Local excision and treatment of early node-negative anal squamous cell carcinomas in a highly HIV prevalent population

Anal squamous cell carcinoma (ASCC) is an uncommon cancer that accounts for 1–2% of gastrointestinal malignancies [2]. Its worldwide incidence is 1–2 cases per 100,000 people per year [3].

The incidence of ASCC is rapidly increasing worldwide [4]. A common risk factor of ASCC is human immunodeficiency virus (HIV), as people living with HIV (PLWH) are living now longer on advanced antiretroviral therapies there is also an associated rise in incidence of ASCC in PLWH and men who have sex with men (MSM).

ASCC has a dysplastic precursor; high-grade squamous interepithelial lesion (HSIL) which is related to persistent oncogenic human papillomavirus (HPV) infection. HSIL can progress to ASCC, however, there is much discrepancy in the literature regarding the progression rates [5‐8].

It is believed, that like cervical cancer, a screening programme for HSIL could prevent the progression of HSIL to ASCC. As yet, there is little consensus on the relevance of HSIL screening for the prevention of ASCC as there is insufficient evidence available of its efficacy in preventing ASCC [9‐14]. Most current clinical guidelines recommend the surveillance of high-risk populations, in particular HIV-positive MSM, but there is an insufficient evidence base to propose a method or schedule of best practice to do so.

One of the suggested benefits of a successful screening programme in high-risk individuals would be the early detection of a cancer to allow for an organ sparing approach to treatment. This would be of significant quality of life benefit to PLWH as they often develop ASCC at a younger age [15] and treatment to the perianal region has a significant impact on the sexual and psychological wellbeing of MSM.

As a result, there is increasing interest in undertaking local excision alone for early-stage ASCC tumours without nodal involvement. Indeed, the PLATO trial (SRCTN88455282) has recently begun; its ACT3 arm is a non-randomised study comparing the outcomes of patients with fully excised T1 perianal ASCC’s (< 1 mm) who will have local excision as their only treatment to patients with T1 perianal ASCC excised with inadequate margins (> 1 mm) who will also receive chemoradiotherapy. [16]. The trial results are not expected in the near future; however, in the meantime, other findings on the management of early ASCC have been published. [17] used the American National Cancer Database to compare the outcomes of 2243 stage 1 tumours after local excision only or chemoradiotherapy [17] and [18] interrogated the Surveillance, Epidemiology and End Results (SEER) database to investigate the outcomes of stage 1 tumours and the outcomes after different treatment modalities [18]. Where other smaller local case series have also been presented [19‐22], none so far have identified any difference in survival, suggesting that the treatment of early ASCC tumours may be successfully limited to local excision alone in selected patients. However, none of the studies in the literature outside our clinical centre [23] have looked specifically at the benefits of local excision alone in PLWH. This is a significant gap in the literature as this patient group are the most likely to achieve early detection due to HSIL surveillance programmes and also as they are more likely to have a later recurrence [15] their long-term outcomes after organ sparing treatment may not be as advantageous.

We present a 20-year case series of the treatment of early-stage node-negative (1, 2A and 2B) ASCC tumours in a tertiary referral centre for HIV where there is a high prevalence of PLWH in our general practice. Our clinical centre also benefits from the availability of a screening programme for PLWH with particular emphasis on PLWH MSM.

We undertook a case series review of all early-stage cancers within a retrospective cohort study completed at our clinical centre in a prospectively collected database. We followed the strengthening the reporting of observational studies in epidemiology (STROBE)” statement in designing and undertaking the cohort study [24]. Ethical approval was granted from the London-Westminster Research and Ethics Committee prior to commencing the cohort study.

One hundred seventy-six patients with primary ASCC diagnosed between January 2000 and January 2020 were identified, within this cohort Ninety-four patients were classified as stage 1, stage 2A or stage 2B (see Figs. 1 and 2 for TMN staging classification) and were included in this study. The STROBE patient flowchart is shown in Fig. 3. Sixty-eight patients were male (72%) and 57 patients were PLWH (61%). Thirty-five patients (37%) had a prior diagnosis of high- or low-grade squamous intraepithelial lesions (LSIL) and 6 patients (6%) had a prior diagnosis of genitourinary intraepithelial neoplasia (GIN) (23% of women in the cohort). Twenty-five patients (27%) of patients in the cohort had well-differentiated tumours or malignant foci of ASCC only on histology.

