ARTICLE
Auteur(s) : G Wamburu1, EJ Masenga1, EZ
Moshi1, P Schmid-Grendelmeier2, W
Kempf2, CE Orfanos3
1Regional Dermatology Training Center (RDTC),
Kilimanjaro Christian Medical Center, Tumaini University Medical
School, Moshi, Tanzania
2Department of Dermatology, University of Zuerich,
Switzerland
3Prof. Emer. Dr. C. E. Orfanos is presently Guest
Physician and Lecturer at the RDTC
Tanzania with a population of 34 million is one of the African
countries most affected by HIV/AIDS. More than 2 million people are
estimated to be living with HIV/AIDS, with almost 700,000
cumulative AIDS cases found by the end of the year 2000 [1].Most
infections are sexually transmitted, i.e. with significant
preference to the sexually active youth. KS is common in the
equatorial belt of Africa including Tanzania, where it occurs
frequently in both HIV-infected and non HIV-infected individuals,
males and females.In the early sixties, endemic KS was recognized
as one of the most common neoplasms in black populations in
equatorial Africa and the designation “African-endemic” KS was
introduced. In Uganda, endemic KS has been reported to account for
9% of all malignancies [2, 3], whereas in North Eastern Congo the
incidence rates were found 10-12.8% [2, 4]. The African-endemic
variant of KS was also frequently seen in females and in children.
Data from Zambia suggested that KS represented up to 25% of all
cancers in children, with a preference for boys 1.76:1 [5].With the
onset of HIV-infection and AIDS, HIV-associated KS has emerged,
also referred to as “epidemic KS”, mostly seen in Europe and the
USA in young male Caucasians who have had sexual contact with other
males. In Africa, the new epidemic variety of KS mostly occurs in a
young sexually active population, with increasing involvement of
females [6, 7]. The burden of HIV infection and AIDS is greatest in
the developing world and neoplastic complications are increasingly
encountered. Overall, the incidence of KS has sharply increased in
developing countries [6, 8-10], showing a 20-fold increase in some
African countries during the 1990s [11-13], particularly in Uganda
and Zimbabwe.Association of the tumour with HIV-infection was
described early in Equatorial East Africa with and without immune
suppression [14]. Oedema of the face is common, accompanied by
nodules and/or plaques on the nose, ear lobes, cheeks, forehead and
neck. A most typical site is mucosal involvement of the hard palate
[15]. HIV-associated KS has a tendency to develop rapidly, in a
bilateral symmetrical distribution, and often tends to follow
Langer’s lines [16]. It seems likely that the immune status governs
the onset and the course of the disease, although not all patients
with HIV-associated KS are clearly immune-suppressed, as shown in
this study.With the introduction of antiretroviral therapy (HAART)
long-term beneficial effects were obtained, sometimes leading to
full regression of KS [9, 17-19]. During the last 10 years a
dramatic decrease in incidence of HIV-associated KS has been seen,
and the clinical manifestations of the tumour appear to be less
aggressive [8, 19-27]. In the USA, the incidence of HIV-associated
KS has been decreasing in all risk groups. At the onset of the
epidemic, KS occurred in up to 40% of patients with AIDS, in 1985
the figure was 28% and today it is less than 10%. This may be a
result of safer sexual practices, awareness of sexually transmitted
diseases and also use of HAART, including protease inhibitors, in
patients with AIDS [28].The purpose of the present study was to
describe the clinical spectrum of KS in an African population, in
both its HIV-associated and non HIV-associated types, as seen at
the Regional Dermatology Training Centre in the Kilimanjaro area in
Moshi, Tanzania. Also, the status of immune suppression and the
presence of HHV 8-antibodies in individuals with Kaposi’s sarcoma
were the subject for this investigation.
