*Department of Medicine and Medical Specialties, Infectious Diseases Clinic, University of Modena and Reggio Emilia, Modena, Italy
†Department of Oncology, Chelsea and Westminster Hospital, London, United Kingdom
‡Department of Histopathology, Imperial College Healthcare NHS Trust, London, United Kingdom
§Department of HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom
Presented at the 18th Annual Conference of the British HIV Association, April 18–20, 2012, Birmingham, United Kingdom.
The authors have no funding or conflicts of interest to disclose.
To the Editors:
Since the advent of highly active antiretroviral therapy (HAART), there has been increasing attention on the non–AIDS-defining cancers, including nonmelanoma skin cancers (NMSCs). Although epidemiological studies frequently exclude NMSCs,1 2 studies have reported an increased relative risk for NMSCs in people living with HIV.2,3 However, little data exist on the pathological details and outcomes of NMSCs in this population.
NMSCs are the most common malignancies in the United Kingdom with nearly 100,000 cases registered in 2008, although registration is known to be incomplete. More than 80% of cases occur in people older than 60 years, and 70%–80% are diagnosed as basal cell carcinoma (BCC) and most of the remaining cases are squamous cell carcinoma (SCC). Risk factors include cumulative solar ultraviolet and ionizing radiation exposure, genetic defects of DNA repair4 and of the Sonic hedgehog pathway,5 and infection with beta (cutaneous) genotypes of human papillomavirus. In addition, immunosuppression has been associated with an increased risk for NMSCs particularly among recipients of solid organ transplants.6 Epidemiological surveys of the incidence of non–AIDS-defining malignancies in seropositive populations usually exclude NMSCs,1 although 2 recent studies have reported an increased relative risk for NMSCs in people living with HIV.2,3 In a meta-analysis published in 2007, the standardized incidence ratio for NMSCs in patients with HIV/AIDS was recorded as 4.1, whereas the value was 28.6 for allograft recipients.7 Underreporting of NMSCs and dermatological care in diverse locations prevent an accurate epidemiological study in our cohort at the Chelsea and Westminster Hospital.
The natural history of NMSCs depends on the site, size, grade, and histopathologic subtypes and the presence of perineural invasion and lymphatic infiltration.8,9 In the case of BCC, adverse histopathologic subtypes include morphoeic, infiltrative, or micronodular histologies.10–12 We have assessed the presence of these features in a cohort of HIV-seropositive patients with histopathologically confirmed NMSCs.
We carried out a retrospective single-center study involving HIV-positive patients diagnosed with histopathologically confirmed NMSCs. Cases were identified from a search of the histopathologic specimen database in the Chelsea and Westminster Hospital from 1996 to 2011. Full clinicopathologic details were sought for all known HIV-seropositive patients identified as having histologically diagnosed NMSCs. For the purposes of this study, HAART was defined as treatment with ≥2 nucleoside reverse transcriptase inhibitors in combination with at least 1 protease inhibitor or 1 nonnucleoside reverse transcriptase inhibitor, or an abacavir-containing or a tenofovir-containing regimen of ≥3 nucleoside reverse transcriptase inhibitors.
Data regarding clinicopathologic features and outcome were analyzed using descriptive statistics. Comparison of variables between groups was performed by χ2 test for nominal variables and Mann–Whitney and Kruskal–Wallis tests for nonparametric continuous variables; all P values presented are 2-sided. Overall survival was calculated from the day of NMSC diagnosis until death or the date of last follow-up.
A total of 159 NMSCs, including 126 BCCs and 33 SCCs, were identified in 58 patients (57 men) with a mean age of 54 years (range: 31–77 years). In the same period of time (1996 to October 2011), 510 patients were diagnosed with cutaneous Kaposi sarcoma. At the time of diagnosis of NMSC, 76% were on HAART, the median CD4 cell count was 343 cells per cubic millimeter (range: 1–937 cells/mm3), 69% had an undetectable plasma HIV viral load, and the median duration of HIV-seropositive status was 10.6 years (range: 0.5–25 years). The clinicopathologic details of the 58 patients are shown in Table 1.
