INTRODUCTION

Since the introduction of highly active antiretroviral therapy (HAART) in 1996 the course of HIV disease has changed considerably. Lasting inhibition of viral replication and restoration of immune function have significantly reduced the morbidity and mortality of HIV-related

illness. However, an increase in non-AIDS-defining cancers (NADC), such as Hodgkin's disease, anal carcinoma, head and neck tumours, lung cancer, testicular tumours and melanoma has been noted [1]. In the HIV-positive population the rate of NADC has increased ten-fold during the post-HAART era compared to the incidence pre-HAART [2]. Before the availability of effective antiretroviral therapy NADCs accounted for <1% of deaths in this population [3], yet a recent study demonstrated that 13% of deaths among HIV-infected patients are now due to NADC [4].

Immunosuppressed patients, such as transplant recipients, are known to have an increased risk of developing skin cancers, especially squamous cell carcinoma. A 2.5-8-fold increased risk of developing malignant melanoma has also been shown in these patients [5,6]. There is a similar increased incidence of non-melanoma skin cancers in HIV-infection and AIDS [7]. Unsurprisingly, there are a number of case reports of HIV-positive individuals with melanoma, all of which describe small patient numbers. In HIV-infection, melanomas often present atypically, have a more aggressive behaviour and carry a poorer prognosis [8].

In the pre-HAART era, dermatologists began to suspect that melanoma was more common in HIV-positive patients although early epidemiological studies using cancer and AIDS registries did not demonstrate a significant increased incidence of melanoma. A cohort study to ascertain cancer risk in HIV-infected individuals in South-east England found few cancers in HIV-positive women and a low risk of cutaneous melanoma in HIV-positive men [standardised incidence rate (SIR) 0.1; 95% confidence interval (CI) 0.004-0.8]. A possible explanation for this is the misdiagnosis of melanoma for Kaposi's sarcoma [9]. A similar risk of melanoma in HIV-positive individuals (SIR 0.8; 95% CI 0.2-2.4), was seen in an Italian record linkage study performed between 1986 and 1998 [10]. However, studies conducted in the post-HAART era report higher incidences of melanoma (SIR 2.4; 95% CI 1.7-3.3), which may reflect improved HIV control with a greater life expectancy and therefore higher risk of developing cancer [11].

METHODS

Using the databases from the HIV Medicine and Oncology departments at a single institution, four patients who were HIV-positive and had a diagnosis of melanoma were reviewed. Standard patient demographics are summarised in Table 1.

CASE REPORTS

CASE 1

A man had undergone a wide local excision and an isolated limb perfusion for a primary melanoma on his right leg in the mid-1970s; the Breslow thickness is unknown. He developed a right inguinal lymph node recurrence and underwent an inguinal lymph node dissection 2 years later. He was diagnosed as being HIV-positive in 1992. He remained well with regard to the melanoma until 2005 when, at the age of 69, he had a second primary melanoma removed from his back, Breslow thickness 9mm, Clark's level V, with no ulceration but areas of focal regression were seen. Staging investigations were negative for metastatic disease. At diagnosis he was receiving HAART (nevirapine, stavudine, indinavir and ritonavir), his CD4 cell count was 438/[mm.sup.3] with an undetectable HIV-1 viral load. He underwent a wide local excision and 11 months later had a right axillary lymph node dissection for relapsed disease; 4/18 lymph nodes were positive for melanoma. At that point he remained on HAART and his CD4 cell count was 423/[mm.sup.3] with an undetectable viral load. Within 4 months he developed further lymph node recurrence and cutaneous chest wall disease. He tolerated dacarbazine chemotherapy with little toxicity but the melanoma progressed. In order to palliate the cutaneous deposits he received radiotherapy to the chest wall and axilla. He died from melanoma 23 months after the diagnosis of the second primary melanoma.