There was no statistically significant difference between age, sex, HIV status, immunosuppression, history of HSIL or LSIL or GIN or tumour differentiation between the stage 1 and stage 2A/B subgroups (Table 1).

Patients classified as stage 1 were less likely to receive chemoradiotherapy when compared to stage 2A and stage 2B (p < 0.000, Fisher’s exact test) and more likely to have local excision of tumour alone as the only treatment for their malignancy (p =  < 0.000, Fisher’s exact test). There was no statistically significant difference between staging groups in patients receiving radiotherapy only (Table 2). The use of chemoradiotherapy was associated with tumour differentiation (p = 0.003, Fishers exact test); indeed 93% of stage 1, 82% of stage 2A and 100% of stage 2B tumours that received chemoradiotherapy were either moderately or poorly differentiated.

Sixty-two patients (66%) had stage 1 disease. Forty-seven were male (76%) and 40 patients were PLWH (65%). Three (5%) had an immunosuppressive state other than HIV, 24 patients (39%) had a history of HSIL or LSIL and 6 (10%) had a previous diagnosis of GIN. Twenty-one (44%) stage 1 tumours were well differentiated or had a foci of malignancy on histopathology.

We undertook a case series review of the treatment of early-stage tumours extrapolated from a retrospective cohort examining the outcomes of the treatment of primary ASCC over 20 years in a HIV tertiary referral centre. Treatment choice was determined in specialist weekly multidisciplinary team meetings with colorectal surgeons, radiologists and oncologists present.

There were three separate analyses included in this case series; the first being the overall demographics and outcomes of all patients treated for stage 1, 2A and 2B disease between January 2000 and January 2020, the second a sub-analysis of stage 1 tumours stratified by patient treatment and the third a sub-analysis of early-stage tumours in PLWH only.

The interest in organ sparing treatment for ASCC stems from the Lower Anogenital Squamous Terminology (LAST) criteria which identified a new category of ASCC; “superficially invasive squamous cell carcinoma” (SISCCA) that may be amenable to local excision alone [25].

As a result, some clinical guidelines now recommend local excision alone in T1N0 well-differentiated tumours with a clear margin.[9, 10, 13, 26]. This is based on several retrospective studies being able to demonstrate no difference in long-term outcomes for patients with stage 1 tumours that are treated with local excision alone when compared to stage 1 patients that receive chemoradiotherapy [17‐22].

Clinical guidelines also recommend that all patients considering local excision alone should be discussed in an expert ASCC multidisciplinary team meeting. We believe this is increasingly important since our results demonstrate that recurrence in PLWH can occur after the classic 5-year follow-up period. An expert ASCC multidisciplinary team meeting should by definition have access to a functioning screening programme for surveillance after treatment. This is not just for identifying ASCC but also as studies have shown that a high number of patients have persistence of high-grade anal intraepithelial neoplasia after local excision [27].

Currently, surveillance programmes are not widespread or are they recommended by clinical guidelines as there is no evidence base that surveillance after treatment for ASCC is beneficial. This can leave patients requiring long-term follow-up for ASCC in a difficult situation as high-resolution anoscopy (HRA), the gold standard for detection of anal HSIL detection, is only recommended when used by expert practitioners with high volumes of patients, therefore, the availability of expert practitioners to perform HRA for long-term follow-up of patients treated for ASCC can be scarce [9]. Societies such as the International Anal Neoplasia Society (IANS) are trying to rapidly train practitioners to be able to provide this service effectively worldwide but until guidance changes all patients that are being considered for a local excision alone should be considered for referral to a clinical centre with an expert multidisciplinary team that has access to an appropriate long-term follow-up programme.

We believe that the patients most likely to benefit from organ sparing treatment are patients with risk factors on surveillance programmes, the most common being PLWH who are also MSM. Research available from other clinical centres has not previously investigated the outcomes of PLWH after local excision. The recommendations in the clinical guidelines regarding the viability of PLWH ha ving local excision alone are based on a previous case series published at our clinical centre in 2016, which was only able to include 15 patients with a median follow-up time of 4 years [23]. We hope that this update from our centre will help to guide recommendations in the future whilst we wait for the results from the ACT3 arm of the PLATO trial [16].

In our experience, local excision alone and close follow-up is an acceptable management plan for stage 1 ASCC with advantageous histology regardless of HIV status. PLWH had late recurrence, therefore, we would recommend they enter a long-term HRA screening programme provided by expert practitioners once 5-year follow-up is completed.