Clinical and laboratory investigations
One hundred and five patients with clinically suspected KS were
carefully examined for the clinical symptomatology of KS by an
experienced dermatologist. The patients then underwent pre-test
counseling, blood samples were taken and lesional skin biopsies
were obtained for histological investigation. HIV status was
determined using Cappillus HIV-1/HIV-2 testing kits (Trinity
biotech, Ireland) and CD4+, CD8+ counts were
measured by Flow cytometry (Partec Cyflow counter, Germany). The
CD4+/CD8+ ratio was then calculated in all
patients. In addition, HHV-8 serology was determined using HHV-8
IgG antibody Elisa kits (Switzerland). Chest pathology was assessed
by X-rays in a number of cases with suspected lung involvement.
Thereafter, the patients received post-test counseling and were
then managed accordingly by the physician.
The diagnosis of KS (n = 77) was reached by confirmation with an
experienced dermatopathologist. Data entry and analysis was
performed by using SPSS 9.0 for Windows. All patients gave oral and
written informed consent to the study which had been approved by
the local ethical committee.
Results
Clinical findings and HIV-serology
Out of 105 patients with clinically suspected Kaposi’s sarcomas, 77
had histologically confirmed KS; in 66 (85.7%) of these patients
HIV-serology was positive, while the remaining 11 (14.3%) patients
were found negative for HIV. The majority of the 66 KS-patients
found to be HIV-seropositive were males (60.6%), giving a male:
female ratio of 1.5:1. Irrespective of gender, most of these
patients were at a sexually active age. The 11 HIV-seronegative
KS-patients registered were all males; most of them older than 50
years (table 1( Table 1 )).
In HIV-seropositive individuals with KS, the tumour seemed to
progress rapidly, causing significant morbidity. In particular, the
lower limbs were mostly affected (table 1). The lesions in
HIV-seropositive patients were widely disseminated all over the
skin and partly the viscera, also showing characteristic
involvement of the oral mucosa. Out of all 77 patients with KS, 41
had oral involvement and 39 (95.1%) of these belonged to the
HIV-seropositive group. Only 2 (4.9%) patients with oral
involvement had non-HIV associated KS. Thirty two (41.6%) of all
patients with KS had disseminated trunk involvement and all of them
belonged to the group with HIV-associated KS. Other localization
sites seen rather exclusively in the HIV-associated KS-group
included craniofacial involvement, seen in 29/66 (43.9%) patients,
eye involvement, seen in 14/66 (21.2%), and also genital
involvement, seen in 10/66 (15.2%) (table 1). Clinically, it was
apparent that nearly all HIV-seropositive KS-patients had multiple
types of mucocutaneous lesions, ranging from plaques, nodules,
infiltrative KS with massive lymphoedema, to fungating and
ulcerated lesions (figures 1, 2 and 3).
In contrast, all 11 patients with non HIV-associated KS showed
skin involvement limited exclusively to their lower limbs (table
1). They had extensive infiltrative and confluent types of lesions
and nodules associated with varying degrees of lymphoedema, showing
rather long lasting course ( (figure 4) ).
The clinical progression of the disease differed in each
individual case. An accurate comparison of the time period for
tumour progression in each group separately was not done, since the
follow-up time was short and the treatment modalities greatly
differed from patient to patient. However, based on the information
given by the patients in their medical history and our clinical
observations, the clinical course appeared clearly faster in the
HIV-seropositive, as compared to the HIV-seronegative KS-group.
