
==== Front
World J Exp Med
WJEM
World Journal of Experimental Medicine
2220-315X
Baishideng Publishing Group Inc

jWJEM.v14.i3.eid98525
10.5493/wjem.v14.i3.98525
98525
Review
Anal carcinoma - exploring the epidemiology, risk factors, pathophysiology, diagnosis, and treatment
English KJ. Anal cancer - a scoping review
English Kevan J Department of Medicine, Division of Gastroenterology & Hepatology, Saint George’s University School of Medicine, Saint George 33334, Saint George, Grenada. kenglish@sgu.edu

Author contributions: English KJ wrote the original draft, contributed to conceptualization, writing, reviewing, and editing of the manuscript; The author read and approved the final version of the manuscript.

Corresponding author: Kevan J English, MD, Doctor, Research Scientist, Department of Medicine, Division of Gastroenterology & Hepatology, Saint George’s University School of Medicine, University Centre, Saint George 33334, Saint George, Grenada. kenglish@sgu.edu

20 9 2024
20 9 2024
14 3 9852528 6 2024
15 7 2024
6 8 2024
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
Anal carcinoma is a relatively rare tumor that accounts for approximately 2% of gastrointestinal malignancies and less than 7% of anorectal cancers. Most anal tumors originate between the anorectal junction and the anal verge. Risk factors for the disease include human papillomavirus infection, human immunodeficiency virus, tobacco use, immunosuppression, female sex, and older age. The pathogenesis of anal carcinoma is believed to be linked to human papillomavirus-related inflammation, leading to dysplasia and progression to cancer. Squamous cell carcinoma is the most common type of anal tumor, with an annual incidence of approximately 1 to 2 per 100000 persons. Treatment regarding anal cancer has emerged over time. However, chemoradiation therapy remains the mainstay approach for early localized disease. Patients with metastatic disease are treated with systemic therapy, and salvage surgery is reserved for disease recurrence following chemoradiation. This article aims to provide background information on the epidemiology, risk factors, pathology, diagnosis, and current trends in the management of anal cancer. Future directions are briefly discussed.

Anal cancer
Squamous cell carcinoma
Chemoradiation therapy
Human papillomavirus
Immunosuppression
==== Body
pmc Core Tip: Anal cancer is a rare malignancy, comprising 1%-6% of anorectal tumors. The incidence of anal carcinoma has been steadily increasing worldwide, and diagnosis is often challenging due to the similarities in clinical presentation to benign rectal diseases such as hemorrhoids. Roughly 85% of anal cancers are squamous cell carcinoma, and human papillomavirus infection and immunosuppression are major risk factors for the disease. Chemoradiation is the treatment of choice for early-stage cancer, while systemic therapy is used for metastatic disease. Novel cytotoxic agents in combination with immunotherapy have produced favorable outcomes in patients with advanced disease.

INTRODUCTION

Anal carcinoma is a rare disease entity that accounts for less than 5% of cancers of the intestine[1]. In the general population, the incidence of anal cancer has steadily increased from 1.2 in 1992 up to 1.9 per 100000 persons in the United States alone, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program in 2024[2]. Among anal cancers, squamous cell carcinoma (SCC) is the predominant histological subtype, followed by adenocarcinoma and rarer tumors such as basal cell carcinoma (BCC), melanoma, and small cell carcinoma[3,4].

Treatment of anal tumors has evolved over several decades, with concurrent mechanism identification. The primary choice of management has undergone a radical shift from abdominoperineal resection (APR) to organ-preserving chemoradiation therapy (CRT) and surgery[5]. Furthermore, recent developments using immunotherapy for advanced disease and metastasectomy in selected cases highlight the continuous changes and evolution of disease management[6,7]. In this article, we provide a scoping review of anal carcinoma and its epidemiology, risk factors, pathophysiology, diagnosis, and management.

EPIDEMIOLOGY

Anal cancer is an uncommon tumor that comprises less than 2% of large bowel malignancies and approximately 1%-6% of anorectal tumors[1,3,4]. This cancer has become more prevalent in Western nations such as Australia and the United States, with little to no change in Asian countries and Spain[8]. In the United States, between the period of 1994 to 2000, the incidence of anal cancer almost doubled, with a rate of 2.04 per 100000 in males and 2.06 per 100000 in females, in comparison with the period between 1973 and 1979, where the incidence was 1.06 per 100000 in males and 1.39 per 100000 in females[2,5]. Incidence rates in the United Kingdom and across Europe range from 0.7 to 1.7 per 100000 persons per year[9,10].

In 2020, the global anal cancer incidence was estimated at 0.65 per 100000 persons, with 50865 cases[11]. The worldwide incidence of anal SCC was 8.2, with a lower incidence observed in the male population (0.28 vs 0.53 in females) and a higher proportion observed in Northern and Western Europe, North America, and Oceania[11,12]. The global incidence of anal adenocarcinoma was 0.54 in the same year, with a higher incidence observed in the male population (0.25 vs 0.19 in females) and a higher proportion observed in eastern Asia and northern and sub-Saharan Africa[11,13]. The growing trend of anal cancer is believed to be linked to the rising rates of human papillomavirus (HPV) infection.

RISK FACTORS

The development of anal cancer is linked to multiple risk factors. Social and cultural dynamics over the last few decades have played a significant role in patient exposure and increased rates of anal tumors. The most notable risk factors are as follows.

HPV infection

HPVs are a group of double-stranded circular DNA oncovirus from the Papillomavirdae family, commonly transmitted by mucosa-mucosa or skin-to-skin contact and entering the body by mucosal or cutaneous trauma in the form of oral sex, vaginal, or anal intercourse[14]. The infection is the most common sexually transmitted disease worldwide, with prevalence variation regionally[15]. The lifetime risk of infection at least once among men and women is 50%, and HPV serves as the underlying cause of cervical cancer[14,16,17]. In fact, female patients with cervical cancers are at increased risk for anal cancer[18].

Anal malignancies are often associated with HPV infection, although it is relatively uncommon for most patients with this infection to acquire anal cancer[12,19]. Anal carcinoma is commonly linked to HPV infection, most notably subtype 16[20]. Another high-risk subtype, HPV-18, is found in some anal tumors, but is less common than HPV-16[19,21]. Subtypes 6 and 11 are less likely to become malignant and are commonly found in anogenital warts[22]. Other subtypes, including HPV-31, 33, and 45, have been implicated in a small number of anal cancer cases and have been linked to vulvar, cervical, and vaginal cancers in females, and penile cancer in males[20,23,24]. Verruca vulgaris (common warts) are often associated with the low-risk subtypes (1, 2, 4, and 7), with occasional high-risk subtypes (16 and 18) as a cause[25]. Anal SCC is the most common histopathological subtype, and HPV is implicated in more than 80% of tumor samples[26].

Male circumcision is associated with lower rates of HPV infection and transmission[27,28]. A meta-analysis across 32 studies that analyzed the relationship between male circumcision and HPV infection rates found decreased odds of prevalence of HPV infections [odds ratio = 0.45; 95% confidence interval (CI): 0.34-0.61], reduced incidence rate of HPV infection (incidence rate ratio = 0.69; 95%CI: 0.57-0.83), and increased risk of clearing HPV infections (risk ratio = 1.44; 95%CI: 1.28-1.61) at the glans penis in male subjects[29]. The HPV vaccine and condoms are also implicated in protecting and reducing virus transmission rates[30,31]. However, condoms do not offer complete protection because they do not mask all areas of the body that may be susceptible to infection, such as the anus[30,31].

Human immunodeficiency virus infection

Patients with human immunodeficiency virus (HIV) are considered high risk for anal cancer[32]. Incidence rates of anal carcinoma among HIV-infected individuals are 30 times higher compared to the general population[33]. A cohort study by Silverberg et al[34] that compared the incidence rates among 34189 HIV-infected [55% men who have sex with men (MSM), 19% other men, 26% women] and 114260 HIV-noninfected (90% men) individuals found the unadjusted incidence rate per 100000 person-years to be 131 for HIV-positive MSM, 46 for other HIV-infected men, and 2 for HIV-negative men. HIV-infected women had an anal carcinoma rate of 30 per 100000 person-years, with no cases observed for HIV-noninfected women[34]. The use of highly active retroviral therapy has not reduced the incidence of anal cancer, and a systematic review revealed a continued increase in the incidence of anal carcinoma among HIV-infected women, despite the use of highly active retroviral therapy[35,36].

Tobacco use

Tobacco use is an independent risk factor for anal carcinoma[37]. It is associated with anal cancer disease recurrence and higher mortality rates[37,38]. A study conducted by Phillips et al[39], which measured smoking-related DNA adducts in the anal epithelium among smokers (n = 20) and age-matched life-long non-smokers (n = 16), showed high adduct levels among smokers compared to controls. The authors concluded that tobacco smoke inflicts genotoxic damage in the anal epithelium of smokers as a plausible mechanism for its association with anal cancer.

Chronic immunosuppression not due to HIV

Compromised immune function is associated with increased risk for anal cancer[40]. According to a population-based cohort study conducted in Denmark by Sunesen et al[41], immunosuppression in the form of autoimmune diseases, solid organ transplantation, and hematologic malignancy are all strongly associated with the development of anal carcinoma.

Men who have sex with men

MSM are 20 times more likely to be diagnosed with anal cancer than heterosexual men, with a rate of approximately 40 cases per 100000 people[42]. HIV-infected MSM are up to 40 times more likely to develop anal cancer, resulting in a rate of 80 cases per 100000 people[42,43]. The high incidence is related to significant HPV infection rates[43,44]. Modifiable behavioral factors such as condom and drug use can lower infection rates and cancer incidence[43].

Female sex

Anal cancer has a predilection for females compared to males, most notably due to high HPV infection rates among the sex[45,46]. Several factors, including multiple sexual partners, sex at an early age, and having an uncircumcised sexual partner, all contribute to higher rates of HPV infection and, therefore, high rates of anal cancer compared to their male counterparts[45-47].

Older age

Anal cancer is rare in people younger than 35 and is mainly found in older adults[48,49]. The development of anal carcinoma in older patients is primarily reflected by the accumulation of cell DNA damage over time[50].

