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The clinicopathologic spectrum of anal cancer in KwaZulu-Natal Province, South Africa
Cancer Epidemiology 39 (2015) 528–533
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
The clinicopathologic spectrum of anal cancer in KwaZulu-Natal Province, South Africa Analysis of a provincial database X.H. Ntombela a, Benn Sartorius c, T.E. Madiba a,*, Poovandren Govender b a b c
Department of Surgery, University of KwaZulu-Natal, Durban, South Africa Department of Oncology, University of KwaZulu-Natal, Durban, South Africa Biostatistics & Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 March 2015 Received in revised form 15 May 2015 Accepted 18 May 2015 Available online 3 June 2015
Background: The occurrence of the considered rare anal cancer has not been documented in the South African context. Patients and methods: Analysis of data extracted from a prospectively collected KwaZulu-Natal anal cancer database for the period 2000–2014. Data analysed included demographics, clinical picture, pathology, treatment and outcome. The study outcome measures were clinicopathologic spectrum, treatment and outcome. Results: The study population comprised 244 patients of mean age 50.1 (SD 14.0) years. The age at presentation was lowest for Black African patients compared to Whites and Indians (p < 0.001) and lower for HIV positive vs HIV negative patients (p < 0.001). Histology was squamous carcinoma in 208 patients (margin 152, canal 56), adenocarcinoma in 34 (all anal canal), neuroendocrine tumour (1) and melanoma (1). Mean age for squamous carcinoma was 48.8 (SD 14.1) years compared to 58.7 years (SD 11.1) for adenocarcinoma. Metastatic disease occurred in 22 patients (9%). Patients received definitive (139), palliative (53) and no (52) oncological therapy. Thirty patients (12%) underwent resection, seven of whom had positive margins. Seventy-six patients (31%) have been confirmed dead. The 5-year survival rate was 33.4% (95% CI: 23.4–44.6%). There was a highly significantly worse prognosis for adenocarcinoma compared to squamous cell carcinoma (p = 0.038). No significant difference was found in survival prospects based on race and tumour location. Conclusion: Squamous carcinoma was more common and presented at a young age. Black African patients and HIV positive patients were younger. Adenocarcinoma was associated with poorer prognosis. Race and tumour location had no influence on survival. ß 2015 Elsevier Ltd. All rights reserved.
Presented at the 9th Congress of the African Organisation for Research and Training in Cancer (AORTIC) in Durban, South Africa on 21–24 November, 2013. Keywords: Anal Anorectal Squamous Carcinoma Adenocarcinoma
1. Introduction Neoplasms of the anus are infrequent [1,2], making up 1–5% of gastrointestinal neoplasms [3–7]. They are classified into anal canal and anal margin tumours [1]. Anal squamous carcinoma is the most common followed by anal adenocarcinoma. The risk factors include human papilloma virus (HPV), smoking, immunosuppression with lower CD4 counts, Herpes Simplex-2 virus and ano-receptive intercourse [1,8–11]. HPV, especially subtypes 16
* Corresponding author at: University of KwaZulu-Natal, Colorectal Unit, Department of Surgery, Private Bag 7 Congella, Durban 4013, South Africa. Tel.: +27 31 260 4219; fax: +27 31 260 4389. E-mail address: [email protected] (T.E. Madiba). http://dx.doi.org/10.1016/j.canep.2015.05.005 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
and 18, with their affinity for the genital epithelium is the main aetiological factor [1,8–17], which causes anal intraepithelial neoplasia and condyloma acuminata, both of which are precursor lesions for anal squamous carcinoma [1,8,10,11,17–19]. Anal canal adenocarcinoma arises from stratified columnar epithelium lining the anal glands [19,20]. Risk factors include chronic fistulae, inflammatory bowel disease, radiation for non-intestinal cancer, and anal intercourse [20]. Anal canal adenocarcinoma can be subclassified into (i) typical colorectal-type adenocarcinoma (CRTA) that occurs proximal to and within the anal transitional zone, and (ii) anal canal adenocarcinoma arising in anal canal mucosa and anorectal fistulae [5]. Little data on anal carcinoma have emanated from South Africa [21,22]. We have analysed data from an on-going anal cancer database for the KwaZulu-Natal (KZN) Province of South Africa.