Table 1 The epidemic and endemic KS in relation to some
demographic variables and the sites of involvement
|
Total (N)
|
Epidemic KS (n = 66)
|
Endemic KS (n = 11)
|
P-value
|
|
Sex:
|
|
|
|
|
|
Male
|
51
|
40 (78.4%)
|
11 (21.6%)
|
|
|
Female
|
26
|
26 (100%)
|
-
|
0.013
|
|
|
|
|
|
|
Age group (yrs):
|
|
|
|
|
|
< 10
|
2
|
2 (100%)
|
-
|
|
|
10-25
|
5
|
3 (60.0%)
|
2 (40.0%)
|
|
|
26-35
|
25
|
25 (100%)
|
-
|
|
|
36-49
|
34
|
32 (94.1%)
|
2 (5.9%)
|
|
|
50+
|
11
|
4 (36.4%)
|
7 (63.6%)
|
< 0.001
|
|
|
|
|
|
|
Site involved
|
|
|
|
|
|
Oral
|
41
|
39 (95.1%)
|
2 (4.9%)
|
0.020
|
|
Cranial-facial
|
29
|
29 (100%)
|
-
|
NS
|
|
Eye
|
14
|
14 (100%)
|
-
|
NS
|
|
Trunk
|
32
|
32 (100%)
|
-
|
0.005
|
|
Back
|
27
|
26 (96.3%)
|
1 (3.7%)
|
NS
|
|
Upper limbs
|
36
|
33 (91.7%)
|
3 (8.3%)
|
NS
|
|
Lower limbs
|
62
|
51 (82.3%)
|
11 (17.7%)
|
NS
|
|
Genital
|
10
|
10 (100%)
|
-
|
NS
|
Histology
Histological examination of lesional biopsies with routine
techniques revealed the presence of KS in different stages of
development. The most frequent finding in tissue was the presence
of vascular lumina and incomplete slits with prominent
extravasation of erythrocytes. Hemorrhage and lymphocytic cell
infiltrates with plasma cells were a common finding. Spindle cell
infiltrates were detected in 45 (68%) HIV-seropositive and in 5
(50%) HIV-seronegative KS-patients.
Based on our observations in tissue, we were not able to
substantiate any prominent differences of KS-features between the
HIV-seropositive and the HIV-seronegative group.
Immunohistochemical investigations of some KS-lesions revealed the
presence of numerous HHV-8 particles.
CD4+/CD8+ cell count profiles
Analysis of lymphocytic populations was performed in 62 out of 66
HIV-seropositive KS-patients. Out of these, 45 patients with
HIV-associated KS (72.6%) were found to be highly immune
suppressed, listed in Group C of the WHO classification (< 200
CD4+ cells/mm3); another 15/62 patients
(24.2%) were classified in Group B (CD4+
200-400 mm3) and only 2/62 KS-patients examined had
CD4+ cells > 500/mm3, equivalent to WHO
Group A. There were no sex differences in regard to the
CD4+ counts.
Thus, in most HIV-seropositive KS-patients the tumour appeared
as an opportunistic malignancy in a highly immune-suppressed
population. In contrast, only 4/9 patients in the HIV-seronegative
group had CD4+ counts below 500/mm3, whereas,
5/9 of them were not immune-suppressed.
Human Herpes Virus-8 (HHV-8) serology
Out of 66 patients with HIV-associated KS, 56 were examined for
HHV-8 and 53 (94.6%) were found HHV-8 seropositive; in 3 patients
no antibodies to HHV-8 could be detected. Among the 11
HIV-seronegative KS-patients, 9 were examined for HHV-8 and all
were shown positive. Individuals seropositive both to HIV and HHV-8
were at high risk to develop KS (OR = 10.6 95% CI, 2.981-37.688; p
< 0.001).
Discussion
In recent years increasing numbers of patients with KS have been
seen at the Regional Dermatology Training Center (RDTC) in
Tanzania. During the period 2002-2004 alone, 170 patients were
recorded, among them 75 females. Their clinical presentation and
serological status had been rather diverse. Hence, the purpose of
this study was to register, describe and evaluate the clinical and
serological data in a large African population with KS. Our study
was expected to shed some light on the occurrence and clinical
spectrum of this entity and the factors influencing the sharp
increase of KS in our region, in contrast to the clearly decreasing
numbers of KS seen in HIV-infected groups in Europe and elsewhere.