ANATOMY

The anal canal (Figure 1) is the terminal portion of the alimentary tract that extends from the anorectal junction to the anal margin[51]. The upper portion of the canal derives from the dorsal section of the cloaca (endoderm), and the lower part is derived from the proctodeum (ectoderm)[51,52]. The canal measures approximately 4 cm and is continual with the rectum at the anorectal junction that forms an angle (anorectal angle) at the levator ani[51-53]. The muscular layer of the canal shapes the internal and external anal sphincters, and the tube contains longitudinal folds of mucosa that join inferiorly to make semicircular anal valves[53,54]. These valves form the pectinate (dentate) line, which demarcates the superior two-thirds of the anal canal from the inferior one-third[55]. The pectinate line is a watershed area that varies in neurovascular supply[55,56]. The epithelium above this line is columnar, while below is a transition zone lined by nonkeratinized stratified squamous epithelium known as the anal pecten[57]. Further below, the anal pecten ends at the anocutaneous (white) line, where the epithelium resembles true skin (i.e. keratinized stratified squamous with sebaceous glands and hair)[57,58].

Figure 1 Image depicting parts of the large bowel. The anal canal is labeled as the terminal portion of the rectum.

The anal canal above the pectinate line receives blood supply from the superior rectal artery (branch of the inferior mesenteric artery), median sacral arteries, and anastomosing branches from the middle rectal artery[55,56,59]. The venous drainage anastomoses with the rectal venous plexus and, above the line, drains from the superior rectal vein to the inferior mesenteric vein (portal venous system)[57-60]. Below the dentate line, the middle and inferior rectal veins drain to the internal pudendal vein, a tributary of the internal iliac vein[58-60]. Lymph drains primarily to the internal iliac nodes above the line, while inferiorly, it drains to the superficial inguinal nodes[60,61]. Above the pectinate line, the anal canal receives visceral innervation via the inferior hypogastric plexus[62]. As a result, the superior portion of the canal is susceptible to stretching[62,63]. Below the line, the canal receives somatic innervation through the inferior rectal branches of the pudendal nerves and, consequently, is sensitive to pain, temperature, and touch[63,64].

PATHOPHYSIOLOGY

Integration of HPV double-stranded DNA into the host cell genome facilitates the expression of viral oncoproteins E6 and E7, promoting tumor oncogenesis of anal SCC[65]. These proteins express stimulatory properties, leading to a complex inflammatory progression to invasive cancer[65,66]. During integration, a destruction of a segment of the E2 domain of the viral genome occurs in the DNA of the infected cells, which leads to a loss of suppressor function of the E2 protein[65-67]. Due to this loss of activity, E6 and E7 proteins have increased expression with stimulatory properties, promoting invasion and keratinocyte immortalization[65-68].

HPV-related neoplasm requires E6 and E7 expressions to establish and maintain a transformed state[67,68]. Within this environment, the E7 complex interacts with the retinoblastoma protein, and E6 binds and inactivates tumor suppression protein p53[67-69]. This complex interplay serves as the primary mechanism for HPV-related anal SCC[65-69]. HIV-associated anal cancer is believed to be related to microsatellite instability, leading to the progression of invasive carcinoma[70].

IMMUNIHISTOCHEMISTRY

Regarding immunohistochemistry (Table 1), SCC express cytokeratin (CK) 5/6, CK 13/19, pan CK antibody (AE1/AE3), and p63 protein[66-71]. The presence of the p63 protein on immunohistochemistry is highly specific for anal SCC[68-71]. Adenocarcinoma of the anal gland, in contrast, commonly expresses CK 7/20 (+/-)[67-71]. Adenoid cystic tumors are usually CK 7+, and melanocytic markers (i.e. S-100, human melanoma black-45, and Melan-A) are positive in melanomas[72,73]. Neuroendocrine tumors are positive for neuroendocrine markers (i.e. chromogranin A and serum neuron-specific enolase), and lymphoid cancers express lymphoid markers[74,75]. Perianal Paget disease commonly expresses CK 7 and gross cystic disease fluid protein 15[76]. Paget disease with associated anorectal cancer is typically CK 20+[76].

Table 1 Immunohistochemistry markers for anal cancers

Tumor markers	Squamous cell carcinoma	Anal adenocarcinoma	Melanoma	Basal cell carcinoma	Neuroendocrine	Paget primary	Paget secondary	
AE1/AE2	+	+	-	+	+	+	+	
Ber-EP4	-	+	-	+	-	+	+	
CAM5.2	+	+	-	Nonspecific	+	+	+	
CDX-2	-	Mostly-	-	-	-	-	+	
CEA	-	-	-	-	-	+	+	
Chromogranin	-	-	-	-	+	-	-	
CK5/6	+	-		+	-	-	-	
CK7/20	-/-	+/Mostly-	-	-/-	-/-	+/-	Mostly-/+	
GCDFP-15	-	-	-	-	-	+	-	
HMB45	-	-	+	-	-	-	-	
MELAN-A	-	-	+	-	-	-	-	
Mucin	-	+	-	-	-	+	+	
p63	+	-	-	+	-	-	-	
S100	-	-	+	-	-	-	-	
Synaptophysin	-	-	-	-	+	-	-	
Vimentin	-	-	+	-	-	-	-	
AE1: Anti-pan cytokeratin AE1; Ber-EP4: Anti-epithelial cell adhesion antibody; CAM5.2: Anticytokeratin CAM5.2; CDX-2: Caudal-related homeobox transcription factor 2; CEA: Carcinoembryonic antigen; CK5/6: Cytokeratin 5/6; GCDFP-15: Gross cystic disease fluid protein 15; MELAN-A: Melanoma antigen recognized by T cells.

PRECURSOR LESIONS

Anal cancer commonly originates at the squamocolumnar junction and arises from precancerous lesions termed anal intraepithelial neoplasia (AIN)[77]. These lesions are frequently called squamous intraepithelial lesions, and are grouped according to their grade and degree of dysplasia[77,78]. AIN 2/3 are commonly classified as high-grade squamous intraepithelial neoplasia and are found in most patients with anal cancer[77,78]. Consequently, patients who are at increased risk for AIN 2/3, which includes MSM, solid organ transplant recipients, immunocompromised patients, and women with any history of vulvar, vaginal, and cervical cancer should undergo regular screening with anal cytology[77-79].

AIN has been found to be biologically similar to cervical intraepithelial neoplasia (CIN) due to its common association with HPV, which is found in most cancers of the anus and cervix[80]. Current modes of treatment include topical medications, laser therapy, fulguration, and ablative techniques in the form of infrared coagulation, surgical excision, and thermal ablation. Topical treatment options include imiquimod, 5-fluorouracil (5-FU), and trichloroacetic acid[81].

PATHOLOGY

The World Health Organization has classified tumors of the anal canal into intraepithelial and invasive neoplasms that are further divided into epithelial and nonepithelial tumors (Table 2). The most notable ones are as follows.

Table 2 World Health Organization histological classification of anal tumors

Tumor type	Characteristics	
Epithelial tumors		
    Premalignant lesions	Intraepithelial neoplasia (dysplasia), low-grade	
Intraepithelial neoplasia (dysplasia), high-grade	
Bowden disease	
Perianal squamous intraepithelial neoplasia	
Paget disease	
    Carcinoma	Squamous cell carcinoma	
Adenocarcinoma	
Mucinous adenocarcinoma	
Small cell carcinoma	
Undifferentiated carcinoma	
Others	
Nonepithelial tumors	Leiomyoma	
Gastrointestinal stromal tumor	
Myofibroma	
Carcinoid tumors	NA	
Melanoma	NA	
Secondary tumors	Direct extension from adjacent organs: Rectal, cervical, and prostate carcinoma	
NA: Not applicable.

Paget disease

Anal Paget disease commonly involves the perianal skin and is found in apocrine-rich areas[76,82]. Malignant cells produce mucus, and perianal spread is characterized by the proliferation of pagetoid cells within the epithelium[76,82,83]. Tumor cells on histological appearance often show large cells with giant nuclei and pale cytoplasm[82-84]. Pagetoid cells also occasionally acquire a signet ring appearance[82-85].

SCC

More than 80% of anal cancers are SCC[3,4]. These tumors arise primarily at the transformation zone between the columnar and squamous epithelium of the canal[3,4,33-36]. The cells that constitute these tumors have varying features, with some having giant pale eosinophilic characteristics and others having no areas of keratinization[86]. Other cells facilitate tumor nests (tumor-cell islands) that may appear with central keratinization and intercellular bridges or peripheral palisading on histology[86,87]. SCC tumors lack a myoepithelial layer within and around the basement membrane, and may resemble adnexal, skin, and salivary gland neoplasms[86,87].

Adenocarcinoma

Adenocarcinoma accounts for approximately 5% to 10% of cancers of the anal canal[4,88,89]. This histological tumor type primarily originates from the anal epithelium and includes primary adenocarcinomas that arise in the mucosa, anal glands, and fistula[89,90]. These tumors may also appear as small, ulcerated lesions near the anal duct, and possess some association with ulcerative colitis, Crohn’s, and Paget’s disease[89-92]. Tumors are commonly mucin-positive and are treated similarly to rectal cancer[4,89-92].

BCC

BCC, the rarest type of anal cancer, accounts for less than 0.2% of anal neoplasms and predominantly affects the skin around the anal region[93,94]. It arises from perianal lesions and tends to remain local[93,94]. Anal BCC shares similar histological features with a known variant of SCC[94]. This variant, termed SCC with basaloid features, tends to show nests of oval cells with varying ratios of eosinophilic to basophilic cytoplasm, assorted mitotic activity, and peripheral nuclear palisading[94-96]. Perianal BCC has a better prognosis than SCC with basaloid features, and the nodular subtype is the predominant histologic type found in most cases[94-97].

Carcinoid tumors

Carcinoid tumors of the anal canal (rectal carcinoid) are rare and account for 1% to 1.3% of all anal cancers[98]. These tumors are commonly asymptomatic and are found incidentally on routine colonoscopy[98,99]. Rectal carcinoids are of neuroendocrine origin and are well differentiated[99]. Due to this fact, they are associated with a favorable prognosis, although they can metastasize[98,99]. This ability to spread is more likely with a tumor size greater than 10 mm and atypical features[99,100]. On histological appearance, these tumors show a trabecular growth pattern with nest- or rose-like structures[100,101]. Immunohistochemistry markers for neuroendocrine tumors include chromogranin A, synaptophysin, and neuro-specific enolase. However, the most sensitive marker for rectal carcinoids is SABT2, which is positive in more than 85% of rectal carcinoids[101,102].

Melanoma

Anal melanomas are rare and account for only 1% of all anorectal malignant tumors[103]. These are often acro-lentiginous and are usually found as pigmented ulcerated lesions[103,104]. Melanomas of the anal canal are typically aggressive and exhibit poor prognosis due to the lack of symptoms and late disease presentation[105]. The histological types of anal melanoma include lymphoma-like, spindle-cell, epithelioid, and pleomorphic[103-105]. The spindle-cell anal melanoma can be easily misdiagnosed as a gastrointestinal stromal tumor[105,106]. For this reason, analysis of immunohistochemistry is vital for the correct diagnosis[105]. Anal melanoma most commonly expresses S-100 on immunohistochemistry and c-Kit positive in over 70% of cases[103-106].