There were no significant differences between patients with SCC and BCC in age (Mann–Whitney P = 0.10), duration of HIV infection (Mann–Whitney P = 0.98), CD4 count (Mann–Whitney P = 0.69), CD4 nadir (Mann–Whitney P = 0.16), or viral load (Mann–Whitney P = 0.85) at NMSC diagnosis.
Nearly a quarter (23%) of the BCCs arising in individuals living with HIV infection were adverse histological subtypes (11% infiltrative, 11% morphoeic, 1% micronodular). No tumors demonstrated dermal lymphatic infiltration, and only 1 tumor showed perineural invasion. The characteristics of BCC in HIV-seropositive individuals are shown in Table 1. There was no correlation between the aggressive histological subtypes and tumor site on the body (χ2 P = 0.25), HAART usage (χ2 P = 0.62), undetectable HIV viral load (either <400 copies/mL, χ2 P = 0.55, or <50 copies/mL, χ2 P = 0.87), CD4 cell count (Mann–Whitney P = 0.14), duration of HIV infection (Mann–Whitney P = 0.65), length of time on HAART (Mann–Whitney P = 0.16), or CD4 nadir (Mann–Whitney P = 0.98).
The median follow-up for patients with BCC was 3.6 years (range: 0.1–16 years), and the 5-year overall survival was 90% (95% confidence interval: 89% to 92%). Three patients with BCC have died: 1 patient from primary cerebral lymphoma, 1 from systemic non-Hodgkin lymphoma, and 1 from progressive Mycobacterium avium complex.
SCC staging results were as follows: pT1, 80%; pT2, 3%; and pT4, 17%. Half the tumors were moderately differentiated, 41% well differentiated, and 9% poorly differentiated. One tumor demonstrated both perineural invasion and lymphatic infiltration, and this patient presented with metastatic lung disease. The characteristics of SCC in HIV-seropositive individuals are shown in Table 1. There was no correlation between tumor grade and tumor site on the body (χ2 P = 0.11), HAART usage (χ2 P = 0.33), undetectable HIV viral load (either <400 copies/mL, χ2 P = 0.17, or <50 copies/mL, χ2 P = 0.47), CD4 cell count (Kruskal–Wallis P = 0.98), duration of HIV infection (Kruskal–Wallis P = 0.34), length of time on HAART (Kruskal–Wallis P = 0.26), or CD4 nadir (Kruskal–Wallis P = 0.11).
The median follow-up for patients with SCC was 2.3 years (range: 0–15 years), and the 5-year overall survival was 78% (95% confidence interval: 54% to 100%). Three patients with SCC have died including the patient with metastatic SCC who died of progressive SCC, and 1 due to an unrelated malignancy (chronic myelomonocytic leukemia) and 1 from a cerebrovascular event.
Immunosuppression, in particular after solid organ transplantation, is associated with an increased risk for NMSCs. Among transplant recipients, SCCs predominate and the risk appears to rise with increasing duration and doses of immunosuppression.6,13–15 Epidemiological analyses of the risk for NMSCs in people living with HIV have produced conflicting results, and a meta-analysis suggests that the standardized incidence ratio, although elevated, is considerably lower than that observed after solid organ transplantation.7 We have not addressed the epidemiology of NMSCs in our HIV-seropositive cohort because of concerns about incomplete reporting and registration of these tumors. However, it is notable that there were 126 BCCs and 33 SCCs diagnosed among the 58 patients, a ratio of 4:1, which is more similar to that seen in the general population than that observed in the transplant population where the ratio is reversed to 1:4 in favor of SCCs.15 Similarly, the median CD4 cell count at the time of NMSC diagnosis was relatively high (343 cells/mm3), and three quarters of the patients were established on HAART with undetectable plasma HIV viral load. Thus, the NMSCs arose in patients with relatively well-preserved cell immunity in contrast with transplantation-associated NMSCs where higher doses of immunosuppression increase the risk.
