital experience. Cancer 1988; 61: 2325-37. 5. Roithmann S, Tourani JM, Andrieu JM. HIV-associated Hodgkin's disease: report of 45 cases. Eur J Cancer 1991; 13 (suppl 2) (abstr). 6. Serrano M, Bellas C, Campo E et al. Hodgkin's disease in patients with antibodies to human immunodeficiency virus: A study of 22 patients. Cancer 1990; 65: 2248-54. 7. Tirelli U, Errante D, Vaccher E et al. Hodgkin's disease in 92 patients with HTV infection: The Italian experience. Ann Oncol 1992; 3 (suppl 4): S69-S72. 8. Rabkin CS, Blattner W. HIV infection and cancer other than non-Hodgkin's lymphoma and Kaposi's sarcoma. In Beral V, Jaffe HW, Weiss RA (eds): Cancer, HIV, and AIDS. Oxford: Cold Spring Harbor Laboratory Press, 1991; 151-60. 9. Hessol AN, Katz MH, Liu JY et al. Increased incidence of Hodgkin's disease in homosexual men with HIV infection. Ann Inter Med 1992; 117: 309-11. 10. Reynolds P, Saunders LD, Layefsky ME et al. The spectrum of acquired immunodeficiency syndrome (AIDS)-associated malignancies in San Francisco, 1980-1987. Am J Epidemiol. 1993; 137:19-30. 11. Biggar RJ. Cancer in acquired immunodeficiency syndrome: An epidemiological assessment. Sem Oncol 1990; 17 (3): 25160. 12. Beral V, Peterman T, Berkelman R et al. AIDS-associated nonHodgkin's lymphoma. Lancet 1991; 337: 805-9. 13. Eghbali H, Hoerni-Simon G, De Mascarel I et al. Hodgkin's disease in the elderly: A series of 30 patients aged older than 70 years. Cancer 1984; 53: 2191-3. 14. Lokich JJ, Pinkus GS, Moloney WC. Hodgkin's disease in the elderly. Oncology 1974; 29: 484-500. 15. Austin-Seymour MM, Hoppe RT, Cox RS et al. Hodgkin's disease in patients over sixty years old. Ann hit Medicine 1984; 100: 13-8. 16. Peterson BA, Pajak TI, Cooper MR et al. The effects of age on therapeutic response and survival in advanced Hodgkin's disease. Cancer Treat Rep 1982; 66: 889-98. 17. Burgers JMV, Ishak Sharouni S, Hart GM et al. Correlation between age and prognosis in Hodgkin's disease (HD). Third International Conference on Malignant Lymphoma. Lugano June 10-13 1987 (abstract 66).
18. Tirelli U, Serraino D, Zagonel V et al. Hodgkin's disease in patients 70 years of age or more: A retrospective EORTC Lymphoma Group Study. Cancer Invest 1990; 8 (6): 643-4. 19. Vaughan Hudson B, MacLennan KA, Easterling MJ et al. The prognostic significance of age in Hodgkin's disease: Examination of 1500 patients. BNLI Report No. 23. Clin Radiol 1983; 34: 503-6. 20. Tubiana M, Henry-Amar M, Carde P et al. Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease: The EORTC Lymphoma Group controlled clinical trials, 1964-1987. Blood 1989; 73: 47-56. 21. Wedelin M, Bjorkholm M, Ogenstad B et al. Prognostic factors in Hodgkin's disease with special reference to age. In Wedelin C (ed): On the prognosis of Hodgkin's disease: A clinical and immunological study. Stockholm: Karolinska Institute, 1982; 1-18. 22. Terblanche AP, Falkson G, Matzner L. The prognostic significance of age in patients with advanced Hodgkin's disease. Eur J Cancer Clin Oncol 1988; 24:1805-9. 23. Gobbi B, Cavalli C, Massimo F et al. Increasing interdependency of prognosis- and therapy-related factors in Hodgkin's disease. Acta Haematol 1989; 81: 34-40. 24. Rossi Ferrini P, Bosi A, Casini A et al. Hodgkin's disease in the elderly: A retrospective clinicopathologic study of 61 patients. Acta Haematol 1987; 87 (suppl 1): 163-70. 25. Walker A, Schoenfeld ER, Lowman JT et al. Survival of the older patient compared with the younger patient with Hodgkin's disease: Influence of histologic type, staging, and treatment. Cancer 1990; 65:1635-40. 26. Guinee VF, Giacco GG, Durand M et al. The prognosis of Hodgkin's disease in older adults. J Clin Oncol 1992; 9 (6> 947-53. 27. Carbone PP, Kaplan HS, Mussohff K et al. Report of the Committee on Hodgkin's disease: Staging classification. Cancer Res 1971; 31:1860-1. 28. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 29. Armitage P, Barry G. 2 x 2 and X2 tests. In Statistical methods in medical research. 2d ed. Blackwell Scientific Publications, 1987; 125-32. 