Anal cancer in people living with HIV: A case series

Introduction

Human papillomavirus (HPV) causes almost 5% of cancers worldwide including cervical cancer, oropharyngeal cancers, vulval cancer, penile cancer and anal cancer. HPV-associated anal squamous cell carcinoma (ASCC) is a rare occurrence in the general population; however, the incidence is increasing. ¹ Certain groups including people living with HIV (PLWH) are disproportionately affected.^2,3 In this case series, we report baseline demographics, clinical characteristics and outcomes of anal cancer presenting in PLWH in single a tertiary referral university hospital in Ireland over a ten-year period (2006–2015).

Methods

PLWH with ASCC were identified using the hospital inpatient enquiry system from 2006 to 2015 in St James’s Hospital, Dublin, Ireland. Demographic data were retrieved from electronic patient records. Characteristics of ASCC including staging, intervention and outcome were recorded. The study protocol was approved by the St James’s Hospital institutional review board.

Results

Seven cases of ASCC were identified in 3161 PLWH who attended the service from 2006 to 2015. There were 16,008 patient years of follow-up recorded during the study period (2006–2015). Crude incidence of ASCC was 44 cases per 100,000 (95% confidence interval [CI]: 20 to 90). Baseline characteristics of cases are outlined in Table 1.

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Table 1.

Baseline characteristics of patients presenting with ASCC from 2006 to 2015.

	ASCC n (%)
Total	7
Median [IQR] age at diagnosis, years	38 [35–49]
Male	6 (86)
Region of Origin
Ireland	7 (100)
Risk of acquisition of HIV
Heterosexual	1 (14)
MSM	4 (57)
IDU	2 (29)
Median [IQR] duration of HIV infection at diagnosis	3 [2–5]
Median [IQR] CD4 T cell count (cells/mm3) a	239 [135–401]
Nadir CD4 T cell count (cells/mm3)	18 [6–19]
On ART  a	6 (86)
HIV VL ND a	6 (86)
Smoker	6 (86)
Hepatitis C RNA positive	2 (29)
Hepatitis B sAg positive	1 (14)

ASCC: anal squamous cell carcinoma; n: number; IQR: interquartile range; MSM: men who have sex with men; IDU: injecting drug user; ART: antiretroviral therapy; VL: viral load; RNA: ribonucleic acid; sAg: surface antigen.

a

At time of diagnosis.

All patients were symptomatic at diagnosis reflecting the absence of a formal anal cancer screening programme. Symptoms included passage of bright red blood per rectum (n = 5, 71%), awareness of a mass in the anal canal (n = 4, 57%), proctalgia (n = 4, 43%) and perianal warts (n = 4, 57%).

ASCC is staged according to size of lesion at diagnosis (T1 < 2 cm, T2 2–5 cm and T3 > 5 cm). Lesions that invade the vagina, urethra or bladder are T4 regardless of size. Four patients in this case series had T2 disease and three patients had T3 disease. A single patient had nodal extension at diagnosis.

Three patients (43%) underwent abdominoperineal resection with de-functioning colostomy and ileostomy. All received combination chemoradiotherapy.

A single patient had recurrence of ASCC. Two patients (29%) died during the study period. Neither death was directly related to ASCC.

Discussion

Anal cancer is relatively rare in the general population (1–2 cases per 100,000); however, incidence is increasing. ¹ HIV-positive men who have sex with men (MSM) are the highest risk group due to a combination of impaired immune function and risk of exposure to HPV. ² Pooled incidence of ASCC is reported at 45.9 cases per 100,000 in HIV-positive MSM (95% CI: 31.2 to 60.3). ³

While HPV typing was not available for ASCC cases included in this case series, types 16 and 18 are known to cause approximately 90% of ASCC. ⁴ Other identified risk factors include female gender, greater number of sexual partners, receptive anal intercourse, HIV with persistent uncontrolled viremia, chronic immunosuppressive states and smoking. ⁵ Six of seven patients in this case series were smokers. Smoking has been reported as an independent risk factor for ASCC although the underlying mechanism remains poorly understood. ⁶

ASCC occurs more frequently with lower CD4 cell count and uncontrolled viraemia. ⁷ Median [IQR] CD4 cell count at ASCC diagnosis was 239 [135–401] cells/mm³, while median nadir CD4 cell count was 8 [6–19] cells/mm³. The advanced level of immunosuppression in patients included in this case series likely reflects a significant period of untreated HIV infection prior to diagnosis.

Six patients in our case series were virally suppressed on antiretroviral therapy (ART) at ASCC diagnosis. The incidence of ASCC has increased in developed countries since the widespread availability of ART. This likely reflects the survival advantage conferred by the successful treatment of HIV; however, it contrasts with trends in AIDS-defining malignancies such as Kaposi sarcoma, lymphoma and cervical carcinoma which have decreased with the widespread use of ART. ⁸

Many experts advocate routine anal cancer screening for high-risk individuals with digital rectal exam (DRE), anal cytology, high-resolution anoscopy (HRA) and HPV surveillance; however, no screening modality has demonstrated improvement in morbidity and mortality. ⁹ No international consensus anal cancer screening guidelines exist.

Despite this, many large institutions have implemented screening programmes for at risk groups. ¹⁰

A large randomised controlled trial currently underway, The ANCHOR (ANal Cancer/HSIL Outcomes Research) Trial, seeks to definitively inform screening strategies. In parallel with this, the AMC 088 study seeks to identify optimal treatment of anal precancer lesions.

All ASCC cases described in this case series were stage T2 (2–5 cm) at diagnosis indicating that lesions may have been detected on DRE. Another retrospective case series (n = 128) suggested that screening high-risk groups by anal inspection and palpation could result in earlier diagnosis. ¹¹

Three patients in this case series underwent abdomino-perineal resection and all underwent chemoradiotherapy. Patients with HIV have a higher risk of acute treatment-related toxic effects, especially hematologic toxic effects; however, survival and ostomy placement rates are equivalent to those of the general population. ¹²

The HPV vaccine has potential to significantly impact the burden of HPV-associated malignancies in populations where high uptake of the vaccine is achieved and long-term efficacy vaccine has been demonstrated. ¹³ HPV vaccine is immunogenic, safe and effective in PLWH. ¹⁴

None of the cases included in this study had received HPV vaccination. A funded HPV vaccination programme was introduced for girls in Ireland in 2012. The programme was extended to include MSM and PLWH up to 26 years of age in 2017. HPV vaccine has been made available to MSM up to 45 years of age in Ireland from 2018.

Conclusion

HPV vaccine has the potential to decrease the incidence of HPV-associated cancers in the future if high levels of vaccine coverage are achieved. However, the vaccine will not impact risk in older patients with HPV exposure prior to the availability of vaccination.

Healthcare providers and patients should have a low threshold to further investigate should symptoms arise particularly as earlier diagnosis is associated with improved outcome.