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533
2. Methods 2.1. Setting The study setting was the Colorectal Unit at the Inkosi Albert Luthuli Central Hospital (IALCH). After histological categorisation all patients with anal cancer are referred to the Multidisciplinary Clinic at IALCH which further stages the patients and makes management recommendations. Treatment delivery logistics are individualised. Follow-up is at the dedicated colorectal oncology clinics situated at IALCH, Addington Hospital and Grey’s Hospitals. The standard curative treatment for anal carcinoma in our centre, regardless of histopathology, is definitive chemo-radiation. Indications for surgical excision are small tumours (2 cm), larger tumours are given chemo-radiation and metastatic disease treated with chemotherapy. The standard protocol utilises external beam radiotherapy to the pelvis to a dose of 45 Gray followed by a tumour boost to 59.4 Gray in 1.8 Gray fractions. An electron boost to the inguinal area [23,24] is indicated for histology/cytology proven inguinal node disease. Concurrent chemotherapy used is weekly intravenous Cisplatin and 5-fluorouracil orally or intravenously. The threshold for concurrent chemotherapy is a CD4 200 in HIV positive patients. A diverting colostomy is performed for obstructive bowel symptoms and for prevention of stool contamination. 2.2. Study design This was an analysis of an on-going anal cancer database which is in the Colorectal Unit of the Department of Surgery, University of KwaZulu-Natal. The dataset analysis included demographic characteristics, clinical presentation, histopathological findings, tumour location and staging, treatment and follow-up. We use the WHO criteria which define anal margin tumours as arising from the skin outside the anal verge and tumours proximal to this landmark are considered anal canal tumours [6,25–27]. 2.3. Patients The data were extracted from the database covering the period 2000–2014. Patients who were referred as anal adenocarcinoma but in whom we could not exclude the possibility of low rectal carcinoma were excluded from the study. Population groups were defined as African, Indian, Coloured and White according to the criteria used by the South African Government. For the purposes of this paper the term ‘‘Black African’’ will be used for the benefit of international readers who may not be familiar with the South African context. In South Africa, ‘‘Coloured’’ is an ethnic label that refers to people of mixed ethnic origin who possess ancestry from Europe, Asia and various Khoisan and indigenous African tribes of Southern Africa. Complete clinical response was defined as disappearance of all target lesions on clinical examination. Complete pathological response was defined as absence of residual tumour or viable tumour cells on histopathological appraisal; intermediate or partial response was defined as an improvement in stage; and poor responders were defined as patients with no change or with persistent lymphadenopathy or metastasis. Ethical approval was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (R057/04). 2.4. Statistical analysis Data were processed and analysed using Stata 13.0 [StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP]. The t-test was employed to identify significant mean differences for continuous variables by dichotomous classifications.
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The one way analysis of variance (ANOVA) was used to compare mean age at presentation across ethnic groups. Pairwise comparisons (between groups) were also performed and adjusted using a Bonferroni correction. The dates of death were identified where possible for patients in this cohort via the Department of Home Affairs. Kaplan–Meier survival curves were constructed and stratified on key characteristics such as ethnicity, tumour location (canal vs margin) and tumour type (adenocarcinoma vs squamous). Survival functions were compared using the log rank test to ascertain if significant differences existed by sub-group. A p-value of <0.05 was deemed statistically significant. Patients who were in poor general condition but whose status data could not be ascertained were presumed dead for the purposes of the study but were not coded as such during the statistical analysis. 3. Results There were 244 patients comprising Africans (183), Indian (35), Coloured (10) and White (16) (Fig. 1). Patient profile is shown in Table 1. The mean age was 50.1 (SD 14.1) years. The peak age was lowest for Black Africans were significantly younger at presentation compared to Indians and Whites respectively by 15.4 and 15.0 years respectively (both p < 0.001) but only marginally significantly younger than Coloured by 6.8 years (p = 0.097). There was a female preponderance of 2:1 for squamous carcinoma and male preponderance of 2:1 for adenocarcinoma. There was no significant difference in age at presentation when comparing Coloured and Indians to Whites. Squamous carcinoma occurred in 208 patients (85%) of mean age 48.8 (SD 14.1). Thirty-four patients (14%) of mean age 58.7 (SD 11.1) years had adenocarcinoma. When comparing age at presentation among the adenocarcinoma group only, Black Africans did not present at a significantly younger mean age, i.e. 59.6 vs 62.4 years in the other ethnic groups combined (pvalue = 0.300). This age gap was however significantly larger for squamous cell carcinoma group only with a mean age of 44.8 years among Black Africans compared to 60.3 years in the other ethnic groups combined (p-value < 0.001). Of 119 patients tested for HIV status 91 patients (mean age 40.1 years [SD 8.6]) tested positive and 28 patients (mean age 53.6 years [SD 10.3]) tested negative. This mean age difference was statistically significant (pvalue < 0.001). Of the 163 patients (67%) that could be staged, the majority were stage II and III (Table 2). Twenty two patients (9%) presented with metastatic disease, the target organs being lungs (10), liver (10), peritoneum (2), bone (1) and pleura (1). Histopathological evidence of HPV or condyloma acuminata was documented in only nine and six patients respectively. Anal margin tumours were more common than anal canal tumours in the whole cohort and in the squamous carcinoma cohort, but all adenocarcinomas arose from the anal canal. Table 3 shows management. Thirty three patients were eligible for surgery, one refused and two did not return after accepting surgery. Of the 30 eligible patients (12%), three underwent resection ab initio and the rest received excision after chemoradiation (Table 3). Seven patients had one or more positive margins (R-1 resection) following wide local excision. There was no tumour at re-resection in one patient. The other six patients were managed with definitive chemo-radiation with resultant complete pathological response in 5 patients and one patient died during subsequent chemo-radiation from advanced HIV disease and complications of chemo-radiation. The rest of the patients had R-0 resections. Of the patients who received chemo-radiation, there was complete clinical response in 34 (14%) patients (including 16 patients with complete pathological response). The reasons for failure to receive treatment in 52 patients are shown in Table 4.