30. Biggar RJ, Horm J, Goedert JJ et al. Cancer in a group at risk of acquired immunodeficiency syndrome (AIDS) through 1984. Am J Epidemiol 1987; 174: 578-86. 31. Harnly ME, Swan SH, Kelter A. The authors reply (letter). Am J Epidemiol 1989; 130:1070-1. 32. Serraino D, Carbone A, Franceschi S et al. Increased frequency of lymphocyte depletion and mixed cellularity subtypes of Hodgkin's disease in HIV-infected patients. Eur J Cancer (in press). 33. Robinson LL, Stoker V, Frizzera G et al. Hodgkin's disease in pediatric patients with naturally occurring immunodeficiency. Am J Ped Hematol Oncol 1987; 9:189-92. 34. Cozen W, Katz J, Mack TM. Risk patterns of Hodgkin's disease in Los Angeles vary by cell type. Cancer Epidemiology, Biomarkers, and Prevention 1992; 1: 261-8. 35. Tirelli U, Errante D, Vaccher E et al. Hodgkin's disease and HIV infection: A report of 92 patients from the GICAT (Italian Cooperative Group on AIDS and Tumors), with emphasis on prospective study with combined chemotherapy and zidovudine in 16 patients. Proc Am Soc Clin Oncol 1992; 11: 44 (abstr).
Original article Hodgkin's disease in patients with HTV infection and in the general population: Comparison of clinicopathological features and survival* D. Errante,1 V. Zagonel,2 E. Vaccher,1 D. Serraino,3 D. Bernardi,1 R. Sorio,2 M. Trovo,4 A. Carbone,5 S. Monfardini2 & U. Tirelli1 'Division of Medical Oncology and AIDS, 2 Division of Medical Oncology, 3Epidemiology Unit, 4 Division of Radiotherapy, s Division of Pathology, Centro di Riferimento Oncologico, Aviano, Italy
in older patients than in the other two groups. HIV-infected patients are more likely to show advanced stages, B sympBackground: Hodgkin's disease (HD) has been described in toms, and extranodal involvement. Chemotherapy (CT) patients with HTV infection in association with unfavourable alone has been the most widely used (83%) treatment in prognostic factors. Similarly, HD in the older general popula- HIV-infected patients, while CT plus radiotherapy (RT) has been mostly employed in the general population. Twelve tion has a poorer prognosis than in younger patients. Patients and methods: With the aim of comparing the (14%) HIV-infected patients did not receive any treatment. clinicopathological features and survival of HD in HTV-in- Complete remission was achieved in 51% of the cases in the fected patients and in the general population, we analysed HIV-infected patients, and around 90% of the cases in the 176 patients with HD from 1986 to 1992. We divided the 84 general population. The estimated 4-year survival rate in the HTV-negative patients into two groups: group A included HIV-infected patients is much lower (33%) than in the other patients less than 55 years old, group B patients of 55 years two groups (100% in group A, and 88% in group B). or older. This division was made in order to compare HD Conclusion: While MC is the most common histological in HIV-infected patients with the less favourable group of subtype both in HIV-infected patients and in the older genpatients with HD in the general population, i.e., older pa- eral population, HD in HIV-infected patients has a worse tients. prognosis than in the older general population, not only beResults: Patients of the older group and HIV-infected pa- cause of underlying HIV infection, but also because of the tients had a significantly lower frequency (31% and 21%, more unfavourable clinicopathological features at presentarespectively) of nodular sclerosis subtype compared to the tion. younger group (85%). Mixed cellularity (MC) is significantly more frequent both in the older group and in HIV-infected Key words: age, general population, HIV infection, patients. Lymphocyte predominance is more frequent (16%) Hodgkin's disease Summary
