Patient Characteristics
176 patients were included (see Fig. 1 for STROBE flow diagram), 55 patients (31%) were female, the mean age at diagnosis was 56.5 years (median 53 years, range 31–92 years) (See Tables 2 and 3 for study demographics). 96 patients were HIV positive (55%) and 32 patients (18%) were HIV negative. 27% of patients did not have a documented HIV status on retrospective chart review, they were statistically more likely to be female (p < 0.001, Chi Squared) and have a previous diagnosis of Genitourinary Intraepithelial Neoplasia (p = 0.011, Fisher’s Exact Test).
Of the patients with a known HIV status, 75% were PLWH in this cohort. 76% of male patients were PLWH whereas only 7% of female patients were PLWH (p < 0.001, Chi Squared). 38% of PLWH included in this cohort had previously met the criteria for AIDS during their treatment for HIV. 38% of PLWH had a concurrent diagnosis of Hepatitis B, 22% Hepatitis C and 10% had both Hepatitis B and C.
Table 2
Patient Demographics and Staging
Demographics
|
Male (n = 121)
|
Female (n = 55)
|
p-value
|
Mean age (years)
|
53.2
Standard Deviation = 13.4
Range 31–92
|
62.8
Standard Deviation = 13.1
Range 33–90
|
p < 0.001
|
HIV status
|
Positive 92 (76%), Negative 13 (11%)
Not tested 16 (13%)
|
Positive 4 (7%), Negative 19 (35%)
Not tested 32 (58%)
|
p < 0.001
|
Previous AIN
|
43 (34%)
|
2 (4%)
|
p < 0.001
|
Previous GIN
|
1 (1%)
|
8 (15%)
|
p < 0.001
|
Stage 1
|
47 (39%)
|
15 (27%)
|
P = 0.191
|
stage 2A
|
17 (14%)
|
10 (18%)
|
|
Stage 2B
|
4 (3%)
|
1 (2%)
|
|
Stage 3A
|
7 (6%)
|
5 (9%)
|
|
Stage 3B
|
13 (11%)
|
2 (4%)
|
|
Stage 3C
|
19 (18%)
|
13 (24%)
|
|
Stage 4
|
8 (7%)
|
2 (4%)
|
|
Risk factors
Age
Men presented with ASCC at an earlier age than women (53.2 years compared to 62.8 years; p < 0.001, ANOVA). PLWH were also statistically more likely to present at younger age when compared to HIV negative patients (47.9 years compared to 64.1 years; p < 0.001, ANOVA). There was no statistical difference in age when comparing patients with and without a previous AIDs diagnosis, previous diagnosis of intraepithelial neoplasia, other predisposing skin conditions and immunosuppression. Patients with metastatic disease were statistically more likely to be older (67.5 years compared to 54.3 years; p = 0.007, ANOVA). With the exception of patients receiving Radiotherapy alone who were statistically older than patients receiving other treatment modalities (78.3 years compared to 54.5 years; p < 0.001, ANOVA) there was no statistical difference in age and choice of treatment modality between groups.
Gender
Men were more likely to have HIV (p < 0.001, Chi Squared), and to have had previous treatment for AIN (p < 0.001, Fisher’s Exact Test). A higher proportion of male patients presented with an early cancer (Stage 1 and 2: 56% compared to 47%) but this was not statistically significant (Fig. 2). There was no difference in gender proportions when comparing treatment modalities, recurrence rates and disease-free survival.
