Salvage surgery

After treatment with Chemoradiotherapy, recurring or persistent disease is treated with salvage surgery. This is usually Radical Abdominoperineal Resection but can also be Total pelvic Exenteration depending on presentation. Recurring disease occurs in up to 15% of patients diagnosed with Anal SCC. Salvage surgery is associated with a  high morbidity and mortality. Many patients with relapsing disease are unfortunately not suitable for high risk surgery.  

If suitable for salvage surgery it has been reported that 40-60% survive 5 years compared to a 5% 3 year survival rate if salvage surgery is not attempted.  

An abdominoperineal resection for recurrent and persistent disease is associated with  low post-operative mortality risk (3%) however, there is a risk of up to 70% of delayed wound healing, perineal hernias (15%) and up to 20% risk of significant cardiovascular or respiratory complications. 

The single most important factor in disease control and survival is achieving a complete (R0) resection. Unfortunately this is only being achieved in 9-16% of available case series in the literature.  

Most of the data reporting success rates of salvage surgery for persistent or recurrent disease is from small single centre case series that are limited by historical data, small sample sizes and patients being largely female and HIV negative. 

Ko et al (2019) has written a great systematic review this year which extensively summarised the findings of 28 retrospective salvage surgery case series. On meta-analysis they demonstrated that there was no significant difference in overall survival between patients receiving salvage surgery for persistent compared to recurrent disease. The median 5 years disease free survival was 44% and 23.5% of patients had a locoregional recurrence after salvage surgery. 14 studies reported HIV status and one study included only HIV positive patients. The authors reported that the included studies did not analyse HIV positive and HIV negative survival outcomes separately. Of 14 studies reporting HIV status, 12 reported less than 20% HIV prevalence in their patients undergoing salvage surgery.  

It is unclear whether the low numbers of HIV positive patients undergoing salvage surgery in the literature are appropriate for the population studied or whether HIV patients are less likely to undergo salvage surgery as either they are not fit for salvage surgery or that they are less likely to have recurrent/persistent disease in the first place.  

We hope that mASCARA, by including HIV outcomes and recurrence outcomes may add further information into this topic.  

Superficially Invasive Squamous Cell Carcinomas (SISCCA’s) and the upcoming PLATO trial

Superficially Invasive Squamous Cell Carcinoma (SISCCA) is a term that is being increasing used in the literature, and it is defined by the LAST guidelines as  a completely excised Anal SCC (R0) that has an invasive depth less than 3mm from the basement membrane and has a maximum horizontal spread of less than 7mm.  

It is quite interesting that since the LAST guidelines in 2012, more study has gone into whether or not it is possible to spare chemoradiotherapy in this subgroup of patients with small T1 tumours that have already undergone a complete resection.  

Anecdotally, particularly in high HIV positive practices, many Anal SCC’s are identified incidentally after benign colorectal surgery in high risk patients.  There have been documented incidences in conference abstracts where no further treatment was given  after wide local excision only of SISCCA’s with good outcomes.   

Within the Colorectal community, organ sparing approaches such as minimally invasive excisions of rectal lesions are increasing in popularity. As they have larger patient numbers, evidence already exists that T1 rectal tumours can be excised and followed up sparing further operative treatment. The impact on patient quality of life after organ sparing treatment is significant.  

A very interesting paper by Chai et al (2018), is certainly worth a read, it reports the outcomes of treating 2243 T1 Anal SCC’s recorded on the American National Cancer Database.  Its demonstrates that there is no difference in survival outcomes between patients treated with chemoradiotherapy or wide local excision alone. However the use of the American Cancer Database is criticised by several authors in letters to the editor as it is not able to include data on position of tumour, chemoradiotherapy regimes used and recurrence rates. HIV status is also not included. 

In the meantime, The Association of Coloproctology of Great Britain and Ireland Guidelines in 2017, recommended that  SISCCA’s could receive wide local excision alone if technically possible. However, in the absence of peer reviewed research including recurrence and patient outcomes it looked to the ongoing PLATO Trial for further clarification.  

The Personalising Anal Cancer Radiotherapy Dose Trial (PLATO) opened for recruitment in 2017 and is set to release its results in 2028. It is including a study arm comparing the outcomes of T1N0M0 tumours receiving either wide local excision alone or IMRT and Chemotherapy.  