era! population has been considered peculiar for its clinical and histological manifestations. In particular, it is associated with poor survival in older patients compared to younger patients [13,25]. Differences in histologic type, stage at diagnosis, frequency of B symptoms, delay in diagnosis, less aggressive staging procedures and treatment, or the inclusion of deaths due to other causes in survival estimates as sustained by Guinee and collegues [26], have all been claimed to explain the poorer survival of the older patients. A conclusive answer is not yet available, although it is clear that age is the most important prognostic factor in HD. The present study was undertaken to compare the clinicopathological features and survival of patients with HD and HTV infection (HTV-HD) with HD patients in the general population (HTV-negative HD) grouped by age <55 and ^55 years.
HD that is commonly observed in young men, irrespective of the HTV infection, has been described in patients with HTV infection both in the United States [1-4] and in Europe [5-7] in association with unfavourable prognostic factors, such as advanced-stage disease at presentation, unfavourable histological subtypes, aggressive clinical course, and an increased prevalence of associated opportunistic infections (OI). Whether HD should be included among the diseases diagnostic of the acquired immunodeficiency syndrome (AIDS) is still widely debated [6, 8, 9]. Recently Reynolds and coworkers found definitive increase in HD incidence in HIV-infected individuals in San Francisco [10]. Among the haematologic malignancies described in patients with HTV infection since the beginning of the HTV epidemic, high-grade B-cell non-Hodgkin's lymphomas (NHLs) has already been observed at an increased inciPatients and methods dence [11,12], and in association with peculiar clinicoThe Italian Cooperative Group on AIDS and Tumours (GICAT) has pathological features. Similarly, HD in the older gen* Supported in part by grants of AIRC '91 and grants of the V AIDS Project ISS '92.
been collecting data on malignant tumours in patients with HIV infection since 1986. Among 870 malignancies observed in HIV setting, 92 patients with HD have been reported [7] and constitute the HIV-HD patient group of this study. The HIV-negative HD
Downloaded from http://annonc.oxfordjournals.org/ at University of Birmingham on June 3, 2015
Introduction
38
Results Table 1 shows patient characteristics and histologic type by group. More males were present in the HTVHD group in comparison with HTV-negative HD. No
IVDU was present among HTV-negative HD. With respect to the histologic type, patients of the older group (B) and HTV-infected patients (C) had a significantly lower frequency (31% and 21%, respectively) of nodular sclerosis (NS) subtype compared to the younger group (A) (85%). Mixed cellularity (MC) subtype is significantly more frequent both in patients of the older group and in HTV-infected patients. Lymphocyte depletion (LD), is much more frequently detected in HTVinfected patients as well. Lymphocyte predominance (LP) subtype is observed at a higher rate (16%) in older patients in comparison to the other two groups. Table 2 reports stage and B symptoms by group. A significantly higher proportion of advanced stages and B symptoms is present in patients of the HTV-infected group than in the other two groups. An involvement only of the lymph nodal sites is seen in about one-third of the HTV-infected patients (around 70% in the other two groups). Treatment of patients is shown in Table 3. Chemotherapy (CT) alone has been the most widely used (83%) treatment in HTV-infected patients, while in the two groups of the general population the chemotherapy plus radiotherapy (RT) association has been more frequently employed (63%). A remarkable point is that 12 HTV-infected patients (14%) did not receive any treatment Response evaluation and survival are reported in Table 4. The CR rate (51%) obtained in HTVinfected patients is significantly lower than that observed in the general population (around 90%). The overall 4-yr survival in the HTV-infected patients is much lower (33%) in comparison to that observed in both the groups of the general population (100% in younger, and 88% in older HTV-negative HD).
