Annals of Oncology Advance Access originally published online on November 25, 2005
Annals of Oncology 2006 17(3):503-506; doi:10.1093/annonc/mdj091
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© 2005 European Society for Medical Oncology
The presentation and survival of patients with non-cutaneous AIDS-associated Kaposi's sarcoma
1 Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College of Science, Technology and Medicine; Departments of 2 HIV Medicine and 3 Oncology, The Chelsea and Westminster Hospital, UK
* Correspondence to: Dr M. Bower, Department of Oncology, The Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44-208-237-5054; Fax: +44-208-746-8863; E-mail: m.bower{at}ic.ac.uk
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Abstract |
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Background: Acquired immune deficiency syndrome related Kaposi's sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease.
Patients and methods: From our cohort of 5932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunological and virological characteristics to other individuals with KS.
Results: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated oedema (P = 0.046) and non-oral gastrointestinal KS (P = 0.042) were significantly more common in patients with non-cutaneous KS. Only one case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART).
Conclusions: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.
Key words: HIV, AIDS, Kaposi's sarcoma, HAART, cutaneous
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In 1872, Moritz Kaposi a Hungarian dermatologist, described five men with aggressive ‘idiopathic multiple pigmented sarcomas of the skin’ [1
]. In 1981, acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) was first identified [2] and compelling epidemiologic evidence prompted speculation about an infectious cause as well as sexual transmission [3, 4]. By 1994, Chang and colleagues had used representational difference analysis to identify DNA fragments of a previously unrecognised 
-herpesvirus, which they called Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus-8) [5] and its 165-kb genome containing numerous oncogenes, growth factor and angiogenic genes was sequenced soon after [6]. KSHV genes have been found in every type of KS including classical, endemic, iatrogenic (post transplant) and the commonest type of KS, AIDS-associated KS. All types of KS share identical histological features and all clinical reports describe the characteristic skin lesions, often complicated by later visceral dissemination at which stage the disease is considered incurable [7].
In those for whom it is available, highly active anti-retroviral therapy (HAART) has decreased the morbidity and mortality associated with HIV, mainly by reducing the incidence of opportunistic infections in particular Pneumocystis carinii pneumonia [8]. The protective effect of HAART has also been shown to result in a decreased incidence of HIV-associated cancers including an increased time to disease progression of AIDS-associated KS [9, 10]. HAART and even sub-optimal HAART with nucleoside analogues as a sole anti-retroviral regimen can also lead to complete resolution of individual lesions [11–14], improvements that have been explained as related to an improvement in immune function, by virtue of reconstitution of the CD4 repertoire [15–17]. Despite these improvements, KS remains the commonest HIV-associated cancer, and a significant cause of morbidity and mortality especially in sub-Saharan Africa [18, 19].
While case series of metastatic melanoma without skin (or choroidal) involvement have been described in up to 4% of cases [20], there are no reports of any of the KS types exhibiting this clinical pattern of disease. We therefore compared the clinical, immunological and virological characteristics of 11 patients in the era of HAART with non-cutaneous KS, to other patients with AIDS-associated KS.
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patients and methods |
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The Chelsea and Westminster HIV cohort is the largest single centre cohort in Europe and we prospectively collect routine data on individuals who attend. HIV-positive patients are seen at regular intervals for clinical assessment, trial follow-up and immunological assessments. All HIV patients who have attended the Chelsea and Westminster since routine prospective data collection commenced in 1983 were identified and we defined HAART as therapy consisting of at least three antiretroviral drugs in accordance with published guidelines (dual nucleoside analogues alone are not considered HAART, although this is considered a ‘backbone’ of therapy) [21
]. This study focused on a cohort of individuals who have continued to be followed-up since the HAART era commenced, which we have defined as 1 January 1996 when HAART became routinely available at our institution and many others. All individuals who ceased follow-up before this date were excluded.
Individuals with non-cutaneous KS in the HAART era were compared with other individuals with disease (AIDS-associated KS). Exclusively non-cutaneous KS was confirmed by biopsy in all cases apart from one (patient declined, obvious ulcerating hard palate disease) and for other cases biopsy confirmation occurred in approximately half of the cases with the diagnosis being made in the context of typical clinical parameters of purple skin lesions with or without metastases and a high viral load/low CD4 count. Patients with non-cutaneous KS had cutaneous KS excluded by visual inspection. Comparison of variables between groups was by 
2 test for nominal variables; all P values presented are two-sided. Survival was calculated from the day of KS diagnosis until death or the date of last follow-up. Overall survival duration curves were plotted according to the method of Kaplan and Meier [22]. The log-rank method was used to test for the significance of differences in survival distributions [23].