DIAGNOSTIC WORK-UP

Most patients with anal cancer typically present with symptoms resembling benign diseases such as fissures and hemorrhoids[4,107]. Patients may complain of abdominal/rectal pain and bleeding on toilet paper after wiping[4,107]. In other cases, patients may be asymptomatic[4,107,108]. A complete history and physical examination are crucial to prognosis as patients with early diagnosis have better clinical outcomes[108-110]. Physicians should have a high index of clinical suspicion for patients presenting with symptoms resembling benign disease, and possess a low threshold for imaging studies and biopsy of suspected lesions[107-111]. Imaging modalities used in the diagnosis of anal cancer are as follows.

Three-dimensional endoanal ultrasound

Three-dimensional endoanal ultrasound (3D-EAUS) is a valuable tool that allows a detailed evaluation of the anatomy and diseases of the anal canal[112]. It can accurately assess the depth of invasion of cancer into the anal sphincter complex and gauge tumor response to CRT[112,113]. 3D-EAUS is easy to perform and reproduce with high diagnostic accuracy[112-114]. A large study by Reginelli et al[114], which compared the diagnostic performance of 3D-EAUS and magnetic resonance imaging (MRI) in the detection of anal cancer, found a detection rate of 100% using ultrasound compared to 93.1% for MRI.

Computed tomography

Computed tomography (CT) scan is a valuable tool in the diagnosis of anal cancer[115]. Contrast-enhanced CT scan may visualize an anal tumor as a hypo-attenuated necrotic mass[5,115]. CT scan is also helpful in evaluating lymph node metastases and distant metastatic disease[115,116]. Although useful in the diagnostic work-up of anal cancer, recent guidelines have geared toward better imaging modalities such as MRI, positron emission tomography (PET), and PET/CT scan[115-117]. A systematic review and meta-analysis by Mahmud et al[117] comparing PET/CT or PET with standard imaging studies showed a 67% sensitivity to detect primary tumors with CT scan alone compared to 99% for PET or PET/CT scan.

Phased-array MRI

Phased-array MRI is a useful tool for the diagnosis and staging of anal cancer[118]. In 2014, the European Society of Medical Oncology guidelines proposed that pelvic MRI should be mandatory in the diagnostic work-up of anal cancer, citing superior soft-tissue resolution compared to conventional (standard) imaging modalities (i.e. 3D-EAUS and CT scan)[119]. MRI detects neoplastic nodes, the extent of tumor infiltration into nearby organs, and the circumferential tumor extent[119,120]. It is greater than 90% sensitive in identifying anal carcinoma, and provides specific detail regarding the position of the tumor[120].

PET/CT scan

PET/CT scan with 18F-fluorodeoxyglucose (FDG-PET/CT) is an accurate and effective imaging modality for the detection and staging of anal cancer[121]. PET detects tumors based on molecular alterations and plays a vital role in post-treatment restaging of anal cancer patients[121,122]. FDG-PET/CT provides details regarding crucial markers for staging, such as the size of the tumor, the lymph nodes involved, and the detection of metastasis[121-123]. Of note, FDG-PET/CT is particularly sensitive for localized tumors less than 2 cm compared to standard imaging modalities[5,121-123].

STAGING

The tumor, node, and metastasis (TNM) classification system (Table 3) published by the American Joint Committee on Cancer is used to stage anal cancer[124]. This system is based on three essential factors.

Table 3 Tumor, node, and metastasis classification system for anal cancer

Primary tumor	Characteristics	
TX	Primary tumor cannot be assessed	
T0	No evidence of primary tumor	
Tis	HSIL (previously termed carcinoma in situ, Bowden disease, anal intraepithelial neoplasia II-III, high-grade anal intraepithelial neoplasia)	
T1	Tumor ≤ 2 cm in greatest dimension	
T2	Tumor > 2 cm but ≤ 5 cm in greatest dimension	
T3	Tumor > 5 cm in greatest dimension	
T4	Tumor of any size invades adjacent organ(s) (e.g., vagina, urethra, bladder)	
Lymph nodes		
NX	Regional lymph nodes cannot be assessed	
N0	No regional lymph node metastasis	
N1	Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes	
N1a: Metastasis in inguinal, mesorectal, or internal iliac lymph nodes	
N1b: Metastasis in external iliac lymph nodes	
N1c: Metastasis in external iliac with any N1a nodes	
Metastasis		
M0	No distant metastasis	
M1	Distant metastasis	
HSIL: High-grade squamous intraepithelial lesion.

Tumor

Tumor (T) describes the extent of the primary tumor and its size in relation to growth into nearby structures or organs[124,125]. A larger value after the T reflects a bigger tumor size and growth into nearby structures[125]. TX indicates that the primary tumor cannot be assessed due to lack of information, and T0 means there is no evidence of a primary tumor[120,125]. T1 indicates tumor sizes less than 2 cm in the greatest dimension, T2 reflects tumor size between 2 and 5 cm, and T3 indicates tumor sizes more than 5 cm[124]. Lastly, T4 represents a tumor of any size that invades adjacent organs[120,124,125].

Regional lymph node

Lymph node (N) describes the spread of cancer to nearby lymph nodes[120,124]. NX indicates that regional lymph nodes cannot be assessed due to insufficient information[120,124]. N0 means no regional lymph node metastasis, and N1 indicates metastasis to nearby lymph nodes, such as the internal or external iliac nodes[120,124,125].

Distant metastasis

Metastasis (M) describes the spread of cancer to distant lymph nodes or organs[124]. M1 represents distant metastasis[120,124]. Anal cancer is staged based on TNM status (Table 4)[124]. Stage I and II are localized diseases[120,124]. Stage III indicates locally advanced cancer and stage IV represents metastatic disease[120,124,125].

Table 4 Anatomic stage of anal cancer

Stage	T	N	M	
0	Tis	N0	M0	
I	T1	N0	M0	
IIA	T2	N0	M0	
IIB	T3	N0	M0	
IIIA	T1-T2	N1	M0	
IIIB	T4	N0	M0	
IIIC	T3-T4	N1	M0	
IV	Any T	Any N	M1	
M: Metastasis; N: Node; T: Tumor.

TREATMENT OF LOCOREGIONAL ANAL CANCER

Anal SCC was predominantly treated with radical resection before the 1970s[121-125]. This procedure involved the removal of the distal colon, rectum, anus, and anal sphincter complex through perineal and anterior abdominal wall techniques, which formed a permanent colostomy[126]. This procedure resulted in 5-year overall survival (OS) rates between 40% and 70% and a surgical mortality rate of 3%[127].

A shift in the approach to the treatment of anal SCC came when researchers at Wayne State University in 1974 investigated a therapeutic regimen for SCC consisting of chemotherapy and radiation[128]. This protocol (the Nigro regimen) consisted of 5-FU, fluoropyrimidine, and mitomycin-C (MMC) with a concurrent dose of gray[128]. The results were promising, as the first three patients treated with the regimen experienced complete tumor regression[128-130]. A subsequent follow-up study was conducted in which patients treated with the protocol only underwent a salvage APR if there was clinical evidence of disease residue[130]. The 5-year OS rate was 67%, and the 5-year colostomy-free survival rate was 59%. A total of 84% of patients in the follow-up study showed complete response to CRT.

These results sparked further investigation into the role of CRT in the management of anal cancer, and several randomized controlled trials (RCTs) have since been done to cement CRT as the definitive treatment for anal cancer[131-135]. These trials have investigated the benefits of CRT vs radiotherapy (RT) alone, sequencing, and optimal chemotherapy protocols with simultaneous RT, and high-dose RT.

CRT vs RT

The United Kingdom Coordination Committee on Cancer Research phase 3 RCT, which involved 585 patients with anal SCC, compared RT to CRT[136]. The trial concluded that the use of 5-FU and MMC in combination with RT resulted in a 46% risk reduction in the local failure rate [relative risk (RR) = 0.54, 95%CI: 0.42-0.69], with a local failure rate of 36% with CRT vs 59% with RT. CRT was also associated with a significant reduction in cancer mortality, citing a 3-year anal cancer mortality of 39% with RT compared to 28% with CRT (RR = 0.71, 95%CI: 0.53-0.95). A RCT by the European Organization for Research and Treatment compared the use of RT or CRT (5-FU and MMC) in patients with anal cancer[135]. CRT was found to be associated with more improvement in local and regional control rates. A 32% difference in colostomy-free time was observed between the two groups, and an 18% difference in local and regional failure rates.

Chemotherapy protocol and sequence

MMC, although associated with toxicity, is an essential drug in chemotherapy regimens[137]. A phase 3 intergroup RCT that compared combined 5-FU and MMC to 5-FU alone showed a favorable colostomy-free rate (71% vs 59%, P = 0.014) and disease-free survival (DFS) (73% vs 51%, P = 0.0003) with combination chemotherapy at 4 years[134]. The addition of MMC to 5-FU, however, was associated with a greater risk of high-grade toxicity (23% vs 7%, P ≤ 0.001). Two RCTs then compared MMC to combined cisplatin and 5-FU, which revealed conflicting results[132,133]. The United States gastrointestinal (GI) intergroup radiation therapy oncology group (RTOG) 98-11 phase 3 trial randomized anal cancer patients to CRT including 5-FU and MMC vs two induction cycles of 5-FU and cisplatin followed by CRT including 5-FU and cisplatin[133]. The 5-FU and MMC combinations were associated with better 5-year DFS and OS than the 5-FU and cisplatin combinations. DFS was 68% for 5-FU and MMC compared to 58% for 5-FU and cisplatin at 5 years; OS was 78% and 71%, respectively. The overall severity of toxicity was similar between the treatment arms. The results of RTOG 98-11 continued to support the use of combined MMC and 5-FU with RT for patients with anal SCC.

A 2 × 2 factorial trial, ACT II, conducted by the United Kingdom Coordination Committee on Cancer Research, also investigated the substitution of MMC with cisplatin[132]. Patients with anal cancer were first randomized to receive CRT with either MMC or cisplatin, followed by randomization to receive adjuvant therapy with 5-FU and cisplatin or observation. Both arms had similar complete response rates at approximately 90%. Toxicity rates were about 70%, with comparable OS and DFS. The progression-free survival was 74% for maintenance chemotherapy vs 73% for no maintenance at 3 years. The results of the ACT II and RTOG 98-11 trials have together solidified 5-FU and MMC as the standard of care for managing locoregional anal SCC[132,133]. Several studies have been published recently, which highlight that capecitabine and MMC appear to have equal efficacy to infusional 5-FU and MMC in the treatment of locally advanced anal SCC[138-140].