Table 1. Patient characteristics and histologic type by group.
No. patients Median age (range) Sex Male Female Histology LP NS MC LD Unclassifiable
Younger patients (A) <55 years
Older patients (B) >55yrs
HTV patients (C)
52 26 yrs (15-51)
32 63.5 yrs (55-76)
92 28 yrs (19-57)
30 22
17 15
84 8
2 (4%) 44 (85%) 5 (10%) 1 (2%)
5 (16%) 10 (31%) 15 (47%) 2 (6%) -
Younger patients (A) <55 years 31/52(60%) 21/52(40%) 18/52 (35%) 38/52 (73%)
P value A vs. B
A vs. C
Bvs. C
1 (1%) 19 (21%) 49 (55%) 20 (23%) 3/92 (3%)
N.S. <0.001 <0.001 N.S.
N.S. <0.001 <0.001 <0.001
0.005 N.S. N.S. 0.06
Older patients (B) >55 years
HTV patients (C)
P value A vs. B
A.vsC
Bvs. C
16/32 (50%) 16/32 (50%) 11/32(34%) 22/32 (69%)
18/89 71/89 65/79 32/87
N.S. N.S. N.S. N.S.
<0.001 <0.001 <0.001 <0.001
0.003 0.003 <0.001 0.004
Table 2. Clinical features by group.
Stage
i-n m-iv
B symptoms Only lymph nodal involvement
(20%) (80%) (82%) (37%)
Downloaded from http://annonc.oxfordjournals.org/ at University of Birmingham on June 3, 2015
group is constituted by a series of 84 patients histologically diagnosed and treated at our institution, Centre di Riferimento Oncologico, Aviano, Italy, between 1986 and 1992. This single-institution series was chosen for comparison with the HIV-HD group because 22 out of 92 patients collected by the GICAT were initially diagnosed or histologically classified after the review by the Pathology Division of the Centro di Riferimento Oncologico. Only patients with histological confirmation of HD were admitted into this study. For this study, in the HTV-negative HD group, we have identified those patients 15 to 55 years of age as the 'younger' group (median age, 26 years) and those patients >55 years of age as the 'older* group (median age, 64 years). Criteria for this division and the median age of the two groups were similar to those used in a previous study on survival of older patients with HD by Walker and colleagues [25J. The medical records were reviewed with special attention to age, sex, histology, sites affected by HD, clinical stage, type of treatment, response, and survival. The clinical stage at presentation was established according to the Ann Arbor system [27]. Complete response (CR) was defined as complete disappearance of all measurable diseases lasting at least 4 weeks. Partial response (PR) was defined as a 50% reduction in the sum of the products of the cross-sectional diameters of known lesions. No response (NR) was defined as less than a PR or as the occurrence of progression. Survival was calculated from the date of diagnosis to death or to patient's latest contact Survival distributions were estimated according to the product-limit method of Kaplan-Meier [28]. The chisquare test was used to test differences between proportion [29]. Owing to the fact that the majority of patients in the HIV-HD group were intravenous drug users (IVDUs), in accordance with the epidemiology of HIV infection in Italy, frequent changes of address, of treating physicians, and of other economic and logistic problems connected with such IVDU group were present Therefore, complete information was not available from all cases.
39 Table 3. Treatment of patients by group.
RT RT + CT CT No treatment Unknown
Younger patients (A) <55 years
Older patients (B) >55 years
HIV patients (C)
10 (19%) 33 (63%) 9 (17%)
2 (6%) 20 (63%) 10 (31%)
Younger patients (A) <55 years
P value A vs. B
A vs. C
B vs. C
7 (9%) 6 (8%) 62 (83%) 12 (14%) 5 (5%)
N.S. N.S. N.S.