While we wait for the results of the PLATO trial, there remains a real need for further data on Anal SCC’s that includes data outcomes such as HIV status, recurrence data, AIN treatment and previous Genitourinary Dysplastic disease. By including these data outcomes in mASCARA we hope that it will be able to answer the research question that National Cancer Databases are unable to do.  

SPANC Trial

Study of the Prevention of Anal Cancer (SPANC) trial began enrolment in 2010 and its results are due to be reported soon.  

It is a clinical study following up homosexual men with and without HIV  after High Resolution Anoscopy (HRA)Screening  for three years. Currently there is insufficient evidence to recommend the wide spread use of HRA as a screening method for AIN. We look forward to the results of this study to see if they can add further evidence into the efficacy of HRA. 

ANCHOR Study

In 2014, the Anal Cancer HSIL Outcomes Research Study, a multicentre stage III Randomised Controlled Trial was launched in the USA.  

It is randomising HIV positive patients over 35 years of age with a new diagnosis of High Grade AIN to receive either topical treatments, ablative treatments or active monitoring.  

They are still recruiting and plan to publish their results in 2022.  

At the moment, there is very little evidence about the best treatment for AIN and whether or not treating AIN prevents the development of Anal SCC. We are looking forward to the results of this trial as we hope it will answer many  questions.  

Staging of Anal Squamous Cell Carcinoma

Up until fairly recently, we used to stage anal margin cancers (cancers up to 5cm away from the anal margin) differently to anal canal tumours, The rationale for this was that anal margin cancer were associated with a better prognosis, perhaps because they were more readily excised without risking sphincter function and also perhaps as patients more likely to notice the lesion sooner.  

This has changed in the most recent edition of the American Joint Committee TMN Staging where the two staging classifications have been merged together for better clarity.  The most recent classification is given below.  

Although this is based on the previous staging classification, the 5 year survival associated with each clinical stage is as follows: Stage 1 86%, Stage 2: 77%, Stage 3: 66%, Stage 4: 37%.  

The literature suggests that approximately half of patients present with Stage 1 or Stage 2 disease.  

American Joint Committee on Cancer recommended TMN staging 8th Edition of Anal Squamous Cell Carcinomas of Anal margin and Anal Canal.  

TMN Anal Squamous Cell Carcinomas: Combined Anal Canal and Anal Margin (within 5cm)
T1 Tumour less than 2 cm N0 No regional lymph nodes M0 No distant metastases
T2 Tumour less than 5 cm but greater than 2cm N1a Metastases in inguinal, mesorectal and/or internal iliac lymph nodes M1 Distant Metastases
T3 Tumour greater than 5 cm N1b Metastases in external iliac lymph nodes
T4 Tumour of any size that invades adjacent organs N1c Metastases in external iliac and in inguinal, mesorectal and/or internal iliac lymph nodes

Classification of TMN staging 8th Edition for Anal Squamous Cell Carcinomas. 

Classificationof staging
Stage I T1 N0 M0
Stage IIA T2 N0 M0
Stage IIB T3 N0 M0
Stage IIIA T1/T2 N1 M0
Stage IIIB T4 N0 M0
Stage IIIC T3/T4 N1 M0
Stage IV Any T Any N M1

Guidelines for Anal SCC and Anal Intraepithelial Neoplasia

Although there are extensive guidelines on Anal SCC, the most recent being: American Society of Colon and Rectal SurgeonsAssociation of Coloproctology in Great Britain and Ireland and the joint guidelines of the European Society of Medical and Surgical Oncology, there is little consensus on the best practice in the treatment of AIN. Recommendations for the treatment and surveillance of AIN  are often based on poor clinical evidence with much discrepancy.  

The guidelines have also significantly changed since they were compared and contrasted in this great paper by Alam et al (2016). In the UK, The ACPGBI guidelines in 2011 were encouraging of High Resolution Anoscopy (HRA) in high volumes centres and gave a preference for 5% imiquimod as a treatment for AIN3 and 1% Cidofovir in female patients with Genitourinary Intraepithelial Neoplasia. They also recommended Photodynamic therapy and Ablative therapies such as electrocautery and Laser treatment as possible treatment modalities. Anal mapping was also advocated after a diagnosis of AIN. 