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533
530
Paents referred as anal cancer 267 Exclusions (anal canal origin cannot be confirmed) 23
Other • Melanoma = 1 • Neuroendocrine carcinoma = 1
Anal cancer (Confirmed) 244
Squamous carcinoma 208 (85%)
HIV Posive = 84 HIV Negave = 25
HIV posive = 5 HIV negave = 3
Adenocarcinoma 34 (14%)
Canal 34 (100%)
Canal 56 (27%)
Margin 152 (73%)
Fig. 1. Disease and site distribution in patients with anal cancer.
Vital status plus relevant time stamps were known in 150 (61.5%) who were included in the survival analyses (Fig. 2). Seventy six of these individuals died (51.0%); the median survival time (point at which the survivor function reaches 50%) was 20.4 months (95% CI: 12.7–37.8 months). The 25th and 75th percentiles for the survivor function were 8.6 and 76.4 months respectively. The 5-year survival proportion was 33.4% (95% CI: 23.4–44.6%). There was no significant difference in survival prospects when comparing Black Africans to other ethnic groups combined in the whole cohort (p = 0.175), in the adenocarcinoma group (p = 0.840) nor in the squamous cell carcinoma group (p-value = 0.137). There was no significant difference in survival prospects observed by gender (p-value = 0.304) and HIV status (p-value = 0.510). As shown in Fig. 3, there was a significantly worse prognosis (survival) for patients with adenocarcinoma compared to Table 1 Profile of 244 patients with anal malignancy. Parameter
Total n = 244
Squamous carcinoma n = 208
Mean age (SD) Black African Indian Coloured White
50.1 (14.1) 183 35 10 16
48.8 (SD 14.1) 155 29 9 15
Gender Males Females M:F ratio
96 148 1:1.6
HIV status Positive Negative
91 28
Site Anal margin Anal canal
153 (63%) 91 (37%)
Adenocarcinoma n = 34 58.7 (11.1) 26 6 1 1
Other (n = 2) – 2 – – –
72 136 1:2
23 11 2:1
1 1 –
84 25
5 3
– –
152 (73%) 56 (27%)
0 (0.00%) 34 (100%)
1 1
squamous cell carcinoma (p-value = 0.009). No significant difference was found in survival prospects based on tumour location (margin vs canal) (p-value = 0.969). 4. Discussion The study has made a number of observations, the first being variation in the age of presentation. The mean age at presentation of 49 years for squamous carcinoma falls within the reported 42– 58 years [22,28,29] and the female preponderance of 2 to 1 is in Table 2 Staging among patients with anal carcinoma. Stage
Squamous n = 208
Adenocarcinoma n = 34
I II III IV Not staged
8 47 65 20 68
3 9 9 2 11
(4%) (22%) (31%) (10%) (33%)
(9%) (27%) (27%) (6%) (32%)
Table 3 Management of patients with anal carcinoma. Overall Surgery Eligible for surgery Underwent surgery Wide local excision Abdomino-perineal resection No Surgery
Squamous
Adenocarcinoma
Other
33 30 21 9
28 25 20 5
5 5 1 4
– – – –
3
3
0
–
Non-surgical (Oncological) therapy Definitive 139 123 Palliative 53 43 No therapy 52 42
16 9 9
– 1 1
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533 Table 4 reasons for not receiving treatment in patients with anal cancer (n = 52). Reason
n
Did not return to Oncology Clinic Poor general condition Complete excision Not referred Refusal of treatment IVC Thrombosis Previous radiotherapy
37 8 2 2 1 1 1
keeping with the literature [3,4,30,31]. Similarly the mean age of 59 years for adenocarcinoma fell within the reported range 50–71 years [20,32] and the reported male preponderance [20] was confirmed in this study. The young age for Black African patients noted in both malignancies, but more pronounced in squamous carcinoma, was surprising and cannot be explained by this study. The younger age at presentation for HIV positive patients confirms previous observations [9,31,33].
