Eruptive basal-cell carcinomas in the setting of human immunodeficiency virus infectionThe Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York
Elizabeth A Gordon Spratt MD, Max Fischer MD MPH, Hideko Kamino MD
Dermatology Online Journal 18 (12): 1
Patients with human immunodeficiency virus are known to have an increased risk for development of cutaneous malignant conditions. We present a 55-year-old man with a history of an isolated squamous-cell carcinoma five years prior, who presented with 27 cutaneous lesions, which had developed over the course of the preceding year. This occurred in the context of a new diagnosis of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). The initiation of anti-retroviral therapy and subsequent restoration of CD4 counts was associated with an increase in the number of lesions. Histopathologic examination of representative tumors showed basal-cell carcinomas, which lead to the diagnosis of eruptive basal-cell carcinomas in the setting of HIV-related immunosuppression. The incidence and epidemiology of malignant conditions that are related and non-related to AIDS are reviewed as well as discussion of the current literature regarding presentation, treatment, and prevention of non-melanoma skin cancers in patients with HIV infection.
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A 55-year-old man presented to the Dermatology Clinic of the Bellevue Hospital Center for evaluation of multiple lesions, which began to develop approximately one year prior and first appeared on the leg. Since that time, he has developed approximately two dozen additional tumors that would occasionally bleed and form crusts. Some would begin to heal and decrease in size but would later enlarge again. They were not pruritic or painful. Six months prior to presentation, a diagnosis of human immunodeficiency virus (HIV) infection with an undetectable CD4 cell count was made. One month later, antiretroviral therapy was started with improvement in the CD4 count to the 500 cells/mm³ and an undetectable viral load at the time of presentation to the dermatology clinic. The patient noted that the reconstitution of his immune system was associated with an increase in the number of growths, but the appearance of the skin lesions had not changed. He denied a history of lesions on the palms or soles, jaw cysts, or other features of nevoid basal-cell carcinoma syndrome. There was a family history of basal-cell carcinoma in his brother and a possible history of a non-melanoma skin cancer on the leg in his mother. He is of Irish descent and has a history of numerous blistering sunburns throughout his life as well as a squamous-cell carcinoma on his back, which was excised five years prior to presentation. He works as an illustrator/designer and denies a history of any outdoor occupations.
Past medical history includes cytomegalovirus infection that was complicated by gastrocolitis and irritable bowel syndrome. He takes darunavir, emtricitabine/tenofovir, ritonavir, mesalamine, loperamide, and valganciclovir; he has no known allergies. Two shave biopsies were taken of representative lesions on the forehead and the shoulder.
Erythematous, oval and circular, thin plaques and papules were present in numerous locations. There were two lesions on the forehead, four on the anterior aspect of the trunk, six on the posterior aspect of the trunk, eight on the arms, and seven on the legs. The majority of the plaques on the lower extremities had white adherent scale. Two growths on the forehead and chest had a raised, pearly border. Several papules on the back had central hemorrhagic crusts. One lesion on the right shoulder was ulcerated. There were no palmar pits and no evidence of jaw cysts. There were no conjunctival or mucosal lesions.
CD4 count was 550 cells/mm³ (normal range 500 to 1500), and HIV viral load was undetectable.
There are aggregates of basaloid cells with hyperchromatic nuclei and peripheral palisading that are separated from the surrounding fibrous stroma by focal artifactual clefts.
The association of immunosuppression and the development of cutaneous malignant conditions has been established in several patient populations with compromised immunity. Most notably, it has been studied in individuals with solid organ transplantation, who experience an increased risk (65- to 250-fold) of skin cancers [1, 2]. The immunosuppression in patients with human immunodeficiency virus (HIV) infection is distinct and is associated with different rates of development of cutaneous malignant conditions. It is estimated that up to 40 percent of patients with acquired immune deficiency syndrome (AIDS) will develop a malignant condition and these patients have a 1.5- to two-fold increased risk of development of malignant conditions when compared to the general population [3, 4, 5]. These cancers include non-Hodgkin lymphoma, Kaposi sarcoma, and cervical cancer. Since the introduction of anti-retroviral therapy, the rates of Kaposi sarcoma and non-Hodgkins lymphoma have declined, whereas the incidence of cervical cancer and cancers unrelated to AIDS has remained stable [4, 6]. Melanoma and non-melanoma skin cancers (NMSC) occur with increased frequency in patients with HIV infection although these malignant conditions are not considered related to AIDS .