CASE 2

A 39-year-old man had a superficial spreading melanoma removed from his anterior abdomen. The lesion was 1.2mm in Breslow thickness, Clark's level IV, with no ulceration, areas of regression and a brisk tumour infiltrating lymphocyte reaction were seen. At the time of diagnosis he was receiving HAART (etravirine, darunavir, Truvuda and ritonavir) and had a CD4 cell count of 179/[mm.sup.3] with an undetectable HIV-1 viral load. Of note, he had been successfully treated with chemotherapy for stage IIIB Hodgkin's disease 5 years earlier. He underwent a wide local excision and 8 months later remains disease free on regular surveillance.

CASE 3

A 41-year-old man had a superficial spreading melanoma in situ, Clark's level I, removed from his anterior abdominal wall. He was taking no medication at diagnosis and had a CD4 cell count of 416/[mm.sup.3] with a viral load of 16,233 copies/ml. He had a wide local excision and 22 months later he remains disease free from melanoma. He has not commenced HAART.

CASE 4

A 60-year-old man presented with a left inguinal mass that was positive for melanoma on fine needle aspiration. He was simultaneously diagnosed as being HIV-positive with a CD4 cell count of 239/[mm.sup.3] and a viral load of 97,814 copies/ml. He commenced HAART (saquinavir, abacavir, lamivudine and ritonavir) and staging computerised tomography (CT) scans demonstrated no other metastatic disease. He had a past medical history of having taken cyclosporin for light-induced dermatitis and excision of a 'benign naevus' from his back 18 years previously as well as excision of several basal and squamous cell carcinomas. He underwent an inguinal lymph node dissection of which 1/5 lymph nodes were positive for melanoma. Review of the histology from the 'naevus' demonstrated a malignant melanoma, Breslow thickness 0.5mm, with no ulceration. He discontinued HAART due to adverse side-effects, but 11 months after lymph node dissection remains disease free from melanoma.

DISCUSSION

Many malignancies have cutaneous manifestations. It is important that dermatologists and physicians who manage patients with HIV disease are aware that skin cancer is more common and may have both a different presentation and natural history than in the general population. Malignant melanoma, in particular, can be difficult to recognise in the HIV-positive or HIV-negative patient and it may be misdiagnosed as Kaposi's sarcoma. It is potentially more aggressive in HIV-positive patients [7,8].

The majority of meta-analyses and cohort linkage studies have demonstrated no increased risk of malignant melanoma in HIV-positive patients. However, many review periods pre-date or straddle the introduction of HAART. Reports in North America and Europe suggest the spectrum of NADC during the HAART era has expanded with the growing HIV-positive population [12]. As patients benefit from improved control of viral replication and from the prevention of opportunistic infection their risk of dying from cancer is increased [13].

A retrospective case-controlled study of HIV-positive and HIV-negative patients with melanoma matched the patients for melanoma subtype, Breslow thickness, Clark's level, tumour location, gender and age, and found that HIV-positive patients with malignant melanoma had a significantly reduced disease-free and overall survival [8]. In this case series the outcome and survival data are relatively immature making it difficult to comment on the behaviour of melanoma in this patient cohort.

None of the published management guidelines is specific to HIV-positive patients with malignant melanoma [14-16]. As a result, patients are currently managed in the same way as those patients who are HIV-negative. The primary treatment remains surgical, with a wide local excision of at least 1-2cm, the diameter being defined by the Breslow thickness of the primary lesion. All four cases described underwent wide local excision as part of standard management.

Since melanoma appears to have a more aggressive behaviour in those patients with HIV-infection, one may argue that the patient should be managed more aggressively. For instance, searching for metastatic disease at an earlier tumour stage or thinner Breslow thickness using CT or positron emission tomography (PET) scans. A suggestion has even been made to offer sentinel lymph node biopsy to HIV-positive patients with a thinner melanoma than would be considered for HIV-negative individuals [8].

More units have access to fluoro-deoxyglucose (FDG) PET or PET-CT scanners. Reports have shown that FDG-PET has a sensitivity for detection of regional lymph node metastases of 0.21 (95% CI 0.10-0.36) and specificity of 0.97 (95% CI 0.93-0.99). Its sensitivity for detection of occult stage IV disease was 0.04 (95% CI 0.001-0.20) and specificity was 0.86 (95% CI 0.79-0.92); it did not impact upon patient care when staging occurred by standard techniques [17]. Similarly, FDG-PET in melanoma patients with T2-4 disease did not alter management [18] and PET/CT changed management in 21 of 76 patient studies (27.6%) but only for those patients with stage II-IV disease [19]. These data suggest that these techniques should not be part of initial staging for early stage disease. It is generally felt that for stage I and IIA disease the true-positive 'pick-up' rate is low and the false-positive rate is high for radiological investigations and therefore they are not recommended [14]. As such, clinicians caring for HIV-positive patients usually follow the clinical guidelines defined for the HIV-negative population.