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Among squamous cell carcinomas anal margin tumours were almost three times as common as anal canal tumours, whereas all adenocarcinomas arose from the anal canal. The limitations of previous studies have been the tendency to group anal margin and anal canal tumours together or to report on only one or the other [33]. This tendency is not helped by the difficulty in determining the primary location of these tumours [27,34,35]. Clinical documentation by rectal examination is therefore crucial [27,34,35]. Squamous carcinoma was almost six times as common as adenocarcinoma, occurring in 85% which falls within the reported 75–85% [1,26,36,37]. Adenocarcinoma on the other hand occurred in 14% which also falls within the reported 3–19% [4,5,20,26,36–40]. Most patients presented at an advanced state of the disease leading to only 12% of our patients fulfilling the criteria for wide local excision [2,13,16,41]. Likewise the majority of tumours fell in stage II and III for both squamous carcinoma and adenocarcinoma. However, despite the advanced presentation, only 9% presented with metastatic disease, which compares favourably to the reported 10–20% [16,37].
Fig. 2. Survival function of all patients with anal carcinoma.
Fig. 3. Survival function for patients with squamous carcinoma vs adenocarcinoma.
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533
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The 5-year survival of 33% for the whole cohort falls far short of the 40–90% reported in literature [6,25,37,42,43]. Indeed the complete clinical response rate of 14% in this series was much lower than the 60–85% reported in literature [13]. The advanced nature of the disease, poor treatment completion rates, and failure to return for treatment in our setting makes it impossible to reach the goal of eventual resection, complete response to therapy and the management of synchronous and metachronous lymph node metastases [23,24] in the majority of cases. The biological behaviour of the tumours themselves [26,27,40,44] as well as anatomical factors such as close proximity to the anal sphincter, profuse blood supply and an abundant lymphatic drainage with consequent early lymphatic involvement of the deep pelvic nodes [41,44] make cure rates for anal canal carcinoma lower than anal margin tumours. Apart from a more aggressive clinical course and the poor survival prospects which have been noted in this series, the natural history of adenocarcinoma remains unclear [20]. Treatment is generally similar to low-lying rectal cancer [3,32,36,45] with recent evidence suggesting the superiority of abdomino-perineal resection with preoperative chemo-radiation to chemo-radiation alone [20,26,32]. We could identify no discernible difference in survival between anal margin and anal canal tumours in squamous carcinoma but we concede that these results may not be generalizable because of inadequate follow-up. There were some limitations to this study. Poor follow-up and low treatment completion rates were a problem mainly due to socioeconomic reasons. Some patients may have sought healthcare outside of the KZN Province and similarly, some patients captured by this database may not be KZN residents. However, since all patients with anal cancer are referred to the KwaZulu-Natal Teaching Hospitals we assume that our database captures the vast majority of these cases, who present in any KZN hospital. Furthermore, the study only included state hospital patients. Finally we could not verify the vital status of all individuals and this is likely to underestimate mortality in this cohort. Despite these limitations we believe that this paper does provide an important contribution to the understanding of anal cancer and forms the basis for future studies in this field in South Africa. In conclusion, the clinicopathologic spectrum of anal cancer in the KZN Province of South Africa differs from world trends with squamous carcinoma being six times as common as adenocarcinoma and tumour location varying between the two malignancies. Black African patients tend to be younger than the other population groups in respect to both major malignancies. Patients with squamous carcinoma were younger than those with adenocarcinoma and so were those with HIV infection compared to their uninfected counterparts. Adenocarcinoma was associated with poorer prognosis. Race and tumour location had no influence on survival. We strongly discourage the practice of electrodessication of anal warts without biopsy as this leads to a missed opportunity to detect high grade dysplasia [8] and will thus not exclude the malignant process. While we were unable to explain the striking observations made in this study we believe that there is a need to investigate the role played by HIV, HPV, genetic predisposition and diet in this variability of presentation. These will be pursued in our unit. Conflict of interest All four authors have no conflict of interest. Author contribution The contribution of the various authors is as follows: Madiba T.E. contributed in study design, data collection, assistance with
first draft, subsequent drafts and final version. Ntombela X.H. contributed in data analysis, first draft and final version. Govender P. contributed in patient follow-up and final version. Sartorius B did statistical analysis and final version. Acknowledgements The authors wish to acknowledge the South African Medical Research Council for providing a developmental grant of R50 000.00 which contributed to the initiation of the anal cancer database from which data for this research project were extracted. Professor S.R. Thomson of the Gastroenterology Department, University of Cape Town, is thanked for providing academic input to the original draft.