Intensity modulated RT

Intensity modulated RT (IMRT) is the preferred method for RT in the treatment of locoregional anal SCC[141]. This modality utilized variations in radiation intensities that facilitate more precise mapping of tumor targets and spares nearby structures[141,142]. The goals of treatment are to optimize radiation dose and duration to limit toxicity and locoregional recurrence[141,143]. IMRT is preferred over conventional RT based on the results of a phase two multicenter prospective RCT (RTOG 0529) that compared 3D-conformal RT to dose-painted IMRT[144]. The primary endpoint was a decrease in the combined rate of grade 2 + GI and genitourinary adverse events by at least 15% compared to previous results in the RTOG 98-11 trial[133,144]. Significant reductions in grade 2 hematologic, grade 3 dermatologic, and GI toxicity were observed in the IMRT group. However, despite the improved toxicity profile, retrospective studies have failed to show a difference in survival outcomes between cancer patients who received standard RT vs IMRT[145,146].

Surgery

In locoregional anal cancer, CRT should be exhausted as the number one option for treatment due to better outcomes historically vs surgery[147,148]. APR and the formation of end colostomy should be reserved for salvage therapy in patients with tumor progression, disease recurrence following CRT, or patients who are ineligible for definitive CRT[148,149]. The exception to CRT as a first-line treatment for locoregional cancer is early-stage (stage I disease) perianal disease excluding the anal sphincter and superficially invasive anal SCC, for which a wide local excision is a treatment option[126,141].

TREATMENT OF RECURRENT AND METASTATIC DISEASE

Locoregional disease recurrence

Recurrent disease is defined as tumor discovery after 6 months post-CRT and a residual tumor if present within 6 months of treatment[150,151]. The average time for tumor recurrence of anal cancer is less than 12 months after CRT, and suspicion should prompt a detailed work-up with imaging and biopsy of all lesions to exclude metastasis[150]. The goal of management is to attain negative tumor margins, and patients are treated with APR with a permanent end colostomy and the creation of a sizable pelvic floor defect[151,152]. Salvage APR results in the control of disease locally in approximately 60% of all cases[151-153]. Salvage surgery also has a 5-year OS rate between 30 and 60%[154,155]. RT or brachytherapy following CRT has limited use in the management of local disease recurrence[141,156]. Similarly, the use of immunotherapy or systemic chemotherapy has limited data, and further research needs to be done to support use, although some articles have justified the use of MMC in the definitive management of local disease recurrence despite higher toxicity levels[141,157,158].

Metastatic disease recurrence

Systemic therapy is the current standard of treatment for patients with metastatic cancer or metastatic disease recurrence[159]. More than 10% of patients commonly experience distant relapse following CRT, and less than 10% of patients with de novo metastatic disease[159,160]. This first-line therapy is a platinum-based doublet regimen with either cisplatin or carboplatin and 5-FU or paclitaxel[161,162]. The phase 2 InterAACT trial randomized cancer patients with advanced anal SCC to treatment with either carboplatin and weekly paclitaxel or infusional 5-FU and cisplatin. Results suggested improvements in OS (20 months vs 12 months, P = 0.01) with the carboplatin/paclitaxel regimen and a favorable toxicity profile (36% vs 62% adverse event rate, P = 0.02) in comparison to the cisplatin and 5-FU regimen[163]. This trial established carboplatin/paclitaxel as the primary therapy for patients with metastatic disease and disease recurrence, and remains the standard of treatment for patients in the United States. Other studies have been done on regimens such as docetaxel, cisplatin, and 5-FU (DCF) and 5-FU, leucovorin, and cisplatin (FOLFCIS)[164,165]. These studies have shown promising results, making DCF and FOLFCIS good alternative options for patients with metastatic disease.

SURVEILLANCE FOLLOWING PRIMARY TREATMENT

According to guidelines from the National Comprehensive Cancer Network, patients should be re-evaluated with a digital rectal examination and anoscopy 8 weeks to 12 weeks after completion of CRT[166]. Following evaluation, patients should be classified according to whether they have complete remission of the disease, persistent disease, or progressive disease.

Patients with complete remission should have digital rectal examinations and lymph node exams every 3 months to 6 months for 5 years after treatment. Anoscopy is also recommended every 6 months to 12 months for 3 years post-treatment. Imaging is suggested for stage II and III anal cancers in complete remission every year for 3 years and takes the form of a CT of the chest, abdomen, and pelvis with contrast or a CT of the chest without contrast, plus an MRI of the abdomen and pelvis with contrast.

Patients who are found to have remaining cancer that has not grown, or spread are classified as having persistent disease. Watchful waiting for a maximum of 6 months can be considered, as some anal cancers take longer to respond to treatment. Following this period, the patient should be reassessed, and then be categorized as progressive disease if there is persistent cancer or worsening following this period. If the cancer goes into remission, surveillance follows the complete remission protocol.

Lastly, if a follow-up examination 8 weeks to 12 weeks after CRT finds that the cancer has grown or spread, the patient should be classified as having progressive disease, and a biopsy should be performed. If biopsy results confirm progression, imaging (CT scan with contrast or non-contrast CT and MRI) should be done to assess the location and spread of the disease, and to determine treatment.

PREVENTION AND SCREENING

Anal cancer is a rare disease that accounts for approximately 0.5% of all new cancers in the United States and less than 3% of cancers of the intestine[4,167,168]. While the incidence of anal cancer is too low for general population screening, there is a specific subset of groups with increased risk for AIN 2/3, including HIV-positive patients, MSM, solid organ transplant recipients, women with any history of cervical, vulvar, or vaginal cancer, and immunocompromised patients not due to HIV[167-169]. The high burden of anal cancer in these populations is partly attributed to the higher prevalence of HPV infection[169,170]. As a result, these patients should be regularly screened with anal cytology (also termed anal pap testing, using a Dacron swab inserted into the anal canal)[171,172]. Patients with an abnormal pap test should then undergo frequent surveillance with high-resolution anoscopy[173,174].

A single-center prospective study that evaluated the diagnostic accuracy of early anal cancer detection in high-risk patients (AIN-2+) using combined anal pap testing and high-resolution anoscopy showed that the diagnostic accuracy of anal cancer improves when the two tests are combined in comparison to anal pap testing alone[175].

HPV vaccination is a proven and cost-effective approach to the prevention of anal cancer in the younger population[176-178]. The administering of the 9-valent HPV vaccine to children could effectively prevent almost all anal tumors (primary prevention of anal SCC)[177]. Furthermore, the vaccine may help prevent AIN 2/3 and possible progression to SCC in high-risk groups[176-178]. This is true for populations that include MSM, HIV-positive men and women, solid organ transplant recipients, and women with a history of cervical cancer or CIN 3[177,179].

FUTURE DIRECTIONS

Although significant progress has been made with respect to the diagnosis and management of anal cancer, knowledge gaps still exist. More research is needed to address the prevention of anal carcinoma, especially in patients who are deemed high risk. Additionally, research focusing on minimizing the adverse effects of CRT in patients with early disease is crucial to improving the quality of life and survivorship care. Immunotherapy is an active area of research in the treatment of anal SCC. Therapeutic agents targeting programmed cell death receptor 1 have been shown to be effective against other HPV-related cancers, such as cutaneous SCC of the skin[6,180]. Due to this fact, several clinical trials are currently ongoing to investigate the efficacy of anti-programmed cell death receptor 1 agents in both metastatic and localized anal cancer (Table 5). Investigators are also currently assessing the role of monoclonal antibodies for use in anal cancer after the success of anti-epidermal growth factor receptor (anti-EGFR) therapies for cancers of the head and neck[181-183]. Cetuximab, an EGFR inhibitor combined with an interleukin-15 receptor superagonist, is currently being studied in the treatment of advanced SCC[184].

Table 5 Ongoing clinical trials investigating the use of anti-programmed cell death-1 agents in anal squamous cell carcinoma

NCT number	Official title	Interventions	Study type	Phase	Status	Location	
NCT04719988	Ezabenlimab (BI 754091) and mDCF (Docetaxel, Cisplatin, and 5-fluorouracil) Followed by Chemoradiotherapy in Patients With Stage III Squamous Cell Anal Carcinoma. A Phase II Study	Biological: Blood sample collection	Interventional	Phase 2	Active	France	
Procedure: Biopsy	
NCT04894370	Spartalizumab, mDCF (Docetaxel, Cisplatin, and 5-fluorouracil) and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. A Phase IIA Study	Biological: Sample collection	Interventional	Phase 2	Recruiting	France	
NCT04708470	A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers	Drug: Bintrafusp Alfa	Interventional	Phases 1 and 2	Recruiting	United States	
Drug: NHS-IL12	
Drug: Entinostat	
NCT04432597	Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV-Positive Cancers	Biological: PRGN-2009 (Phase I)	Interventional	Phases 1 and 2	Active	United States	
Biological: PRGN-2009 (Phase II)	
Biological: M7824	
Diagnostic test: MRI	
Diagnostic test: Bone scan	
Diagnostic test: CT scan	
Diagnostic test: Brain CT	
Diagnostic test: Brain MRI	
Procedure: Biopsy (Phase I)	
Procedure: Biopsy (Phase II)	
NCT05544929	A Phase I, Open-label, Multicenter Study of KFA115 as a Single Agent and in Combination With Pembrolizumab in Patients With Select Advanced Cancers	Drug: KFA115	Interventional	Phase 1	Recruiting	United States	
Drug: Pembrolizumab	
NCT04357873	Phase II Basket Trial Evaluating the Efficacy of a Combination of Pembrolizumab and Vorinostat in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma	Drug: Pembrolizumab; vorinostat	Interventional	Phase 2	Active	France	
NCT04802876	Efficacy of Tislelizumab and Spartalizumab Across Multiple Cancer-types in Patients With PD1-high mRNA Expressing Tumors Defined by a Single and Pre-specified Cutoff	Drug: Spartalizumab	Interventional	Phase 2	Recruiting	Spain	
Drug: Tislelizumab	
CT: Computed tomography; HPV: Human papillomavirus; mDCF: Modified DCF regimen; MRI: Magnetic resonance imaging; PD1: Programmed cell death 1; PD-L1: Programmed cell death ligand 1; TGF: Transforming growth factor.