The role of sentinel lymph node biopsy (SLNB) remains controversial in the HIV-negative population and there are few or no data regarding its role for the HIV-positive patient. Although often performed in the USA, it is generally agreed that SLNB provides important prognostic information but does not confer a survival benefit in patients with cutaneous melanoma [20]. Current European management guidelines suggest SLNB is a useful staging investigation for patients entering clinical trials but not a routine part of clinical management until further data evolves [14-16]. It should not be recommended in a high-risk subgroup, such as the HIV-positive population, without further investigation.

There is extensive evidence that the immune system can recognise and destroy tumour cells [21]. Spontaneous regression of primary melanoma appears to occur since approximately 3-15% of metastatic melanomas arise from an unknown primary site [22]. Tumour infiltrating lymphocytes have been reported to be an independent prognostic factor for cutaneous vertical growth phase melanoma and lymph node metastases [23-25]. As a result, a number of immunotherapeutic agents have been studied in melanoma, primarily in the adjuvant setting. Currently, in the USA high-dose interferon-alfa (IFN) as adjuvant therapy in high-risk melanoma is Food and Drug Administration (FDA)approved on the basis of the E1684 study despite the survival benefit not reaching the accepted level of significance [26]. In Europe, guidelines support the use of IFN within the context of clinical trials until further data becomes available, especially as high-dose IFN produces considerable toxicity. The FDA has also approved the use of interleukin-2 (IL-2) in the treatment of patients with metastatic melanoma. IL-2 has potent activating effects on T cells, natural killer (NK) cells and lymphokine activating killer (LAK) cells. Its effectiveness has yet to be proven on a large scale.

For immunotherapy to be effective in the treatment of melanoma, functional T cells are important. Investigation of IL-2 with HAART in HIV-disease has demonstrated an effect in improving CD4 cell count but not without toxicity [27,28] and combination treatment with pegylated IFN and ribavirin in co-infected HIV/hepatitis C patients is recommended as a standard of care [29]. However, there are no data relating to immunotherapy in the treatment of HIV-positive patients with melanoma. There appears to be no relationship between Breslow thickness and CD4 cell count at diagnosis, yet a low CD4 cell count may predict a poorer prognosis for HIV-positive patients with melanoma [8]. It may be that immune reconstitution with HAART will improve outcome and reduce the chance of melanoma recurrence in this patient group and may be recommended. Immunotherapy has a role in other spheres of HIV-medicine, therefore studies investigating IFN and IL-2 in HIV-positive patients with melanoma may be possible in the future; this would require international collaboration to ensure accrual numbers.

A number of immunotherapy strategies have been investigated in the treatment of melanoma, including the manipulation of dendritic cells, allogeneic whole cell vaccines and recombinant viral vectors, with mixed results reported [30]. Vaccine therapy is controversial for melanoma; it may be less beneficial in advanced disease since the patient's immune system is often impaired and cell kill may be compromised [30]; a similar argument may be made against its use in the HIV-positive population with melanoma because of immunocompromise.