Patients with AIDS are three-to-five times more likely to develop squamous-cell (SCC) or basal cell (BCC) carcinomas. A prospective study found that 6 percent of patients with HIV infection would develop a cutaneous malignant condition over 7.5 years of follow up . BCCs are found six-to-seven times more often than are SCCs, which highlights the distinct immunosuppressive state in HIV infection because SCC is more common after solid-organ transplantation [5, 8]. The clinical presentations and risk factors for the development of NMSC are the same in individuals with and without HIV infection and include blond hair, blue eyes, light skin, sun exposure (both sunbathers or occupational sun exposure), and family history [4, 5, 7, 8]. Our patient manifested the majority of these risk factors. The tumors, especially SCCs, are thought to be more aggressive in patients with HIV infection and they have a higher risk of recurrence (up to 20%), metastasis, and mortality [5, 9]. BCCs are noted to occur more frequently in individuals with HIV, but their clinical course is not altered and they are not of a more aggressive subtype . Anti-retroviral therapy does not influence the rate of development of NMSC and there is no association between cutaneous malignant conditions and CD4 lymphocyte counts, HIV RNA levels, or the use of anti-retroviral therapy .
In a prospective study, BCC was noted to be the second most common skin malignant condition in AIDS patients, the most common being Kaposi sarcoma . Since the advent of anti-retroviral therapy, BCC has now exceeded Kaposi sarcoma as the most common cutaneous cancer unrelated to AIDS . Basal-cell carcinomas occur in patients without HIV infection between the ages of 40 and 60 and occur in sun-exposed areas of the body, most commonly on the head and neck [9, 10]. In comparison, in patients with HIV, BCC was most commonly found on the trunk or extremities . A study of NMSC in HIV-infected patients showed that 87 percent were BCC, with the superficial subtype being the most common. This type accounted for 67 percent of the total, with 62 percent of the lesions occurring on the trunk. This study notes the unusual propensity of BCC to develop on the trunk, which may be specific to HIV-associated skin cancers . In our patient the tumors were fairly evenly distributed between the trunk and extremities, with ten lesions on the trunk, 15 on the extremities, and two on the head. HIV-infected patients with a NMSC have a high likelihood of developing additional cutaneous malignant conditions and 24 percent of patients with BCC developed an additional BCC .
It is recommended that patients with HIV be targeted for more careful primary prevention, with emphasis on counseling regarding sun avoidance, sun protection, and regular skin examinations. Recommendations urge excision of SCC with negative margins and consideration of adjunctive chemotherapy or radiation in high-risk tumors, owing to the more aggressive nature of SCC in HIV-infected individuals regardless of the CD4 count. The treatment of BCC is recommended to be the same as standard of care for patients without HIV infection . Case reports and anecdotal experience have described the use of imiquimod in the treatment of BCC in the setting of AIDS and HIV infection, with reports of success and erradication of the tumor . However, this treatment has not been studied, and the role of immune-induction therapy and tumor clearance in the setting of immunosuppression is poorly understood. Because our patient had 27 BCCs, he was started on topical imiquimod while awaiting surgical excision and electrodesiccation and curettage of multiple neoplasms. He reported a response to topical imiquimod after two weeks of use, with robust erythema developing at all applied sites except for one lesion on the leg. However, clinical clearance and histopathologic confirmation of tumor destruction remains to be documented at this time.
The mechanism of enhanced tumorigenesis in the setting of different types of immunosuppression is poorly understood. HIV infection results in deficiency of activation of both CD4 and CD8 cells as well as a shift in cytokine production to favor the synthesis of TH2 cytokine subsets. This shift results in broad cell-mediated immunity deficits, proliferation of B cells, transcription of oncogenes, and accumulation of genetic damage. There are reductions in tumor detection and destruction, suppression of oncogenic viruses, and decreased apoptosis and antigen presentation. HIV produces specific proteins, nef and tat, that alter MHC signaling and chemokine production . How these mechanisms result in the increased development of NMSC in patients with HIV infection is poorly understood and the relationship is complicated by the fact that oncogenesis appears to occur irrespective of CD4 counts, viral loads, and overall immune status .
Our patient is a novel case and presented with 27 eruptive cutaneous tumors over the course of approximately 12 months, which are presumed to be basal-cell carcinomas based on clinical appearance and histopathologic confirmation of representative lesions. Clinically, the BCCs appeared to be predominantly of the superficial subtype as well as nodular (on the forehead and chest). The appearance of 27 neoplasms in the course of one year is unusual and it is interesting to note the temporal association of the diagnosis of HIV infection and AIDS with the onset of the tumors. The patient noted a rapid increase in the development of lesions when he began anti-retroviral therapy, which may suggest a relationship between immune reconsitution and neoplasm genesis or which may be coincidental. Owing to the widespread and numerous growths at presentation, cutaneous malignant conditions were lower on the differential diagnosis prior to biopsy. This case highlights the importance of the heightened risk for development of cutaneous malignant conditions in patients with HIV infection as well as the possibility for patients to present with numerous and diffuse cutaneous involvement of NMSC.
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