This is quite different to the ACPGBI guidelines in 2017  which downgraded the importance of anal mapping due to futility and patient experience, were less enthusiastic about the benefits of HRA and, with the exception of HIV positive MSM where they suggested electrocautery may be the optimal treatment, they did not recommend a particular AIN treatment modality. They also had a new recommendation that all high grade AIN patients should be discussed at a specialist Anal SCC MDT.  

The 2008 ASCRS guidelines recommended the treatment of AIN in all stages by either 5% Imiquimod, 5% Fluorouracil, targeted surgical destruction or Photodynamic therapy. There were no recommendations on High Resolution Anoscopy. The current ASCRS 2018 guidelines restricts ablative treatments to High Grade AIN only and recommends HRA in high risk populations when experienced practitioners are available. Unlike in the UK, ASCRS 2018 guidelines recommend the use of cytology for the diagnosis of AIN but recommends adding in HPV serology and p16 status.  

Overall,  there are 7 guidelines available for review in the literature, from 5 different countries between 2011 – 2018. Most recommend that screening could be beneficial to high risk populations, however there is insufficient evidence to suggest screening prevents malignancy.  Guidelines from European countries recommend surgical excision (where possible) as the first line treatment, this conflicts with USA guidelines which prefer ablative or topical treatments. Except for one UK guideline that recommends the use of Imiquimod in lesions too large for surgical resection, no guideline expressed a strong preference for a specific AIN treatment. 

Sexual Practices and Anal Squamous Cell Carcinoma

When I first started my research into Anal SCC, I was told by multiple clinicians that the rise in incidence of ASCC in England is due to the relaxation of social stereotypes and the rise of sexual freedom. In particular in women, who were within the first generation to benefit from oral contraceptives and the rise of feminism.  

To put bluntly; women were more able to have sexual relationships and therefore were more likely to be exposed to different strains of HPV from different partners.  

Their evidence for this was that this patient subgroup are associated with the highest incidence increase worldwide and that patients in England are more likely to be female Caucasians in their 60’s and 70’s. 

However the more I read about Anal SCC the more I think that it cannot be so simple. 

Firstly, this generation would have been within the first cohorts of cervical screening, although the risk of cervical cancer is increasing over the last few years (in particular in younger women who did not participate in screening) there is a net reduction in cervical cancer incidence by 24% in the UK since the 1990’s. However, geographical areas with high incidence rates of cervical cancer are not necessarily associated with high incidence rates of Anal SCC.  

Secondly, as the highest risk of ASCC is actually associated with being an HIV positive MSM, is the risk actually associated with receptive anal intercourse? 

In demographic areas where HIV prevalence is high, the majority of patients seen with Anal SCC  and AIN are HIV positive MSM.  There is less of an association with HIV negative MSM.  

There are some papers in the literature that demonstrate a higher risk of AIN in women and men who practice receptive anal intercourse, however there are also papers that also show that there is no difference identified between sexual practices and risk.

I think this theory is difficult to prove, firstly due to recall bias, sexual practices change over time, just because you practiced receptive anal intercourse with one partner does not mean that you regularly do so. Nor does it mean that interaction was the time you were exposed to an oncogenic HPV. Patients can also be, understandably sensitive about their sexual practices and not wish to disclose them. In particular the paper I refer to above which did not show a different with sexual practices and risk, the group denying receptive anal intercourse were statistically older. It’s possible that this group were less likely to disclose due to social stigma.  

Like cervical cancer, Anal SCC has been associated with promiscuity and a higher number of sexual partners. There are some interesting papers that suggest patients with sexually transmitted infections are more likely to have High Grade AIN. I also think that this is not the most simple answer as being exposed to sexually transmitted infections also increases your risk of HIV which is known to be a much greater risk factor in AIN and Anal SCC.  

Unfortunately, at the moment the data we have is limited by the clinical data we have access to. From talking to female patients, in particular, after a diagnosis with Anal SCC, they do report concerns about social stigma that Anal SCC is a cancer associated with promiscuity and sexual practices.  

I think that this is unfair as although, in theory, promiscuity increases your likelihood of eventually becoming infected with an oncogenic HPV, you do not need to have multiple HPV exposures before unfortunately becoming infected with a high risk one.  