Table 3
Patient Demographics by Documented HIV Status
Demographics
|
HIV Positive
(n = 96)
|
HIV Negative
(n = 32)
|
Not Tested
(n = 48)
|
p-value
|
Mean age (Years)
|
47.9
Standard Deviation = 8.6 Range 31–73 years
|
64.1
Standard Deviation = 14.2 Range 32–90 years
|
66.0
Standard Deviation = 12.5 Range 38–92
|
P < 0.001
|
Previous AIN
|
39 (41%)
|
3 (9%)
|
3 (6%)
|
p < 0.001
|
Previous GIN
|
1 (1%)
|
3 (10%)
|
5 (10%)
|
p = 0.011
|
Stage 1
|
40 (42%)
|
11 (34%)
|
11 (23%)
|
P = 0.071
|
Stage 2A
|
13 (14%)
|
5 (16%)
|
9 (19%)
|
|
Stage 2B
|
4 (4%)
|
1 (3%)
|
0 (0%)
|
|
Stage 3A
|
7 (7%)
|
1 (3%)
|
4 (8%)
|
|
Stage 3B
|
11 (12%)
|
1 (3%)
|
3(6%)
|
|
Stage 3C
|
16 (17%)
|
6 (19%)
|
10 (21%)
|
|
Stage 4
|
3 (17%)
|
4 (13%)
|
3 (6%)
|
|
Intraepithelial Neoplasia and other predisposing skin conditions
Three patients had predisposing anal skin conditions linked to ASCC such as lichen sclerosis and only 3% of patients had a pre-disposing co-morbidity leading to immunosuppression other than HIV status.
Four patients had concurrent cervical and or vulval intraepithelial neoplasia and three patients had a prior treated vulval squamous cell carcinoma. One patient with high-grade cervical intraepithelial neoplasia was also HIV positive. 26% were previously diagnosed with AIN and had received follow up and/or treatment before ASCC diagnosis.
Having a previous known diagnosis of AIN before ASCC diagnosis was associated with being HIV positive (p < 0.001, Fisher’s Exact Test), but there was not a similar effect with patients diagnosed with other non-anal genitourinary intraepithelial neoplasia. Being known to have AIN was associated with PLWH presenting with a stage 1 cancer when compared to PLWH without a previous AIN diagnosis (p < 0.001, Fisher’s Exact Test). As a result, they were also more likely to have local excision as treatment (p < 0.001, Fisher’s Exact Test) and less likely to have chemoradiotherapy.
Table 4
Treatment received by HIV status
Treatment Received
|
HIV positive
(n = 96)
|
HIV Negative
(n = 32)
|
p-value
|
Chemoradiotherapy
|
63 (66%)
|
19 (59%)
|
p = 0.009
|
Palliative Radiotherapy only
|
1 (1%)
|
3 (9%)
|
p < 0.000
|
Local Excision of Tumour
|
30 (31%)
|
19 (59%)
|
p = 0.07
|
Abdominoperineal Resection
|
2 (2%)
|
3 (9%)
|
p = 0.140
|
Defunctioning Stoma
|
16 (17%)
|
4 (13%)
|
p = 0.419
|
Local Excision of Tumour only
|
24 (25%)
|
6 (19%)
|
p = 0.016
|
TMN Staging and Treatment of ASCC
50% of patients presented with early-stage disease (Stage 1 35%; Stage 2A 15%) and 5% of patients presented with metastatic disease.
42% had their tumour locally excised, 61% had Chemoradiotherapy and 4% had Radiotherapy alone. 14% had a defunctioning colostomy for symptomatic control and 5% eventually underwent an abdominoperineal excision for recurrent disease. PLWH were more likely to receive chemoradiotherapy (p = 0.009, Fisher’s Exact Test) and less likely to have palliative radiotherapy alone (p < 0.001, Fisher’s Exact Test) (Table 4).
Clinical Outcomes
Recurrence
19% (n = 33) of patients developed a recurrence; 30 patients after completing chemoradiotherapy. 7 patients underwent an Abdominoperineal Resection as salvage surgery after their recurrence, no immediate post-operative complications were identified. There was no statistical association between recurrence rate and age, sex, hepatitis status, previous AIN treatment or previous cervical or vulval dysplasia. PLWH were more likely to develop a recurrence compared to HIV negative and non-tested patients (Table 5). However, PLWH also took longer to develop recurrent disease when compared to HIV negative patients (46.1 months compared to 17.5 months) but this was not statistically significant; (p = 0.077, ANOVA) (Fig. 2). Interestingly, as they are demographically very similar (see Table 3) if we group untested and HIV negative patients together this statistic becomes significant (46.1 months vs. 18.1 months; p = 0.022, ANOVA).