Additional novel therapies, including triplet immunotherapy and HPV-targeted vaccines, are presently being studied in clinical trials. Pembrolizumab, in combination with a bifunctional EGFR/transforming growth factor β fusion protein, is actively being investigated in the phase I KEYNOTE-E28 clinical trial in patients with recurrent or metastatic SCC[185]. UCPVax, derived from telomerase, is a CD4 helper T-inducer vaccine currently being studied in combination with immune checkpoint inhibitors for HPV-positive malignancies, including SCC, in the VolATIL trial[186]. Lastly, circulating tumor DNA is an emerging tool being investigated in the current NOAC9 phase 2 clinical trial[187]. This trial compares standard surveillance vs HPV-positive circulating tumor DNA-guided image follow-up to assess for improved detection of early treatment failure or recurrence.

CONCLUSION

Although anal cancer is rare in the general population, its incidence has been steadily increasing over the past decade. SCC is the predominant subtype of anal cancer and is HPV-mediated in most cases. The overall management of anal cancer has evolved over the past few decades. Currently, CRT, with the use of 5-FU and MMC, is the standard treatment for patients with early and locoregional disease. Wide local excision is a treatment option for a small subset of patients with stage I disease. Recurrence occurs in more than 20% of patients and requires salvage APR. A platinum-based doublet regimen is the mainstay of treatment for patients with metastatic disease. Immunotherapy is a treatment option for disease progression, and HPV vaccination is an effective long-term approach to limiting HPV-related anal cancer, especially in younger patients. Physical examination, in conjunction with routine screening, may increase detection of anal cancer in high-risk patients, which ultimately may reduce patient morbidity and mortality.

Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Corresponding Author’s Membership in Professional Societies: American College of Physicians