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Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
The clinicopathologic spectrum of anal cancer in KwaZulu-Natal Province, South Africa Analysis of a provincial database X.H. Ntombela a, Benn Sartorius c, T.E. Madiba a,*, Poovandren Govender b a b c
Department of Surgery, University of KwaZulu-Natal, Durban, South Africa Department of Oncology, University of KwaZulu-Natal, Durban, South Africa Biostatistics & Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 March 2015 Received in revised form 15 May 2015 Accepted 18 May 2015 Available online 3 June 2015
Background: The occurrence of the considered rare anal cancer has not been documented in the South African context. Patients and methods: Analysis of data extracted from a prospectively collected KwaZulu-Natal anal cancer database for the period 2000–2014. Data analysed included demographics, clinical picture, pathology, treatment and outcome. The study outcome measures were clinicopathologic spectrum, treatment and outcome. Results: The study population comprised 244 patients of mean age 50.1 (SD 14.0) years. The age at presentation was lowest for Black African patients compared to Whites and Indians (p < 0.001) and lower for HIV positive vs HIV negative patients (p < 0.001). Histology was squamous carcinoma in 208 patients (margin 152, canal 56), adenocarcinoma in 34 (all anal canal), neuroendocrine tumour (1) and melanoma (1). Mean age for squamous carcinoma was 48.8 (SD 14.1) years compared to 58.7 years (SD 11.1) for adenocarcinoma. Metastatic disease occurred in 22 patients (9%). Patients received definitive (139), palliative (53) and no (52) oncological therapy. Thirty patients (12%) underwent resection, seven of whom had positive margins. Seventy-six patients (31%) have been confirmed dead. The 5-year survival rate was 33.4% (95% CI: 23.4–44.6%). There was a highly significantly worse prognosis for adenocarcinoma compared to squamous cell carcinoma (p = 0.038). No significant difference was found in survival prospects based on race and tumour location. Conclusion: Squamous carcinoma was more common and presented at a young age. Black African patients and HIV positive patients were younger. Adenocarcinoma was associated with poorer prognosis. Race and tumour location had no influence on survival. ß 2015 Elsevier Ltd. All rights reserved.
Presented at the 9th Congress of the African Organisation for Research and Training in Cancer (AORTIC) in Durban, South Africa on 21–24 November, 2013. Keywords: Anal Anorectal Squamous Carcinoma Adenocarcinoma
1. Introduction Neoplasms of the anus are infrequent [1,2], making up 1–5% of gastrointestinal neoplasms [3–7]. They are classified into anal canal and anal margin tumours [1]. Anal squamous carcinoma is the most common followed by anal adenocarcinoma. The risk factors include human papilloma virus (HPV), smoking, immunosuppression with lower CD4 counts, Herpes Simplex-2 virus and ano-receptive intercourse [1,8–11]. HPV, especially subtypes 16
* Corresponding author at: University of KwaZulu-Natal, Colorectal Unit, Department of Surgery, Private Bag 7 Congella, Durban 4013, South Africa. Tel.: +27 31 260 4219; fax: +27 31 260 4389. E-mail address: [email protected] (T.E. Madiba). http://dx.doi.org/10.1016/j.canep.2015.05.005 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
and 18, with their affinity for the genital epithelium is the main aetiological factor [1,8–17], which causes anal intraepithelial neoplasia and condyloma acuminata, both of which are precursor lesions for anal squamous carcinoma [1,8,10,11,17–19]. Anal canal adenocarcinoma arises from stratified columnar epithelium lining the anal glands [19,20]. Risk factors include chronic fistulae, inflammatory bowel disease, radiation for non-intestinal cancer, and anal intercourse [20]. Anal canal adenocarcinoma can be subclassified into (i) typical colorectal-type adenocarcinoma (CRTA) that occurs proximal to and within the anal transitional zone, and (ii) anal canal adenocarcinoma arising in anal canal mucosa and anorectal fistulae [5]. Little data on anal carcinoma have emanated from South Africa [21,22]. We have analysed data from an on-going anal cancer database for the KwaZulu-Natal (KZN) Province of South Africa.