PLWH that recurred were more likely to have received chemoradiotherapy (p = 0.031, Fisher’s Exact Test) and have a moderately or poorly differentiated malignancy (Table 6).
Table 5
Recurrence and disease-free survival in HIV positive and HIV negative patients
End Outcomes
|
HIV positive
(n = 96)
|
HIV Negative
(n = 32)
|
p-value
|
Recurrence
|
22
(23%)
|
4
(13%)
|
P < 0.001
|
5-Year Disease Free Survival
|
49
(51%)
|
9
(28%)
|
p = 0.181
|
Table 6
Recurrence Variable analysis
HIV status
|
HIV positive
|
HIV negative
|
p-value
|
Demographics
|
Recurrence (N = 22)
|
No Recurrence (N = 74)
|
Recurrence (N = 4)
|
No Recurrence (N = 28)
|
(Fishers Exact Test)
|
Gender
|
Male 19 (86%)
Female 3 (14%)
|
Male 73 (99%)
Female 1 (1%)
|
2 (50%)
2 (50%)
|
11 (39%)
17 (61%)
|
P = 0.037
|
Previous AIN
|
8 (36%)
|
31 (42%)
|
1 (25%)
|
2 (7%)
|
P = 0.780
|
Previous GIN
|
1 (5%)
|
0 (0%)
|
0 (0%)
|
3 (11%)
|
P = 0.229
|
Previous AIDs criteria
|
9 (41%)
|
27 (37%)
|
n/a
|
n/a
|
P = 0.763
|
Hepatitis status
HBV
HCV
HBV and HCV
|
9 (41%)
5 (23%)
3 (14%)
|
23 (31%)
14 (19%)
6 (8%)
|
0 (0%)
0 (0%)
0 (0%)
|
2 (7%)
2(7%)
1 (4%)
|
P = 0.775
P = 0.927
P = 0.927
|
Staging
1
2A
2B
3A
3B
3C
4
Not staged
|
7 (32%)
3 (14%)
4 (18%)
2 (9%)
3 (14%)
7 (32%)
0 (0%)
0 (0%)
|
33 (45%)
10 (14%)
4 (5%)
5 (7%)
8 (11%)
9 (12%)
3 (4%)
2 (3%)
|
1 (25%)
2 (50%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (25%)
|
10 (36%)
3 (11%)
1 (4%)
1 (4%)
1 (4%)
6 (21%)
4 (14%)
2 (7%)
|
P = 0.443
P = 0.433
P = 0.750
P = 0.750
P = 0.067
P = 0.600
|
Chemoradiotherapy
|
19 (89%)
|
44 (60%)
|
3 (75%)
|
16 (57%)
|
P = 0.031
|
Local excision of tumour
|
4 (18%)
|
26 (35%)
|
2 (50%)
|
17 (60%)
|
P = 0.104
|
Tumour differentiation
Foci of SCC
Well differentiated
Moderately differentiated
Poorly differentiated
|
1 (5%)
2 (9%)
12 (55%)
3 (14%)
|
7 (10%)
9 (12%)
29 (39%)
7 (10%)
|
0 (0)
0 (0)
2 (50%)
1 (25%)
|
4 (14%)
1 (4%)
8 (29%)
6 (21%)
|
P = 1.000
P = 1.000
P = 0.028
P = 0.286
|
Disease Free Survival
23% of patients died of ASCC during routine 5-year follow-up. Overall, 42% of patients achieved 5-year disease free survival and 9% were lost to follow up. 26% were diagnosed within the last 5 years and therefore could not be included in the survival analysis.
Survival was associated with < 5 cm tumour size (p < 0.000, Chi Squared) and the absence of nodal or metastatic disease at presentation (p < 0.000, Chi Squared). 70% of patients achieving 5-year Disease Free Survival were T1/2 compared to only 27% of patients with T3/T4 tumours. No patients with distant metastatic disease on presentation achieved 5-year Disease Free survival.
There was no statistical association between disease free survival and HIV status, gender, and previous AIN or non-anal intraepithelial dysplasias and malignancies.
50% of patients who were given a stoma for symptomatic control were eventually reversed. 33% patients died with a stoma in situ.