Among the 77 African patients with KS seen by us in Tanzania,
there was considerable clinical overlap between the features of
HIV-associated and non HIV-associated KS. There was predominance of
lower limb involvement in both groups, a feature that traditionally
was associated with the African, endemic KS-type. On the other
hand, some HIV-seronegative patients with KS may also show a
rapidly progressive, disseminated course in late stages, as seen in
HIV-seropositive patients. The increasing prevalence of HIV
infection in 16 Sub-Saharan countries including Tanzania [1],
complicates all efforts to clearly distinguish the earlier
described African endemic KS-variant in HIV-seropositive African
patients [29]. There has been considerable confusion related to the
overlap of the concurrent presence of HIV-associated epidemic KS
and the widespread non HIV-associated endemic form of the tumour,
occurring simultaneously among African patients [29].
In our series, 11 African patients with KS were registered as
HIV-seronegative, and 9 of them were tested positive for HHV-8.
They were all males, most of them older than 50 years in age
(7/11), thus showing a rather homogeneous clinical spectrum. We
believe that this group clearly represents a well-defined cohort of
patients with the endemic African KS-variant in which preference to
the lower limbs with lymphadenopathy, lymphoedema and less oral
and/or craniofacial involvement is evident. The course of the
endemic KS patients was rather long and immune suppression was less
developed (only 1/9 patient listed in WHO Group C), as compared to
the epidemic KS-group. No children less than 10 years in age were
registered among these HIV-seronegative patients, unlike the
HIV-associated KS-group where 2 children were seen (2/66).
The findings obtained in our study concur with the knowledge
that both HIV-1 and HHV-8 viruses are closely related to KS. It
seems that each of these viruses may lead to development of KS [5,
14, 15, 30-34], with varying clinical courses. All patients
examined with non HIV-associated KS were found positive to HHV-8,
whereas, the high HHV-8 seropositivity in patients with
HIV-associated KS appeared related to the high prevalence of HHV-8
in the Tanzanian population. When the two viruses occurred
together, their oncogenic potential seemed to trigger tumour
development and more rapid course, showing a tendency for
craniofacial manifestation, involvement of the oral cavity, and
tumour dissemination.
These observations are compatible with recent molecular
biological findings on the interaction of the two viruses [35].
HIV-1 tat protein is a known short-term growth factor for KS [5].
In addition, it directly promotes HHV-8 transmission by enhancing
the entry of HHV-8 into endothelial and other cells [21]. Tat
protein also promotes HIV-associated KS by increasing serum β-FGF
and activating HHV-8 [28]. On the other hand, HHV-8 is known to
activate nuclear receptors NF-kappa B and NF-AT and this level of
activation is synergistically increased by HIV-1 tat protein [36].
Thus, infection with HHV-8 is associated with KS and risk for KS
has been repeatedly reported to increase with increasing titres of
HHV-8 antibodies. However, for a given HHV-8 titer, the risk is
greater in HIV-seropositive, as compared to HIV-seronegative
individuals [12, 13, 25, 37-39].
Clinical expression of KS in equatorial Africa (Tanzania) may be
also modified by local factors such as lymphoedema and/or
podoconiosis, which is prevalent in the region [23, 40, 41].
Despite recent developments for treating HIV-infection including
introduction of HAART, it is necessary to recognize that KS remains
a permanent life threatening tumour in areas with high HHV-8
seroprevalence and in developing countries unable to provide HAART
to the large numbers of HIV-infected individuals [9, 42].
In conclusion, in our series there was a considerable clinical
overlap between the features of HIV-associated and non
HIV-associated KS. There was predominance of lower limb involvement
in both groups, a feature that traditionally has been associated
with the African, endemic KS-type. HIV-associated KS differed from
the non-HIV-associated by its widespread clinical dissemination on
the trunk, the frequent involvement of the oral mucosa and the
craniofacial region and its more rapidly progressive course.
References
1 National Guidelines for Clinical Management of HIV/AIDS. The
United Republic of Tanzania, Ministry of Health, April 2002.
2 Modlin RL, Crissey JT, Rea T. Kaposi’s sarcoma.
Int J Dermatol 1983; 22: 443-6.
3 Friedman-Kien AE, Saltzman B. Clinical
manifestations of classical, endemic, African and epidemic
AIDS-associated Kaposi’s sarcoma. J Am Acad Dermatol 1990; 22:
1237-50.