Specialty type: Medicine, research and experimental

Country of origin: Grenada

Peer-review report’s classification

Scientific Quality: Grade C

Novelty: Grade C

Creativity or Innovation: Grade C

Scientific Significance: Grade B

P-Reviewer: Ding MX S-Editor: Wang JJ L-Editor: Filipodia P-Editor: Yu HG
==== Refs
1 Young AN Jacob E Willauer P Smucker L Monzon R Oceguera L Anal Cancer Surg Clin North Am 2020 100 629 634 32402305
2 National Cancer Institute SEER*Explorer: An interactive website for SEER cancer statistics [Internet] Surveillance Research Program, National Cancer Institute; 2023 Apr 19. Data source(s): SEER Incidence Data, November 2022 Submission (1975-2020), SEER 22 registries. [cited 20 May 2024]. Available from: https://seer.cancer.gov/statistics-network/explorer/
3 Grulich AE Poynten IM Machalek DA Jin F Templeton DJ Hillman RJ The epidemiology of anal cancer Sex Health 2012 9 504 508 22958581
4 Morton M Melnitchouk N Bleday R Squamous cell carcinoma of the anal canal Curr Probl Cancer 2018 42 486 492 30497849
5 Salati SA Al Kadi A Anal cancer - a review Int J Health Sci (Qassim) 2012 6 206 230 23580899
6 Dhawan N Afzal MZ Amin M Immunotherapy in Anal Cancer Curr Oncol 2023 30 4538 4550 37232801
7 Ciardiello D Guerrera LP Maiorano BA Parente P Latiano TP Di Maio M Ciardiello F Troiani T Martinelli E Maiello E Immunotherapy in advanced anal cancer: Is the beginning of a new era? Cancer Treat Rev 2022 105 102373 35279535
8 Islami F Ferlay J Lortet-Tieulent J Bray F Jemal A International trends in anal cancer incidence rates Int J Epidemiol 2017 46 924 938 27789668
9 Wilkinson JR Morris EJ Downing A Finan PJ Aravani A Thomas JD Sebag-Montefiore D The rising incidence of anal cancer in England 1990-2010: a population-based study Colorectal Dis 2014 16 O234 O239 24410872
10 Mignozzi S Santucci C Malvezzi M Levi F La Vecchia C Negri E Global trends in anal cancer incidence and mortality Eur J Cancer Prev 2024 33 77 86 38047709
11 Huang J Lok V Zhang L Lucero-prisno DE Xu W Zheng Z Elcarte E Withers M Wong M IDDF2022-ABS-0273 Global incidence of anal cancer by histological subtypes Clin Gastroenterol 2022
12 Silva Dalla Libera L Almeida de Carvalho KP Enocencio Porto Ramos J Oliveira Cabral LA de Cassia Goncalves de Alencar R Villa LL Alves RRF Rabelo Santos SH Aparecida Dos Santos Carneiro M Saddi VA Human Papillomavirus and Anal Cancer: Prevalence, Genotype Distribution, and Prognosis Aspects from Midwestern Region of Brazil J Oncol 2019 2019 6018269 31641354
13 Mduma E Dharsee N Samwel K Mwita CJ Lidenge SJ Clinicopathological Characteristics and Outcomes of Anal Squamous Cell Carcinoma Patients With and Without HIV Infection in Sub-Saharan Africa JCO Glob Oncol 2023 9 e2200394 37216622
14 Brianti P De Flammineis E Mercuri SR Review of HPV-related diseases and cancers New Microbiol 2017 40 80 85 28368072
15 Plotzker RE Vaidya A Pokharel U Stier EA Sexually Transmitted Human Papillomavirus: Update in Epidemiology, Prevention, and Management Infect Dis Clin North Am 2023 37 289 310 37105644
16 Choi S Ismail A Pappas-Gogos G Boussios S HPV and Cervical Cancer: A Review of Epidemiology and Screening Uptake in the UK Pathogens 2023 12
17 Chan CK Aimagambetova G Ukybassova T Kongrtay K Azizan A Human Papillomavirus Infection and Cervical Cancer: Epidemiology, Screening, and Vaccination-Review of Current Perspectives J Oncol 2019 2019 3257939 31687023
18 Sehnal B Dusek L Cibula D Zima T Halaska M Driak D Slama J The relationship between the cervical and anal HPV infection in women with cervical intraepithelial neoplasia J Clin Virol 2014 59 18 23 24315797
19 Gami B Kubba F Ziprin P Human papilloma virus and squamous cell carcinoma of the anus Clin Med Insights Oncol 2014 8 113 119 25288893
20 Lin C Franceschi S Clifford GM Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis Lancet Infect Dis 2018 18 198 206 29158102
21 Palmer JG Scholefield JH Coates PJ Shepherd NA Jass JR Crawford LV Northover JM Anal cancer and human papillomaviruses Dis Colon Rectum 1989 32 1016 1022 2556252
22 Tyros G Mastraftsi S Gregoriou S Nicolaidou E Incidence of anogenital warts: epidemiological risk factors and real-life impact of human papillomavirus vaccination Int J STD AIDS 2021 32 4 13 33167803
23 Zaki SR Judd R Coffield LM Greer P Rolston F Evatt BL Human papillomavirus infection and anal carcinoma. Retrospective analysis by in situ hybridization and the polymerase chain reaction Am J Pathol 1992 140 1345 1355 1318640
24 Kidd LC Chaing S Chipollini J Giuliano AR Spiess PE Sharma P Relationship between human papillomavirus and penile cancer-implications for prevention and treatment Transl Androl Urol 2017 6 791 802 29184775
25 Muršić I Včev A Kotrulja L Kuric I Milavić T Šustić N Tolušić Levak M Treatment of verruca vulgaris in traditional medicine Acta Clin Croat 2020 59 745 750 34285446
26 Ortiz-Ortiz KJ Ramos-Cartagena JM Deshmukh AA Torres-Cintrón CR Colón-López V Ortiz AP Squamous Cell Carcinoma of the Anus Incidence, Mortality, and Survival Among the General Population and Persons Living With HIV in Puerto Rico, 2000-2016 JCO Glob Oncol 2021 7 133 143 33493020
27 Giuliano AR Nyitray AG Albero G Male circumcision and HPV transmission to female partners Lancet 2011 377 183 184 21216001
28 Shapiro SB Wissing MD Khosrow-Khavar F El-Zein M Burchell AN Tellier PP Coutlée F Franco EL Male Circumcision and Genital Human Papillomavirus (HPV) Infection in Males and Their Female Sexual Partners: Findings From the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) Cohort Study J Infect Dis 2022 226 1184 1194 35429378
29 Shapiro SB Laurie C El-Zein M Franco EL Association between male circumcision and human papillomavirus infection in males and females: a systematic review, meta-analysis, and meta-regression Clin Microbiol Infect 2023 29 968 978 37011808
30 Pierce Campbell CM Lin HY Fulp W Papenfuss MR Salmerón JJ Quiterio MM Lazcano-Ponce E Villa LL Giuliano AR Consistent condom use reduces the genital human papillomavirus burden among high-risk men: the HPV infection in men study J Infect Dis 2013 208 373 384 23644283
31 Ellingson MK Sheikha H Nyhan K Oliveira CR Niccolai LM Human papillomavirus vaccine effectiveness by age at vaccination: A systematic review Hum Vaccin Immunother 2023 19 2239085 37529935
32 Arnold JD Byrne ME Monroe AK Abbott SE District of Columbia Cohort Executive Committee The Risk of Anal Carcinoma After Anogenital Warts in Adults Living With HIV JAMA Dermatol 2021 157 283 289 33439220
33 Shiels MS Cole SR Kirk GD Poole C A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals J Acquir Immune Defic Syndr 2009 52 611 622 19770804
34 Silverberg MJ Lau B Justice AC Engels E Gill MJ Goedert JJ Kirk GD D'Souza G Bosch RJ Brooks JT Napravnik S Hessol NA Jacobson LP Kitahata MM Klein MB Moore RD Rodriguez B Rourke SB Saag MS Sterling TR Gebo KA Press N Martin JN Dubrow R North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America Clin Infect Dis 2012 54 1026 1034 22291097
35 Duncan KC Chan KJ Chiu CG Montaner JS Coldman AJ Cescon A Au-Yeung CG Wiseman SM Hogg RS Press NM HAART slows progression to anal cancer in HIV-infected MSM AIDS 2015 29 305 311 25686679
36 Piketty C Selinger-Leneman H Grabar S Duvivier C Bonmarchand M Abramowitz L Costagliola D Mary-Krause M FHDH-ANRS CO 4 Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy AIDS 2008 22 1203 1211 18525266
37 McMahon KR Gemma N Clapp M Sanchez-Montejo P Dibello J Laipply E Relationship between anal cancer recurrence and cigarette smoking World J Clin Oncol 2023 14 259 264 37583947
38 Ramamoorthy S Luo L Luo E Carethers JM Tobacco smoking and risk of recurrence for squamous cell cancer of the anus Cancer Detect Prev 2008 32 116 120 18639388
39 Phillips DH Hewer A Scholefield JH Skinner P Smoking-related DNA adducts in anal epithelium Mutat Res 2004 560 167 172 15157654
40 Bingmer K Ofshteyn A Dietz DW Stein SL Steinhagen E Outcomes in immunosuppressed anal cancer patients Am J Surg 2020 219 88 92 31477240
41 Sunesen KG Nørgaard M Thorlacius-Ussing O Laurberg S Immunosuppressive disorders and risk of anal squamous cell carcinoma: a nationwide cohort study in Denmark, 1978-2005 Int J Cancer 2010 127 675 684 19960431
42 Zhang Z Ling X Liu L Xi M Zhang G Dai J Natural History of Anal Papillomavirus Infection in HIV-Negative Men Who Have Sex With Men Based on a Markov Model: A 5-Year Prospective Cohort Study Front Public Health 2022 10 891991 35646789
43 Khandwala P Singhal S Desai D Parsi M Potdar R HIV-Associated Anal Cancer Cureus 2021 13 e14834 34104584
44 Hoots BE Palefsky JM Pimenta JM Smith JS Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions Int J Cancer 2009 124 2375 2383 19189402
45 Dunne EF Unger ER Sternberg M McQuillan G Swan DC Patel SS Markowitz LE Prevalence of HPV infection among females in the United States JAMA 2007 297 813 819 17327523
46 Wang L Yu C Ni X Wang F Wen C Jin M Chen J Zhang K Wang J Prevalence characteristics of human papillomavirus (HPV) infection among women receiving physical examinations in the Shangcheng District, Hangzhou city, China Sci Rep 2021 11 16538 34400720
47 Chelimo C Wouldes TA Cameron LD Elwood JM Risk factors for and prevention of human papillomaviruses (HPV), genital warts and cervical cancer J Infect 2013 66 207 217 23103285
48 Liu Y Bhardwaj S Sigel K Winters J Terlizzi J Gaisa MM Anal cancer screening results from 18-to-34-year-old men who have sex with men living with HIV Int J Cancer 2024 154 21 27 37728489
49 Dale JE Sebjørnsen S Leh S Rösler C Aaserud S Møller B Fluge Ø Erichsen C Nadipour S Kørner H Pfeffer F Dahl O Multimodal therapy is feasible in elderly anal cancer patients Acta Oncol 2017 56 81 87 27808666
50 Martinez-Cannon BA Perez ACT Hincapie-Echeverri J Roy M Marinho J Buerba GA Akagunduz B Li D Soto-Perez-de-Celis E Anal cancer in older adults: A Young International Society of Geriatric Oncology review paper J Geriatr Oncol 2022 13 914 923 35437216
51 Takahashi T Ohta H Azekura K Ueno M Coloanal anastomosis in surgery for rectal cancer Acta Chir Iugosl 2000 47 7 11 11432247
52 Yamaguchi K Kiyokawa J Akita K Developmental processes and ectodermal contribution to the anal canal in mice Ann Anat 2008 190 119 128 18413265
53 Tsukada Y Ito M Watanabe K Yamaguchi K Kojima M Hayashi R Akita K Saito N Topographic Anatomy of the Anal Sphincter Complex and Levator Ani Muscle as It Relates to Intersphincteric Resection for Very Low Rectal Disease Dis Colon Rectum 2016 59 426 433 27050605
54 Lee JM Kim NK Essential Anatomy of the Anorectum for Colorectal Surgeons Focused on the Gross Anatomy and Histologic Findings Ann Coloproctol 2018 34 59 71 29742860
55 Siddharth P Ravo B Colorectal neurovasculature and anal sphincter Surg Clin North Am 1988 68 1185 1200
56 Guntz M Parnaud E Bernard A Chome J Regnier J Toulemonde JL [Vascularization of the anal canal] Bull Assoc Anat (Nancy) 1976 60 527 538 1028448
57 Tanaka E Noguchi T Nagai K Akashi Y Kawahara K Shimada T Morphology of the epithelium of the lower rectum and the anal canal in the adult human Med Mol Morphol 2012 45 72 79 22718291
58 Fenger C Histology of the anal canal Am J Surg Pathol 1988 12 41 55 3337339
59 Lund JN Binch C McGrath J Sparrow RA Scholefield JH Topographical distribution of blood supply to the anal canal Br J Surg 1999 86 496 498 10215822
60 Pandey P Anal anatomy and normal histology Sex Health 2012 9 513 516 23380234
61 Hardy KJ The lymphatic drainage of the anal margin Aust N Z J Surg 1971 40 367 369 5280958