N.S. <0.001 <0.001
N.S. <0.001 <0.001
Older patients (B) >55 years
HTV patients (C)
P value A vs. B
A vs. C
B vs. C
48/52
31/32
51V75
44 (92%) 3 (6%) 1 (2%) 100%
29 (93%) 1 (3%) 1 (3%) 88%
26(51%) 22 (43%) 3 (6%) 33%
N.S. N.S. N.S. N.S.
<0.001 <0.001 N.S. <0.001
<0.001 <0.001 N.S. <0.001
Table 4. Response to treatment and survival by group.
24 patients were not evaluable for response because of incomplete information available (see text).
Discussion
25] have reported an increased rate of advanced stages in the older general population. Our data do not conMany studies have reported a higher incidence of HD firm this feature, but this may be due to the low number among HTV-infected patients [30,31], even if there is of patients. up to now only one epidemiological study demonstratAlthough a significantly higher rate of B symptoms ing a statistical link between HD and HTV infection is registered in the HTV-infected group than in the other [10]. Therefore, HD is not yet accepted as an ATDS- two groups, it is difficult in the first group to evaluate defining pathology. Serraino and colleagues [32] docu- whether fever, night sweats, and weight loss are related mented for the first time a significant difference in the either to malignancy or to HTV status. Another peculiar distribution of HD histologic subtypes in HTV-infected feature observed in our study within the HTV-infected patients as compared to HD in the general population. group, often reported in the literature [2-6], is the low In particular, they registered a 4-fold high frequency of incidence of only lymph nodal involvement of HD at MC and approximately 12-fold higher frequency of LD onset [7]. among HTV-infected patients. In our study, we found a Some difficulties have been encountered by many very similar MC subtype rate between HTV-infected authors in the treatment of HD both in elderly patients patients and elderly patients. A higher incidence of MC [15, 25, 26] and in HTV-infected patients [6, 7, 35]. Pain elderly HD patients has been previously described tients of the general population were more likely to [14, 19, 21, 25], without clear evidence that the poor receive RT after CT than the HTV-infected patients. prognosis of these patients is merely influenced by the This may be due, first, to the fact that the HTV-negative histologic subtype [21]. On the other hand, there is a HD patients of our study were in most cases included lack of NS in elderly patients and HTV patients; this in prospective studies employing RT after CT, whereas feature has been found also among other groups of HD treatment of HIV-positive HD was dependent on indipatients with naturally occurring immunodeficiency, in vidual patient and physician choice. In fact the use of particular among pediatric patients [33]. The evidence RT after CT in an immunocompromised patient might of a high rate of LP in the older general population has play a negative role by increasing immunosuppression. been reported by other previous studies [13,25]. More- Even though the objective response rate obtained does over, variations of HD risk patterns according to histo- not differ within the three groups, the CR rate in the logic subtype have been shown in the general popula- HIV-positive patients is significantly lower. Probably tion, suggesting that the histologic subtypes of HD this unsatisfactory result is linked to the limited posrepresent distinct entities with at least partially differ- sibility of an adequate treatment in these patients, ent etiologies [34]. The rate of advanced stages in HTV- owing to the frequent occurrence of opportunistic and infected patients is significantly higher in comparison nonopportunistic infections and the reduced bone marto both older and younger HD groups, while in our row tolerance. The recent availability of bone marrow study there is no statistical difference within the two growth factors could significantly ameliorate the bone groups of the general population. Other studies [13,18, marrow tolerance after CT and could probably permit
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Eval. patients/total patients Response CR PR NR Actuarial overall survival at 4 years;
40
an association of antineoplastic and antiretroviral drugs in this setting. Beside the unfavourable clinicopathological features of HD at presentation, the underlying HTV infection, together with the low CR rate, accounts for the significantly lower 4-year crude survival rate in these patients. Only by controlling HIV infection will it be possible to improve the survival of HIV-positive HD patients significantly. References
Correspondence to: Umberto Tirelli Division of Medical Oncology and AIDS Centra di Riferimento Oncologico 33081 Aviano Italy
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