4 Tappero JW, Conant MA, Wolfe SF, et al.
Kaposi’s sarcoma epidemiology, pathogenesis, histology, clinical
spectrum, staging criteria and therapy. J Am Acad Dermatol 1993;
28: 371-85.
5 Schwartz RA. Kaposi’s Sarcoma, advances and perspectives.
J Am Acad Dermatol 1996; 34: 804-8.
6 Onyango JF, Njiru A. Kaposi’s sarcoma in a Nairobi
Hospital. East Afri Med J 2004; 81: 120-3.
7 Dedicoat M, Newton K. Review of the distribution of
KSHV in Africa in relation to the incidence of Kaposi’s sarcoma. Br
J Cancer 2003; 88: 1-3.
8 Orem J, Otieno MW, Remick SC. AIDS-associated
cancer in developing nations. Curr Opin Oncol 2004; 16: 468-76.
9 Mbulaiteye SM, Parkin DM, Rabkin CS.
Epidemiology of AIDS-related malignancies, an international
perspective. Hematol Oncol Clin North Am 2003; 17: 673-96.
10 Ocheni S. Aken’Ova YA: Association between HIV/AIDS and
malignancies in a Nigerian tertiary institution. West Afri J Med
2004; 23: 151-5.
11 Cook-Mozaffari P, Newton R, Beral V,
et al. The geographical distribution of Kaposi’s sarcoma and
of lymphomas in Africa before the AIDS epidemic. Br J Cancer 1998;
78: 1521-8.
12 Sitas F, Newton R. Kaposi’s sarcoma in South
Africa. J Natl Cancer Inst Monog 2001: 1-4.
13 Newton R, Ziegler J, Bourboulia D, et al.
Infection with Kaposi’s sarcoma associated herpesvirus (KSHV) and
human immunodeficiency virus (HIV) in relation to the risk and
clinical presentation of Kaposi’s sarcoma in Uganda. Br J Cancer
2003; 4(89): 502-4.
14 Craighaed J, Moore A, Grossman H, et al.
Pathogenetic role of HIV infection in Kaposis´sarcoma in Equatorial
East Africa. Arch Pathol Lab Med 1988; 112: 259-65.
15 Searles GE, Markman S, Yazdi HM. Primary oral
Kaposi’s sarcoma of the hard palate. J Am Acad Dermatol 1990; 23:
518-9.
16 Gross JD, Safai B. Kaposi’s sarcoma /Aids
cofactors. Int J Dermatol 1989; 28: 571-3.
17 Orem J, Otieno MW, Remick SC. AIDS-associated
cancer in developing nations. Curr Opin Oncol 2004; 16: 468-76.
18 Pantanowitz L, Dezube BJ. Advances in pathobiology
and treatment of Kaposi’s sarcoma. Curr Opin Oncol 2004; 16:
443-9.
19 Boue F, Lebbe C. Kaposi’s sarcoma. Bull Cancer
2003; 90: 393-8.
20 Cheung TW. AIDS –related cancer in the era of highly
active antiretroviral therapy (HAART): a model of the interplay of
the immune system, virus and cancer. “On the offensive- the Trojan
horse is being destroyed”.Part A: Kaposi’s sarcoma. Cancer Invest
2004; 22: 774-86.
21 Aoki Y, Tosato G. HIV-1 Tat enhances Kaposi’s
sarcoma associated virus (KSHV) infectivity. Blood 2004; 104:
810-4.
22 Bourboulia D, Aldam D, Lagos D, et al.
Short and long term effects of highly active antiretroviral therapy
on Kaposi’s sarcoma-associated herpes virus immune responses and
viraemia. AIDS 2004; 20(18): 485-93.
23 Gallafent JH, Buskia SE, De Turk PB,
Aboulafia DM. Profile of patients with Kaposi’s sarcoma in the
era of highly active antiretroviral therapy. J Clin Oncol 2005;
20(23): 1253-60.