A recent review reported the survival of patients with HIV-related malignancies to have significantly improved since the introduction of HAART [31]. The chemotherapies administered for HIV-related tumours are similar to those given in the HIV-negative population, although toxicity is frequently increased in the HIV-positive patients. This is thought to be in part due to inhibition of the cytochrome P450 metabolism of cytotoxic agents by protease inhibitors. Dacarbazine, a DNA alkylating agent, is the standard chemotherapy for patients with metastatic melanoma and has a palliative response rate of ~20%. Combination dacarbazine-based chemotherapy regimens have a similar response rate with greater toxicity. Dacarbazine is extensively hepatically metabolised by the cytochrome P450 system, and this may result in increased patient toxicity when administered in conjunction with protease inhibitors. The one patient in this series who received chemotherapy did not experience unexpected toxicities. Co-administration of HAART with cytotoxic agents is generally recommended, albeit with care, owing to the survival benefits reported. Increased patient monitoring, dose reduction in chemotherapy or changing from a protease inhibitor may be necessary. Interestingly, a recent report has shown in vitro activity of the protease inhibitor, nelfinavir, against human melanoma cells. The agent acts by inhibiting cyclin-dependent kinase 2 (CDK2), promoting cell cycle arrest and apoptosis, leading the authors to suggest further investigation of the drug in advanced melanoma [32].

The follow-up guidelines for HIV-positive patients with melanoma are as for the HIV-negative population. However, it is important to remember that melanoma in HIV-positive patients can present atypically. Therefore a high index of suspicion should be entertained for all new or changing pigmented and non-pigmented lesions with a low threshold for excisional biopsy. Patients should be educated about skin cancer, encouraged to reduce their sun exposure and monitor their skin carefully and regularly. They should report anything new or changing promptly to their attending physician. The aim of follow-up for patients with established cutaneous melanoma is to detect recurrent disease at an earlier time point; no study has, however, shown any benefit in disease-free or overall survival associated with follow-up surveillance [33]. Sub-groups of patients, such as patients with atypical naevus syndrome and transplant recipients remain under long-term dermatological follow-up as they have an increased risk of skin malignancies. Similarly, HIV-positive patients remain in a high-risk group for second malignancies and recurrent melanoma as can be seen by the four cases described in which one patient had a second primary melanoma 30 years later, one patient relapsed 18 years after primary diagnosis and a third patient had been successfully treated for Hodgkin's disease. As a result, this patient group may well benefit from prolonged surveillance, although there remains no consensus regarding the outpatient setting in which this should occur.

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Correspondence to: Dr CS Brock, Department of Oncology, Charing Cross Hospital, Fulham Palace Road, London W8 6RF, UK. Email: cbrock@hhnt.org

Table 1: Patient demographics.

Case             Gender          Age at             Age at
                                diagnosis          diagnosis
                                 of HIV           of melanoma
                                 (years)            (years)

1                  M               57            1st primary:
                                                      36
                                                 2nd primary:
                                                      69

2 *                M               25                 39

3                  M               31                 41

4 ([double         M               60                 42
  dagger])

Case              Site           Breslow          Ulceration
                               thickness;
                              Clark's level
                                  (CL)

1                 Limb        1st primary:          Unknown
                                 unknown
                 Trunk        2nd primary:            No
                                   9mm

2 *              Trunk           1.2mm;               No
                                  CL IV

3                Trunk          In situ;              No
                                  CL I

4 ([double       Trunk           0.5mm;               No
  dagger])                       CL III

Case         TIL ([dagger])       Stage         CD4/[mm.sup.3]
                                                     count

1                  --              --                 n/a

               Non--brisk          IIB                438

2 *              Brisk             IB                 179

3                  --               0                 416

4 ([double     Non--brisk          IA                 239
  dagger])

Case           Viral load          On            Disease-free
              (copies/ml)         HAART            survival
                                                     (DFS)

1                 n/a              n/a                n/a

                  <50              Yes             11 months
                                              (right axilliary LN
                                              dissection: 4/18 LN
                                                 positive for
                                                   melanoma)

2 *               <40              Yes           No recurrence
                                                 at 8 months+

3                16,233            No            No recurrence
                                                 at 12 months+

4 ([double       97,814           Yes,             18 years
  dagger])                    discontinued      (left inguinal
                                 due to               LN
                                toxicity          dissection:
                                                    1/5 LN
                                                 positive for
                                                   melanoma)

* Previously treated stage IIIB Hodgkin's disease; ([dagger]) tumour
infiltrating lymphocytes; ([double dagger]) HIV disease diagnosed at
same time as melanoma lymph node relapse; n/a, not applicable; M,
male; HAART, highly active antiretroviral therapy; +, ongoing; LN,
lymph node.