Histological classification of NMSCs identifies tumors at increased risk for relapse, and increasingly, dermato-oncologists are employing histology-based treatment stratification in the clinical management of these tumors.16 In this series, the adverse histological characteristics in BCCs were not associated with more advanced immunosuppression whether measured as CD4 cell count, plasma HIV viremia, HAART use or duration, length of time HIV infected, or CD4 nadir. Similarly, the histological grade of the SCCs was not correlated with any of these surrogate markers of immune function.
Although the risk for NMSCs may not be as high in people living with HIV as among solid organ transplant recipients, the age of the patients who developed these malignancies in our cohort was relatively young (mean age: 54 years). In contrast, >80% of NMSCs in the UK population occur in people older than 60 years. However, this difference between the HIV-seropositive patients and the general population in age at NMSC diagnosis probably simply reflects the younger age of HIV-seropositive individuals in our cohort. This is supported by the finding that patients with NMSCs had been diagnosed with HIV for a median of >10 years. We predict that NMSCs will become an increasing health burden among our cohort as the age of the individuals with HIV increases. As with other non–AIDS-defining malignancies, HIV physicians need to be aware of the risk for NMSCs.
In summary, NMSCs are part of the growing list of cancers that may be encountered in patients living longer with chronic HIV infection. Although our patients presented at a younger age and frequently with more aggressive pathological subtypes, NMSCs do not appear to be significantly associated with immune function or HAART.
1. Lanoy E, Costagliola D, Engels EA. Skin cancers associated with HIV infection and solid-organ transplantation among elderly adults. Int J Cancer. 2010;126:1724–1731.
2. Crum-Cianflone N, Hullsiek KH, Satter E, et al.. Cutaneous malignancies among HIV-infected persons. Arch Intern Med. 2009;169:1130–1138.
3. Lanoy E, Spano JP, Bonnet F, et al.. The spectrum of malignancies in HIV-infected patients in 2006 in France: the ONCOVIH study. Int J Cancer. 2011;129:467–475.
4. Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005;5:564–573.
5. Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001;10:757–762.
6. Jemec GB, Holm EA. Nonmelanoma skin cancer in organ transplant patients. Transplantation. 2003;75:253–257.
7. Grulich AE, van Leeuwen MT, Falster MO, et al.. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370:59–67.
8. Dubin N, Kopf AW. Multivariate risk score for recurrence of cutaneous basal cell carcinomas. Arch Dermatol. 1983;119:373–377.
9. McCord MW, Mendenhall WM, Parsons JT, et al.. Skin cancer of the head and neck with incidental microscopic perineural invasion. Int J Radiat Oncol Biol Phys. 1999;43:591–595.
10. Sloane JP. The value of typing basal cell carcinomas in predicting recurrence after surgical excision. Br J Dermatol. 1977;96:127–132.
11. Salasche SJ, Amonette RA. Morpheaform basal-cell epitheliomas. A study of subclinical extensions in a series of 51 cases. J Dermatol Surg Oncol. 1981;7:387–394.
12. Dixon AY, Lee SH, McGregor DH. Histologic features predictive of basal cell carcinoma recurrence: results of a multivariate analysis. J Cutan Pathol. 1993;20:137–142.
13. Jensen P, Hansen S, Moller B, et al.. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 pt 1):177–186.
14. Lindelof B, Sigurgeirsson B, Gabel H, et al.. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–519.
15. Kwasniak LA, Garcia-Zuazaga J. Basal cell carcinoma: evidence-based medicine and review of treatment modalities. Int J Dermatol. 2011;50:645–658.
16. Mosterd K, Arits AH, Thissen MR, et al.. Histology-based treatment of basal cell carcinoma. Acta Derm Venereol. 2009;89:454–458.