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533
2. Methods 2.1. Setting The study setting was the Colorectal Unit at the Inkosi Albert Luthuli Central Hospital (IALCH). After histological categorisation all patients with anal cancer are referred to the Multidisciplinary Clinic at IALCH which further stages the patients and makes management recommendations. Treatment delivery logistics are individualised. Follow-up is at the dedicated colorectal oncology clinics situated at IALCH, Addington Hospital and Grey’s Hospitals. The standard curative treatment for anal carcinoma in our centre, regardless of histopathology, is definitive chemo-radiation. Indications for surgical excision are small tumours (2 cm), larger tumours are given chemo-radiation and metastatic disease treated with chemotherapy. The standard protocol utilises external beam radiotherapy to the pelvis to a dose of 45 Gray followed by a tumour boost to 59.4 Gray in 1.8 Gray fractions. An electron boost to the inguinal area [23,24] is indicated for histology/cytology proven inguinal node disease. Concurrent chemotherapy used is weekly intravenous Cisplatin and 5-fluorouracil orally or intravenously. The threshold for concurrent chemotherapy is a CD4 200 in HIV positive patients. A diverting colostomy is performed for obstructive bowel symptoms and for prevention of stool contamination. 2.2. Study design This was an analysis of an on-going anal cancer database which is in the Colorectal Unit of the Department of Surgery, University of KwaZulu-Natal. The dataset analysis included demographic characteristics, clinical presentation, histopathological findings, tumour location and staging, treatment and follow-up. We use the WHO criteria which define anal margin tumours as arising from the skin outside the anal verge and tumours proximal to this landmark are considered anal canal tumours [6,25–27]. 2.3. Patients The data were extracted from the database covering the period 2000–2014. Patients who were referred as anal adenocarcinoma but in whom we could not exclude the possibility of low rectal carcinoma were excluded from the study. Population groups were defined as African, Indian, Coloured and White according to the criteria used by the South African Government. For the purposes of this paper the term ‘‘Black African’’ will be used for the benefit of international readers who may not be familiar with the South African context. In South Africa, ‘‘Coloured’’ is an ethnic label that refers to people of mixed ethnic origin who possess ancestry from Europe, Asia and various Khoisan and indigenous African tribes of Southern Africa. Complete clinical response was defined as disappearance of all target lesions on clinical examination. Complete pathological response was defined as absence of residual tumour or viable tumour cells on histopathological appraisal; intermediate or partial response was defined as an improvement in stage; and poor responders were defined as patients with no change or with persistent lymphadenopathy or metastasis. Ethical approval was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (R057/04). 2.4. Statistical analysis Data were processed and analysed using Stata 13.0 [StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP]. The t-test was employed to identify significant mean differences for continuous variables by dichotomous classifications.
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The one way analysis of variance (ANOVA) was used to compare mean age at presentation across ethnic groups. Pairwise comparisons (between groups) were also performed and adjusted using a Bonferroni correction. The dates of death were identified where possible for patients in this cohort via the Department of Home Affairs. Kaplan–Meier survival curves were constructed and stratified on key characteristics such as ethnicity, tumour location (canal vs margin) and tumour type (adenocarcinoma vs squamous). Survival functions were compared using the log rank test to ascertain if significant differences existed by sub-group. A p-value of <0.05 was deemed statistically significant. Patients who were in poor general condition but whose status data could not be ascertained were presumed dead for the purposes of the study but were not coded as such during the statistical analysis. 3. Results There were 244 patients comprising Africans (183), Indian (35), Coloured (10) and White (16) (Fig. 1). Patient profile is shown in Table 1. The mean age was 50.1 (SD 14.1) years. The peak age was lowest for Black Africans were significantly younger at presentation compared to Indians and Whites respectively by 15.4 and 15.0 years respectively (both p < 0.001) but only marginally significantly younger than Coloured by 6.8 years (p = 0.097). There was a female preponderance of 2:1 for squamous carcinoma and male preponderance of 2:1 for adenocarcinoma. There was no significant difference in age at presentation when comparing Coloured and Indians to Whites. Squamous carcinoma occurred in 208 patients (85%) of mean age 48.8 (SD 14.1). Thirty-four patients (14%) of mean age 58.7 (SD 11.1) years had adenocarcinoma. When comparing age at presentation among the adenocarcinoma group only, Black Africans did not present at a significantly younger mean age, i.e. 59.6 vs 62.4 years in the other ethnic groups combined (pvalue = 0.300). This age gap was however significantly larger for squamous cell carcinoma group only with a mean age of 44.8 years among Black Africans compared to 60.3 years in the other ethnic groups combined (p-value < 0.001). Of 119 patients tested for HIV status 91 patients (mean age 40.1 years [SD 8.6]) tested positive and 28 patients (mean age 53.6 years [SD 10.3]) tested negative. This mean age difference was statistically significant (pvalue < 0.001). Of the 163 patients (67%) that could be staged, the majority were stage II and III (Table 2). Twenty two patients (9%) presented with metastatic disease, the target organs being lungs (10), liver (10), peritoneum (2), bone (1) and pleura (1). Histopathological evidence of HPV or condyloma acuminata was documented in only nine and six patients respectively. Anal margin tumours were more common than anal canal tumours in the whole cohort and in the squamous carcinoma cohort, but all adenocarcinomas arose from the anal canal. Table 3 shows management. Thirty three patients were eligible for surgery, one refused and two did not return after accepting surgery. Of the 30 eligible patients (12%), three underwent resection ab initio and the rest received excision after chemoradiation (Table 3). Seven patients had one or more positive margins (R-1 resection) following wide local excision. There was no tumour at re-resection in one patient. The other six patients were managed with definitive chemo-radiation with resultant complete pathological response in 5 patients and one patient died during subsequent chemo-radiation from advanced HIV disease and complications of chemo-radiation. The rest of the patients had R-0 resections. Of the patients who received chemo-radiation, there was complete clinical response in 34 (14%) patients (including 16 patients with complete pathological response). The reasons for failure to receive treatment in 52 patients are shown in Table 4.