Histology and Cytology – What should we use?

The Papanikolaou (Pap) smear or cytology screening has long been used for cervical screening with reliable results. This can be used for screening of patients with or at risk of AIN.  

However, its reliability in the use in AIN is controversial. Many papers report that cytological testing often under-reports AIN grade. Unlike the cervix, which is a fixed structure, taking a cytological sample of the anus can be technically difficult.  

In fact the American Guidelines (ASCRS) for the treatment of Anal SCC do not recommend its use.  

In European countries, the use of anal cytology is more widespread and although its limitations are accepted it is often used with High Resolution Anoscopy and Histology of concerning lesions to form a complete clinical picture.  

In Anal SCC there is not sufficient evidence that cytology alone could be a suitable screening technique.  

It is accepted practice that before considering the treatment of an area diagnosed with AIN that a biopsy should be taken for formal histopathology.  

HIV and Anal Squamous Cell Carcinoma

Human Immunodeficiency Virus (HIV) has long been associated with Anal Squamous Cell Carcinoma. It is the 3rd most common cancer in patients with HIV.  

Patients at the highest risk of Anal Squamous Cell Carcinoma are men with HIV and a concurrent oncogenic HPV infection who are also men who have sex with other men (MSM). Their risk of Anal SCC is higher than the risk of an average person getting a common cancer.  

There is also noted to be an increase in incidence worldwide of Anal SCC . This is likely in part due to HIV prevalence increasing as advanced antiretrovirals are now able to give patients with well controlled HIV a near to normal life expectancy. However, these patients are then at risk of developing the long term sequelae of an immunocompromised state.  

HIV positive MSM are at 5x higher risk of ASCC than HIV negative MSM and HIV positive MSM, on screening, have up to 86% prevalence of Anal Intraepithelial Neoplasia (AIN), the dysplastic precursor to Anal SCC.  

There are many reports of HIV positive MSM having a high prevalence of High Grade AIN with some papers reporting up to a third of HIV positive MSM having High Grade AIN detected on anoscopy. Although HIV negative MSM do also have a risk of AIN, their risk is frequently reported as lower than HIV positive MSM.  

Due to their high risk profile, HIV positive MSM are regularly within screening programmes such as High Resolution Anoscopy, therefore this patient group’s AIN prevalence is widely reported in the literature. As they have the most contact with anoscopists, most studies assessing the treatment of AIN are involving HIV positive MSM. Consistently the treatment studies show that HIV positive patients are more likely to relapse after successful treatment of AIN and are more likely to have multifocal disease.  

The persistence of a immunocompromised state is likely to prevent the clearance of HPV, however, the treatment of HIV with antiretrovirals does not reduce the risk of developing Anal SCC, just having the virus itself is all it takes. Although it is possible that this will not always be the case, as more and more patients are receiving treatment and are successfully being classified as having an undetectable viral load.   

Previous viral loads and HIV treatment outcomes have been included in the mASCARA dataset, we hope that mASCARA will be able to answer some of the unanswered questions.  

High Resolution Anoscopy

High Resolution Anoscopy (HRA) is seen as the gold diagnostic standard for the diagnosis and surveillance of AIN. 

It is a reliable and well tolerated procedure that can be performed in the outpatient setting.   

It’s problems lie in that the best operator outcomes are from experienced anoscopists and as the transformation rate of AIN to Anal SCC is low. In the hospital I am currently working at, which has one of the highest HIV prevalence rates in the country, 116 anoscopies needed to take place to diagnose one high risk patient with Anal SCC. (3% of anoscopies performed) 

In areas with less high risk patients the yield is likely to be much lower, as such High Resolution Anoscopy has been downgraded in the American (ASCRS) guidelines to only take place if they high risk patient and an experienced anoscopists is available. In the UK, there is equipoise whether to undertake HRA, as in theory it should be beneficial but currently there is insufficient evidence to support it.  

The low yield also has an effect on whether HRA is cost effective leading to some clinical centres abandoning the practice in all but the highest risk patients.  

There are clinical societies such as the International Anal Intraepithelial Neoplasia Society that provide standardised HRA training and support for clinicians wishing to undertake HRA as part of their clinical practice.