62 Hieda K Cho KH Arakawa T Fujimiya M Murakami G Matsubara A Nerves in the intersphincteric space of the human anal canal with special reference to their continuation to the enteric nerve plexus of the rectum Clin Anat 2013 26 843 854 23512701
63 Gagnard C Godlewski G Prat D Lan O Cousineau J Maklouf Y The nerve branches to the external anal sphincter: the macroscopic supply and microscopic structure Surg Radiol Anat 1986 8 115 119 3097851
64 Kinugasa Y Arakawa T Murakami G Fujimiya M Sugihara K Nerve supply to the internal anal sphincter differs from that to the distal rectum: an immunohistochemical study of cadavers Int J Colorectal Dis 2014 29 429 436 24306822
65 Krzowska-Firych J Lucas G Lucas C Lucas N Pietrzyk Ł An overview of Human Papillomavirus (HPV) as an etiological factor of the anal cancer J Infect Public Health 2019 12 1 6 29980478
66 Soheili M Keyvani H Soheili M Nasseri S Human papilloma virus: A review study of epidemiology, carcinogenesis, diagnostic methods, and treatment of all HPV-related cancers Med J Islam Repub Iran 2021 35 65 34277502
67 Longworth MS Laimins LA Pathogenesis of human papillomaviruses in differentiating epithelia Microbiol Mol Biol Rev 2004 68 362 372 15187189
68 Hebner CM Laimins LA Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity Rev Med Virol 2006 16 83 97 16287204
69 Ashique S Hussain A Fatima N Altamimi MA HPV pathogenesis, various types of vaccines, safety concern, prophylactic and therapeutic applications to control cervical cancer, and future perspective Virusdisease 2023 34 1 19
70 Gervaz P Calmy A Durmishi Y Allal AS Morel P Squamous cell carcinoma of the anus-an opportunistic cancer in HIV-positive male homosexuals World J Gastroenterol 2011 17 2987 2991 21799644
71 van der Zee RP Meijer CJLM Cuming T Kreuter A van de Sandt MM Quint WGV de Vries HJC Prins JM Steenbergen RDM Characterisation of anal intraepithelial neoplasia and anal cancer in HIV-positive men by immunohistochemical markers p16, Ki-67, HPV-E4 and DNA methylation markers Int J Cancer 2021 149 1833 1844 34310698
72 Weinstein D Leininger J Hamby C Safai B Diagnostic and prognostic biomarkers in melanoma J Clin Aesthet Dermatol 2014 7 13 24
73 Lee SK Kwon MS Lee YS Choi SH Kim SY Cho KJ Nam SY Prognostic value of expression of molecular markers in adenoid cystic cancer of the salivary glands compared with lymph node metastasis: a retrospective study World J Surg Oncol 2012 10 266 23231994
74 Eriksson B Oberg K Stridsberg M Tumor markers in neuroendocrine tumors Digestion 2000 62 Suppl 1 33 38 10940685
75 Morra E The biological markers of non-Hodgkin's lymphomas: their role in diagnosis, prognostic assessment and therapeutic strategy Int J Biol Markers 1999 14 149 153 10569136
76 Chumbalkar V Jennings TA Ainechi S Lee EC Lee H Extramammary Paget's Disease of Anal Canal Associated With Rectal Adenoma Without Invasive Carcinoma Gastroenterology Res 2016 9 99 102 28058078
77 Roberts JR Siekas LL Kaz AM Anal intraepithelial neoplasia: A review of diagnosis and management World J Gastrointest Oncol 2017 9 50 61 28255426
78 Brzeziński M Stukan M Anal Cancer and Anal Intraepithelial Neoplasia Risk among Patients Treated for HPV-Related Gynecological Diseases-A Systematic Review J Clin Med 2023 12
79 Albuquerque A Cytology in Anal Cancer Screening: Practical Review for Clinicians Acta Cytol 2020 64 281 287 31533094
80 Stanley MA Winder DM Sterling JC Goon PK HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues BMC Cancer 2012 12 398 22958276
81 Siddharthan RV Lanciault C Tsikitis VL Anal intraepithelial neoplasia: diagnosis, screening, and treatment Ann Gastroenterol 2019 32 257 263 31040622
82 Thompson HM Kim JK Perianal Paget's Disease Dis Colon Rectum 2021 64 511 515 33661234
83 Santos MD Soares F Presa-Fernandes JM Silva DS Perianal Paget Disease: Different Entities With the Same Name Cureus 2021 13 e15161 34168927
84 Goldblum JR Hart WR Perianal Paget's disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma Am J Surg Pathol 1998 22 170 179 9500217
85 Tang M Gao X Wang L Liu W Li J A brief review of perianal paget disease Int J Clin Exp Med 2020 13 7241 7249
86 Wietfeldt ED Thiele J Malignancies of the anal margin and perianal skin Clin Colon Rectal Surg 2009 22 127 135 20436838
87 Sahai A Kodner IJ Premalignant neoplasms and squamous cell carcinoma of the anal margin Clin Colon Rectal Surg 2006 19 88 93 20011315
88 Taliadoros V Rafique H Rasheed S Tekkis P Kontovounisios C Management and Outcomes in Anal Canal Adenocarcinomas-A Systematic Review Cancers (Basel) 2022 14
89 Tsay CJ Pointer T Chandler JB Nagar AB Protiva P Anal adenocarcinoma: case report, literature review and comparative survival analysis BMJ Open Gastroenterol 2021 8
90 Lukovic J Kim JJ Krzyzanowska M Chadi SA Taniguchi CM Hosni A Anal Adenocarcinoma: A Rare Malignancy in Need of Multidisciplinary Management JCO Oncol Pract 2020 16 635 640 33049179
91 Lightner AL Vaidya P McMichael J Click B Regueiro M Steele SR Hull TL Anal Squamous Cell Carcinoma in Ulcerative Colitis: Can Pouches Withstand Traditional Treatment Protocols? Dis Colon Rectum 2021 64 1106 1111 33951686
92 Slater G Greenstein A Aufses AH Jr Anal carcinoma in patients with Crohn's disease Ann Surg 1984 199 348 350 6703795
93 Patil DT Goldblum JR Billings SD Clinicopathological analysis of basal cell carcinoma of the anal region and its distinction from basaloid squamous cell carcinoma Mod Pathol 2013 26 1382 1389 23599161
94 Alvarez-Cañas MC Fernández FA Rodilla IG Val-Bernal JF Perianal basal cell carcinoma: a comparative histologic, immunohistochemical, and flow cytometric study with basaloid carcinoma of the anus Am J Dermatopathol 1996 18 371 379 8879301
95 Tsai TY Liao CK Zhang BY Huang YL Tsai WS You JF Yeh CY Hsieh PS Perianal Basal Cell Carcinoma-A Systematic Review and Meta-Analysis of Real-World Data Diagnostics (Basel) 2023 13
96 Bulur I Boyuk E Saracoglu ZN Arik D Perianal Basal cell carcinoma Case Rep Dermatol 2015 7 25 28 25848349
97 Pang LS Morson BC Basaloid carconoma of the anal canal J Clin Pathol 1967 20 128 135 5602502
98 Peralta EA Rare anorectal neoplasms: gastrointestinal stromal tumor, carcinoid, and lymphoma Clin Colon Rectal Surg 2009 22 107 114 20436835
99 Jetmore AB Ray JE Gathright JB Jr McMullen KM Hicks TC Timmcke AE Rectal carcinoids: the most frequent carcinoid tumor Dis Colon Rectum 1992 35 717 725 1643994
100 Patterson S Sogunro O Rectal carcinoid in a 30-year-old male: a review of current treatment options Dig Med Res 2020 3 74 74
101 Li Z Yuan J Wei L Zhou L Mei K Yue J Gao H Zhang M Jia L Kang Q Huang X Cao D SATB2 is a sensitive marker for lower gastrointestinal well-differentiated neuroendocrine tumors Int J Clin Exp Pathol 2015 8 7072 7082 26261600
102 Bellizzi AM SATB2 in neuroendocrine neoplasms: strong expression is restricted to well-differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas Histopathology 2020 76 251 264 31233624
103 Husain M Rashid T Ahmad MM Hassan MJ Anorectal malignant amelanotic melanoma: Report of a rare aggressive primary tumor J Cancer Res Ther 2022 18 249 252 35381792
104 Charifa A Zhang X Morphologic and Immunohistochemical Characteristics of Anorectal Melanoma Int J Surg Pathol 2018 26 725 729 29759015
105 Fastner S Hieken TJ McWilliams RR Hyngstrom J Anorectal melanoma J Surg Oncol 2023 128 635 644 37395165
106 Lagha A Ayadi M Krimi S Chraiet N Allani B Rifi H Raies H Mezlini A Primary anorectal melanoma: A case report with extended follow-up Am J Case Rep 2012 13 254 257 23569542
107 Sauter M Keilholz G Kranzbühler H Lombriser N Prakash M Vavricka SR Misselwitz B Presenting symptoms predict local staging of anal cancer: a retrospective analysis of 86 patients BMC Gastroenterol 2016 16 46 27048435
108 Pessia B Romano L Giuliani A Lazzarin G Carlei F Schietroma M Squamous cell anal cancer: Management and therapeutic options Ann Med Surg (Lond) 2020 55 36 46 32461801
109 Stier EA Chiao EY Anal Cancer and Anal Cancer precursors in Women with a History of HPV-Related Dysplasia and Cancer Semin Colon Rectal Surg 2017 28 97 101 29204065
110 Ciombor KK Ernst RD Brown G Diagnosis and Diagnostic Imaging of Anal Canal Cancer Surg Oncol Clin N Am 2017 26 45 55 27889036
111 Chiu S Joseph K Ghosh S Cornand RM Schiller D Reasons for delays in diagnosis of anal cancer and the effect on patient satisfaction Can Fam Physician 2015 61 e509 e516 26889506
112 Jacopo M Endoanal ultrasound for anal cancer staging Int J Colorectal Dis 2011 26 385 386 20567837
113 Tarantino D Bernstein MA Endoanal ultrasound in the staging and management of squamous-cell carcinoma of the anal canal: potential implications of a new ultrasound staging system Dis Colon Rectum 2002 45 16 22 11786758
114 Reginelli A Granata V Fusco R Granata F Rega D Roberto L Pellino G Rotondo A Selvaggi F Izzo F Petrillo A Grassi R Diagnostic performance of magnetic resonance imaging and 3D endoanal ultrasound in detection, staging and assessment post treatment, in anal cancer Oncotarget 2017 8 22980 22990 28152518
115 Tonolini M Bianco R MRI and CT of anal carcinoma: a pictorial review Insights Imaging 2013 4 53 62 23208584
116 Congedo A Mallardi D Danti G De Muzio F Granata V Miele V An Updated Review on Imaging and Staging of Anal Cancer-Not Just Rectal Cancer Tomography 2023 9 1694 1710 37736988
117 Mahmud A Poon R Jonker D PET imaging in anal canal cancer: a systematic review and meta-analysis Br J Radiol 2017 90 20170370 28972796
118 Matsuoka H Nakamura A Masaki T Sugiyama M Takahara T Hachiya J Atomi Y Comparison between endorectal coil and pelvic phased-array coil magnetic resonance imaging in patients with anorectal tumor Am J Surg 2003 185 328 332 12657384
119 Golia Pernicka JS Rauch GM Gangai N Bates DDB Ernst R Hope TA Horvat N Sheedy SP Gollub MJ Imaging of Anal Squamous Cell Carcinoma: Survey Results and Expert Opinion from the Rectal and Anal Cancer Disease-Focused Panel of the Society of Abdominal Radiology Abdom Radiol (NY) 2023 48 3022 3032 36932225
120 Durot C Dohan A Boudiaf M Servois V Soyer P Hoeffel C Cancer of the Anal Canal: Diagnosis, Staging and Follow-Up with MRI Korean J Radiol 2017 18 946 956 29089827
121 Mirshahvalad SA Mesci A Murad V Kohan A Ortega C Veit-Haibach P Metser U [(18)F]-FDG PET in anal canal cancer: a systematic review and meta-analysis Eur J Nucl Med Mol Imaging 2023 51 258 277 37592085
122 Duimering A Riauka T Nijjar Y Ghosh S MacEwan R Warkentin H Schiller D Tankel K Usmani N Severin D Nijjar T Fairchild A Mulder K Doll C Wong C Joseph K Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma Radiother Oncol 2019 136 21 28 31015125
123 Nguyen BT Joon DL Khoo V Quong G Chao M Wada M Joon ML See A Feigen M Rykers K Kai C Zupan E Scott A Assessing the impact of FDG-PET in the management of anal cancer Radiother Oncol 2008 87 376 382 18453023
124 Janczewski LM Asare EA Goodman KA Updates on the Version 9 American Joint Committee on Cancer Staging System for Anal Cancer Ann Surg Oncol 2024 31 4155 4158 38735904
125 Dahl O Myklebust MP Dale JE Leon O Serup-Hansen E Jakobsen A Pfeiffer P Løes IM Pfeffer F Spindler KG Guren MG Glimelius B Johnsson A Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version Acta Oncol 2020 59 1016 1023 32574087
126 Hagemans JAW Blinde SE Nuyttens JJ Morshuis WG Mureau MAM Rothbarth J Verhoef C Burger JWA Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience Ann Surg Oncol 2018 25 1970 1979 29691737
127 Carr RM Jin Z Hubbard J Research on Anal Squamous Cell Carcinoma: Systemic Therapy Strategies for Anal Cancer Cancers (Basel) 2021 13
128 El-Haddad M Ahmed RS Al-Suhaibany A Al-Hazza M Al-Sanae N Al-Jabbar AA Hamoud S Ashaary L Bazerbashy S Balaraj K Anal canal carcinoma treatment results: the experience of a single institution Ann Saudi Med 2011 31 158 162 21403412