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Paents referred as anal cancer 267 Exclusions (anal canal origin cannot be confirmed) 23
Other • Melanoma = 1 • Neuroendocrine carcinoma = 1
Anal cancer (Confirmed) 244
Squamous carcinoma 208 (85%)
HIV Posive = 84 HIV Negave = 25
HIV posive = 5 HIV negave = 3
Adenocarcinoma 34 (14%)
Canal 34 (100%)
Canal 56 (27%)
Margin 152 (73%)
Fig. 1. Disease and site distribution in patients with anal cancer.
Vital status plus relevant time stamps were known in 150 (61.5%) who were included in the survival analyses (Fig. 2). Seventy six of these individuals died (51.0%); the median survival time (point at which the survivor function reaches 50%) was 20.4 months (95% CI: 12.7–37.8 months). The 25th and 75th percentiles for the survivor function were 8.6 and 76.4 months respectively. The 5-year survival proportion was 33.4% (95% CI: 23.4–44.6%). There was no significant difference in survival prospects when comparing Black Africans to other ethnic groups combined in the whole cohort (p = 0.175), in the adenocarcinoma group (p = 0.840) nor in the squamous cell carcinoma group (p-value = 0.137). There was no significant difference in survival prospects observed by gender (p-value = 0.304) and HIV status (p-value = 0.510). As shown in Fig. 3, there was a significantly worse prognosis (survival) for patients with adenocarcinoma compared to Table 1 Profile of 244 patients with anal malignancy. Parameter
Total n = 244
Squamous carcinoma n = 208
Mean age (SD) Black African Indian Coloured White
50.1 (14.1) 183 35 10 16
48.8 (SD 14.1) 155 29 9 15
Gender Males Females M:F ratio
96 148 1:1.6
HIV status Positive Negative
91 28
Site Anal margin Anal canal
153 (63%) 91 (37%)
Adenocarcinoma n = 34 58.7 (11.1) 26 6 1 1
Other (n = 2) – 2 – – –
72 136 1:2
23 11 2:1
1 1 –
84 25
5 3
– –
152 (73%) 56 (27%)
0 (0.00%) 34 (100%)
1 1
squamous cell carcinoma (p-value = 0.009). No significant difference was found in survival prospects based on tumour location (margin vs canal) (p-value = 0.969). 4. Discussion The study has made a number of observations, the first being variation in the age of presentation. The mean age at presentation of 49 years for squamous carcinoma falls within the reported 42– 58 years [22,28,29] and the female preponderance of 2 to 1 is in Table 2 Staging among patients with anal carcinoma. Stage
Squamous n = 208
Adenocarcinoma n = 34
I II III IV Not staged
8 47 65 20 68
3 9 9 2 11
(4%) (22%) (31%) (10%) (33%)
(9%) (27%) (27%) (6%) (32%)
Table 3 Management of patients with anal carcinoma. Overall Surgery Eligible for surgery Underwent surgery Wide local excision Abdomino-perineal resection No Surgery
Squamous
Adenocarcinoma
Other
33 30 21 9
28 25 20 5
5 5 1 4
– – – –
3
3
0
–
Non-surgical (Oncological) therapy Definitive 139 123 Palliative 53 43 No therapy 52 42
16 9 9
– 1 1
X.H. Ntombela et al. / Cancer Epidemiology 39 (2015) 528–533 Table 4 reasons for not receiving treatment in patients with anal cancer (n = 52). Reason
n
Did not return to Oncology Clinic Poor general condition Complete excision Not referred Refusal of treatment IVC Thrombosis Previous radiotherapy
37 8 2 2 1 1 1
keeping with the literature [3,4,30,31]. Similarly the mean age of 59 years for adenocarcinoma fell within the reported range 50–71 years [20,32] and the reported male preponderance [20] was confirmed in this study. The young age for Black African patients noted in both malignancies, but more pronounced in squamous carcinoma, was surprising and cannot be explained by this study. The younger age at presentation for HIV positive patients confirms previous observations [9,31,33].