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results |
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Clinical information on a total of 9621 HIV-1 seropositive patients was prospectively collected since 1983 and of these, 5932 patients were observed in the HAART era comprising 62% of the total cohort. In the HAART era, 319 individuals developed AIDS-associated KS for the first time, representing 5.4% of all HAART era patients. Of these 319 individuals, 11 individuals (3.4% of the KS patients, 0.2% of the total) had solely non-cutaneous KS (Table 1). Remarkably, while KS was significantly more frequent in the pre-HAART era, only one patient was diagnosed with non-cutaneous KS during this time, out of a total of 1006 patients who were diagnosed.
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The majority of these individuals were male, reflecting the 7:1 male:female ratio of the entire cohort. The one female with non-cutaneous KS presented with cervical lymphadenopathy and was pregnant at the time. Of the three deaths that have occurred so far since these patients were diagnosed (median date of KS diagnosis was June 2001), none has been confirmed as being due to progressive KS. One of the patients with pulmonary KS developed skin lesions at a later date.
All patients received further therapy with HAART (non-nucleoside reverse transcriptase inhibitor based in six cases, protease inhibitor regimens in five cases). Four of the patients received radiotherapy, five received chemotherapy (all liposomal anthracyclines) and one patient (gastric KS) received intra-lesional chemotherapy. One of the patients with lymph node disease was also diagnosed with multicentric Castleman's disease and responded to rituximab anti-CD20 monoclonal antibody treatment, as previously described [24].
In a comparison of non-cutaneous KS with other KS, we found that tumour-associated oedema (P = 0.046) and non-oral GI KS (P = 0.042) were significantly more common in patients with non-cutaneous KS, and all other variables measured were not significant. Table 3 shows no significant differences in HIV viral load at presentation (P = 0.6) and there were no differences between CD4 count at presentation (P = 0.57). Similarly, the overall survival (Figure 1) was not significantly different (P = 0.08).
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discussion |
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KS is the most common tumour in patients with AIDS. We have described for the first time a cohort of patients with non-cutaneous KS and demonstrated that the outcome of this disease sub-group, contrary to expectations, is not worse than other individuals with AIDS-KS. Although the major limitation is the small size of the dataset, there were no significant differences with regard to presenting immunological or virological features.
In our cohort of 9621 HIV-1 infected individuals, we observed only one case of non-cutaneous KS diagnosed prior to the era of HAART. While several investigators have reported a decline in the incidence of KS [10, 13], the new finding of non-cutaneous KS and its non-inferior survival compared with others with KS, may reflect a superior host–tumour interaction in such patients. It seems plausible to suggest that the immune response is able to control the development of tumour lesions in the skin, perhaps because of a local environment facilitating dendritic cell presentation to T cells [25]. The poor prognosis in visceral KS especially with pulmonary involvement, the most serious form of KS, with a high fatality rate is well known [7]. The lack of a survival disadvantage that we observed, relative to an entire KS cohort containing only 24 individuals (8%) with pulmonary KS is likely to reflect this immune activation.
As preparations of ß-human chorionic gonadotrophin have been shown to inhibit growth of KS cell lines in vitro (probably by inducing apoptosis) and in immunodeficient mice [26–28], the finding of non-cutaneous KS in a pregnant female (one of only 2 in our cohort) is also particularly interesting. However, it is unlikely that non-cutaneous KS has a different aetiology than ‘standard’ cutaneous AIDS-KS, as histologies are identical and all forms of KS have been found to contain KSHV [14].
As we embark on the third decade of the HIV pandemic, AIDS-related mortality remains a major focus of world attention with stated aims of 3 million HIV-infected individuals receiving HAART by the end of 2005 [29–31]. Anti-retroviral therapy for HIV-1 infection decreases viremia, increases CD4 cell counts and delays clinical progression and death [32, 33]. The era of HAART has also resulted in a change in the natural history of the commonest AIDS-defining malignancy, such that we are now observing cases of non-cutaneous KS. As such cases do not have an inferior outcome, management should be the same as for other individuals with KS.
Received for publication October 10, 2005. Accepted for publication October 26, 2005.
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