24 Schwartz RA. Kaposi’s sarcoma: an update. J Surg Oncol
2004; 87: 146-51.
25 Inoue N, Spira T, Lam L, et al.
Comparison of serologic responses between KS positive and negative
men who were seropositive for both HHV-8 and HIV. J Med Virol 2004;
74: 202-6.
26 Mocroft A, Kirk O, Clumeck N, et al. The
changing pattern of Kaposi’ s sarcoma in patients with HIV
1994-2003: the EuroSida study. Cancer 2004; 100: 2644-54.
27 Catlelan AM, Trevenzoli M, Aversa SM. Novel
pharmacological therapies for the treatment of AIDS-related
Kaposi’s sarcoma. Expert Opin Invest Drugs 2004; 13: 501-13.
28 Pedram G, Omeed M, Iris A, et al.
Kaposi’s Sarcoma and other manifestations of Human Herpesvirus. J
Am Acad Dermatol 2002; 47: 641-51.
29 Friedman-Kien AE, Ostreicher R, Saltzman B.
Clinical manifestations of classical, endemic, african and epidemic
AIDS-associated Kaposi’s sarcoma. In: Colour Atlas of AIDS.
Philadelphia: Saunders, 1989: 11-81.
30 Cleste L, Felix A, Patricia C, et al.
Detection of human herpevirus-8 and T cell lymphotropic virus type
1 sequences in Kaposi’s sarcoma. Arch Dermatol 1997; 133: 25-9.
31 Dupin N, Rubin De Cervens V, Gorin I. The
influence of highly active antiretroviral therapy on AIDS
associated KS. Br J Dermatol 1999; 140: 875-80.
32 Schwartz EJ, Dorfman RF, Koeler S. Human
Herpes Virus-8 latent nuclear antigen-1 expression in endemic
Kaposi’s sarcoma: An immunohistochemical study of 16 cases. Am J
Surg Pathol 2003; 27: 1546-50.
33 Plancoulaine S, Abel L, Van Beveren M,
et al. High titres of anti-human Herpes-8 antibodies in
elderly males in an endemic population. J Natl Cancer Inst 2003;
94: 1333-5.
34 Jenson HB. Human Herpes virus-8 infection. Curr Opin
Pediatr 2003; 15: 85-91.
35 Chandra A, Demirhan I, Massambu C, et al.
Cross talk between human Herpesvirus-8 and the transactivator
protein in the pathogenesis of Kaposi’s sarcoma in HIV infected
patients. Anticancer Res 2003; 23: 723-8.
36 Guo HG, Pati S, Sadowska M, et al.
Tumorigenesis of human herpes virus 8 vGPCR is accelerated by human
immunodeficiency virus type 1 Tat. J Virol 2004; 78: 9336-42.
37 Polstra AM, Cornelissen M, Goudsmit J,
et al. Retrospective, longitudinal analysis of serum HHV-8
viral load DNA in AIDS- related KS patients before and after
diagnosis. J Med Virol 2004; 74: 390-6.
38 Alagiozoglou L, Morris L, Bredell H,
et al. Human herpes virus 8 antibodies and DNA in HIV-1
infected patients in South Africa. Epidemiol Infect 2003; 131:
1125-9.
39 Campbell TB, Borok M, Gwanzura L, et al.
Relationship of human herpes virus 8 peripheral viral load and
Kaposi’s sarcoma clinical stage. AIDS 2000; 14: 2109-16.
40 Shwartz RA, Cohen JB, Ankami RN, et al.
Penile Kaposi’s sarcoma preceded by chronic penile lymphoedema. Br
J Dermatol 2002; 142: 153-6.
41 Ziegler JL, Simonart T, Snoeck R. Kaposi’s
sarcoma, oncogenic viruses and iron. J Clin Virol 2001; 20:
127-30.
42 Mhalu FS, Lyamuya E. Human immunodeficiency virus
infection and AIDS in East Africa: Challenges and possibilities for
prevention and control. East Afr Med J 1996; 73: 13-9.
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