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Among squamous cell carcinomas anal margin tumours were almost three times as common as anal canal tumours, whereas all adenocarcinomas arose from the anal canal. The limitations of previous studies have been the tendency to group anal margin and anal canal tumours together or to report on only one or the other [33]. This tendency is not helped by the difficulty in determining the primary location of these tumours [27,34,35]. Clinical documentation by rectal examination is therefore crucial [27,34,35]. Squamous carcinoma was almost six times as common as adenocarcinoma, occurring in 85% which falls within the reported 75–85% [1,26,36,37]. Adenocarcinoma on the other hand occurred in 14% which also falls within the reported 3–19% [4,5,20,26,36–40]. Most patients presented at an advanced state of the disease leading to only 12% of our patients fulfilling the criteria for wide local excision [2,13,16,41]. Likewise the majority of tumours fell in stage II and III for both squamous carcinoma and adenocarcinoma. However, despite the advanced presentation, only 9% presented with metastatic disease, which compares favourably to the reported 10–20% [16,37].
Fig. 2. Survival function of all patients with anal carcinoma.
Fig. 3. Survival function for patients with squamous carcinoma vs adenocarcinoma.
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The 5-year survival of 33% for the whole cohort falls far short of the 40–90% reported in literature [6,25,37,42,43]. Indeed the complete clinical response rate of 14% in this series was much lower than the 60–85% reported in literature [13]. The advanced nature of the disease, poor treatment completion rates, and failure to return for treatment in our setting makes it impossible to reach the goal of eventual resection, complete response to therapy and the management of synchronous and metachronous lymph node metastases [23,24] in the majority of cases. The biological behaviour of the tumours themselves [26,27,40,44] as well as anatomical factors such as close proximity to the anal sphincter, profuse blood supply and an abundant lymphatic drainage with consequent early lymphatic involvement of the deep pelvic nodes [41,44] make cure rates for anal canal carcinoma lower than anal margin tumours. Apart from a more aggressive clinical course and the poor survival prospects which have been noted in this series, the natural history of adenocarcinoma remains unclear [20]. Treatment is generally similar to low-lying rectal cancer [3,32,36,45] with recent evidence suggesting the superiority of abdomino-perineal resection with preoperative chemo-radiation to chemo-radiation alone [20,26,32]. We could identify no discernible difference in survival between anal margin and anal canal tumours in squamous carcinoma but we concede that these results may not be generalizable because of inadequate follow-up. There were some limitations to this study. Poor follow-up and low treatment completion rates were a problem mainly due to socioeconomic reasons. Some patients may have sought healthcare outside of the KZN Province and similarly, some patients captured by this database may not be KZN residents. However, since all patients with anal cancer are referred to the KwaZulu-Natal Teaching Hospitals we assume that our database captures the vast majority of these cases, who present in any KZN hospital. Furthermore, the study only included state hospital patients. Finally we could not verify the vital status of all individuals and this is likely to underestimate mortality in this cohort. Despite these limitations we believe that this paper does provide an important contribution to the understanding of anal cancer and forms the basis for future studies in this field in South Africa. In conclusion, the clinicopathologic spectrum of anal cancer in the KZN Province of South Africa differs from world trends with squamous carcinoma being six times as common as adenocarcinoma and tumour location varying between the two malignancies. Black African patients tend to be younger than the other population groups in respect to both major malignancies. Patients with squamous carcinoma were younger than those with adenocarcinoma and so were those with HIV infection compared to their uninfected counterparts. Adenocarcinoma was associated with poorer prognosis. Race and tumour location had no influence on survival. We strongly discourage the practice of electrodessication of anal warts without biopsy as this leads to a missed opportunity to detect high grade dysplasia [8] and will thus not exclude the malignant process. While we were unable to explain the striking observations made in this study we believe that there is a need to investigate the role played by HIV, HPV, genetic predisposition and diet in this variability of presentation. These will be pursued in our unit. Conflict of interest All four authors have no conflict of interest. Author contribution The contribution of the various authors is as follows: Madiba T.E. contributed in study design, data collection, assistance with
first draft, subsequent drafts and final version. Ntombela X.H. contributed in data analysis, first draft and final version. Govender P. contributed in patient follow-up and final version. Sartorius B did statistical analysis and final version. Acknowledgements The authors wish to acknowledge the South African Medical Research Council for providing a developmental grant of R50 000.00 which contributed to the initiation of the anal cancer database from which data for this research project were extracted. Professor S.R. Thomson of the Gastroenterology Department, University of Cape Town, is thanked for providing academic input to the original draft.
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