129 Osborne MC Maykel J Johnson EK Steele SR Anal squamous cell carcinoma: an evolution in disease and management World J Gastroenterol 2014 20 13052 13059 25278699
130 Leichman L Nigro N Vaitkevicius VK Considine B Buroker T Bradley G Seydel HG Olchowski S Cummings G Leichman C Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy Am J Med 1985 78 211 215 3918441
131 Peiffert D Tournier-Rangeard L Gérard JP Lemanski C François E Giovannini M Cvitkovic F Mirabel X Bouché O Luporsi E Conroy T Montoto-Grillot C Mornex F Lusinchi A Hannoun-Lévi JM Seitz JF Adenis A Hennequin C Denis B Ducreux M Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial J Clin Oncol 2012 30 1941 1948 22529257
132 James RD Glynne-Jones R Meadows HM Cunningham D Myint AS Saunders MP Maughan T McDonald A Essapen S Leslie M Falk S Wilson C Gollins S Begum R Ledermann J Kadalayil L Sebag-Montefiore D Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial Lancet Oncol 2013 14 516 524 23578724
133 Gunderson LL Winter KA Ajani JA Pedersen JE Moughan J Benson AB 3rd Thomas CR Jr Mayer RJ Haddock MG Rich TA Willett CG Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin J Clin Oncol 2012 30 4344 4351 23150707
134 Flam M John M Pajak TF Petrelli N Myerson R Doggett S Quivey J Rotman M Kerman H Coia L Murray K Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study J Clin Oncol 1996 14 2527 2539 8823332
135 Bartelink H Roelofsen F Eschwege F Rougier P Bosset JF Gonzalez DG Peiffert D van Glabbeke M Pierart M Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups J Clin Oncol 1997 15 2040 2049 9164216
136 Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research Lancet 1996 348 1049 1054 8874455
137 Cummings BJ Keane TJ O'Sullivan B Wong CS Catton CN Mitomycin in anal canal carcinoma Oncology 1993 50 Suppl 1 63 69
138 Mineur L Vazquez L Belkacemi M Toullec C Bentaleb N Boustany R Plat F Capecitabine/Mitomycin versus 5-Fluorouracil/Mitomycin in Combination with Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy for Anal Cancer Curr Oncol 2023 30 8563 8574 37754536
139 Thind G Johal B Follwell M Kennecke HF Chemoradiation with capecitabine and mitomycin-C for stage I-III anal squamous cell carcinoma Radiat Oncol 2014 9 124 24885554
140 Goodman KA Julie D Cercek A Cambridge L Woo KM Zhang Z Wu AJ Reidy DL Segal NH Stadler ZK Saltz LB Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using Intensity Modulated Radiation Therapy for Anal Cancer Int J Radiat Oncol Biol Phys 2017 98 1087 1095 28721892
141 Upadhyay L Hartzell M Parikh AR Strickland MR Klempner S Malla M Recent Advances in the Management of Anal Cancer Healthcare (Basel) 2023 11
142 Caravatta L Mantello G Valvo F Franco P Gasparini L Rosa C Slim N Manfrida S De Felice F Gerardi MA Vagge S Krengli M Palazzari E Osti MF Gonnelli A Catalano G Pittoni P Ivaldi GB Galardi A Lupattelli M Rosetto ME Niespolo RM Guido A Durante O Macchia G Munoz F El Khouzai B Lucido MR Porreca A Di Nicola M Gambacorta MA Donato V Genovesi D Radiotherapy with Intensity-Modulated (IMRT) Techniques in the Treatment of Anal Carcinoma (RAINSTORM): A Multicenter Study on Behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology) Gastrointestinal Study Group Cancers (Basel) 2021 13
143 Joseph K Vos LJ Warkentin H Paulson K Polkosnik LA Usmani N Tankel K Severin D Nijjar T Schiller D Wong C Ghosh S Mulder K Field C Patient reported quality of life after helical IMRT based concurrent chemoradiation of locally advanced anal cancer Radiother Oncol 2016 120 228 233 27406441
144 Kachnic LA Winter K Myerson RJ Goodyear MD Willins J Esthappan J Haddock MG Rotman M Parikh PJ Safran H Willett CG RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal Int J Radiat Oncol Biol Phys 2013 86 27 33 23154075
145 Sauter C Peeken JC Borm K Diehl CD Münch S Combs SE Dapper H Influence of radiation treatment technique (IMRT vs 3D-RT) on acute toxicity and prognostic factors for survival for anal cancer Sci Rep 2022 12 19914 36402828
146 Chuong MD Freilich JM Hoffe SE Fulp W Weber JM Almhanna K Dinwoodie W Rao N Meredith KL Shridhar R Intensity-Modulated Radiation Therapy vs 3D Conformal Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal Gastrointest Cancer Res 2013 6 39 45 23745158
147 Gilshtein H Khoury W Surgical management of anal cancer Minerva Chir 2015 70 141 145 25690347
148 Aigner F Siegel R [Diagnostics, treatment and aftercare of anal cancer] Chirurgie (Heidelb) 2023 94 890 898 37042989
149 Bogach J Fenech D Chu W Ashamalla S Ung Y Taggar AS Chan KKW Earle CC Wong CS Salvage surgery for locally recurrent anal cancer after intensity modulated radiation therapy with concurrent chemotherapy Cancer Treat Res Commun 2021 26 100287 33360327
150 Nilsson MP Nilsson ED Johnsson A Leon O Gunnlaugsson A Scherman J Patterns of recurrence in anal cancer: a detailed analysis Radiat Oncol 2020 15 125 32460785
151 Pocard M Tiret E Nugent K Dehni N Parc R Results of salvage abdominoperineal resection for anal cancer after radiotherapy Dis Colon Rectum 1998 41 1488 1493 9860327
152 Glynne-Jones R Nilsson PJ Aschele C Goh V Peiffert D Cervantes A Arnold D European Society for Medical Oncology (ESMO) European Society of Surgical Oncology (ESSO) European Society of Radiotherapy and Oncology (ESTRO) Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up Eur J Surg Oncol 2014 40 1165 1176 25239441
153 Kitaguchi D Tsukada Y Ito M Horasawa S Bando H Yoshino T Yamada K Ajioka Y Sugihara K Survival outcomes following salvage abdominoperineal resection for recurrent and persistent anal squamous cell carcinoma Eur J Surg Oncol 2023 49 106929 37210274
154 Ko G Sarkaria A Merchant SJ Booth CM Patel SV A systematic review of outcomes after salvage abdominoperineal resection for persistent or recurrent anal squamous cell cancer Colorectal Dis 2019 21 632 650 30689272
155 Park IJ Chang G Survival and Operative Outcomes After Salvage Surgery for Recurrent or Persistent Anal Cancer Ann Coloproctol 2020 36 361 373 33486907
156 Frakulli R Buwenge M Cammelli S Macchia G Farina E Arcelli A Ferioli M Fuccio L Tagliaferri L Galuppi A Frezza GP Morganti AG Brachytherapy boost after chemoradiation in anal cancer: a systematic review J Contemp Brachytherapy 2018 10 246 253 30038645
157 Saint A Evesque L Falk AT Cavaglione G Montagne L Benezery K Francois E Mitomycin and 5-fluorouracil for second-line treatment of metastatic squamous cell carcinomas of the anal canal Cancer Med 2019 8 6853 6859 31524335
158 Khawandanah M Baxley A Pant S Recurrent metastatic anal cancer treated with modified paclitaxel, ifosfamide, and cisplatin and third-line mitomycin/cetuximab J Oncol Pharm Pract 2015 21 232 237 24627343
159 Sclafani F Rao S Systemic Therapies for Advanced Squamous Cell Anal Cancer Curr Oncol Rep 2018 20 53 29728940
160 Rao S Guren MG Khan K Brown G Renehan AG Steigen SE Deutsch E Martinelli E Arnold D ESMO Guidelines Committee Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(☆) Ann Oncol 2021 32 1087 1100 34175386
161 Sclafani F Morano F Cunningham D Baratelli C Kalaitzaki E Watkins D Starling N Chau I Rao S Platinum-Fluoropyrimidine and Paclitaxel-Based Chemotherapy in the Treatment of Advanced Anal Cancer Patients Oncologist 2017 22 402 408 28209745
162 Kim R Byer J Fulp WJ Mahipal A Dinwoodie W Shibata D Carboplatin and paclitaxel treatment is effective in advanced anal cancer Oncology 2014 87 125 132 25012155
163 Rao S Sclafani F Eng C Adams RA Guren MG Sebag-Montefiore D Benson A Bryant A Peckitt C Segelov E Roy A Seymour MT Welch J Saunders MP Muirhead R O'Dwyer P Bridgewater J Bhide S Glynne-Jones R Arnold D Cunningham D International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct J Clin Oncol 2020 38 2510 2518 32530769
164 Kim S François E André T Samalin E Jary M El Hajbi F Baba-Hamed N Pernot S Kaminsky MC Bouché O Desrame J Zoubir M Ghiringhelli F Parzy A De La Fouchardiere C Smith D Deberne M Spehner L Badet N Adotevi O Anota A Meurisse A Vernerey D Taieb J Vendrely V Buecher B Borg C Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study Lancet Oncol 2018 19 1094 1106 30042063
165 Mondaca S Chatila WK Bates D Hechtman JF Cercek A Segal NH Stadler ZK Varghese AM Kundra R Capanu M Shia J Schultz N Saltz L Yaeger R FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer Clin Colorectal Cancer 2019 18 e39 e52 30316684
166 Benson AB Venook AP Al-Hawary MM Azad N Chen YJ Ciombor KK Cohen S Cooper HS Deming D Garrido-Laguna I Grem JL Hecht JR Hoffe S Hubbard J Hunt S Hussan H Jeck W Johung KL Joseph N Kirilcuk N Krishnamurthi S Maratt J Messersmith WA Meyerhardt J Miller ED Mulcahy MF Nurkin S Overman MJ Parikh A Patel H Pedersen K Saltz L Schneider C Shibata D Skibber JM Sofocleous CT Stotsky-Himelfarb E Tavakkoli A Willett CG Williams G Algieri F Gurski L Stehman K Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology J Natl Compr Canc Netw 2023 21 653 677 37308125
167 Cattelan L Ghazawi FM Le M Savin E Zubarev A Lagacé F Sasseville D Waschke K Litvinov IV Investigating epidemiologic trends and the geographic distribution of patients with anal squamous cell carcinoma throughout Canada Curr Oncol 2020 27 e294 e306 32669936
168 Wells J Chandler R Flowers L Paul S Sharma A Kalifa N Holstad M Perceptions of Anal Cancer Risk Among HIV-Positive and High-Risk HIV-Negative Women J Low Genit Tract Dis 2022 26 181 185 35019899
169 Clarke MA Wentzensen N Strategies for screening and early detection of anal cancers: A narrative and systematic review and meta-analysis of cytology, HPV testing, and other biomarkers Cancer Cytopathol 2018 126 447 460 29797691
170 Luo Q Zeng X Luo H Pan L Huang Y Zhang H Han N Epidemiologic characteristics of high-risk HPV and the correlation between multiple infections and cervical lesions BMC Infect Dis 2023 23 667 37805467
171 Stier EA Clarke MA Deshmukh AA Wentzensen N Liu Y Poynten IM Cavallari EN Fink V Barroso LF Clifford GM Cuming T Goldstone SE Hillman RJ Rosa-Cunha I La Rosa L Palefsky JM Plotzker R Roberts JM Jay N International Anal Neoplasia Society's consensus guidelines for anal cancer screening Int J Cancer 2024 154 1694 1702 38297406
172 Pisano L Tiradritti L Lorenzoni E Zuccati G Matucci M Butera D Foxi P Confortini M Pap smear in the prevention of HPV-related anal cancer: preliminary results of the study in a male population at risk G Ital Dermatol Venereol 2016 151 619 627 26199089
173 Albuquerque A High-resolution anoscopy: Unchartered territory for gastroenterologists? World J Gastrointest Endosc 2015 7 1083 1087 26421104
174 Bull-Henry K Morris B Buchwald UK The importance of anal cancer screening and high-resolution anoscopy to gastroenterology practice Curr Opin Gastroenterol 2020 36 393 401 32701604
175 Pisano L Grandi V Tiradritti L Zuccati G Caminati F Giani I Bisanzi S Matucci M Carozzi F Pimpinelli N Elbetti C New Screening Strategy Combining Anal Papanicolaou and Human Papillomavirus Tests for Human Papillomavirus-Related Anal Cancer: A Prospective, Single-Center Study Sex Transm Dis 2022 49 622 627 35687884
176 Gosens KCM van der Zee RP van Heukelom MLS Jongen VW Cairo I van Eeden A van Noesel CJM Quint WGV Pasmans H Dijkgraaf MGW de Vries HJC Prins JM HPV vaccination to prevent recurrence of anal intraepithelial neoplasia in HIV+ MSM AIDS 2021 35 1753 1764 33966029
177 Stier EA Chigurupati NL Fung L Prophylactic HPV vaccination and anal cancer Hum Vaccin Immunother 2016 12 1348 1351 26933898
178 Berenson AB Guo F Chang M Association of Human Papillomavirus Vaccination With the Incidence of Squamous Cell Carcinomas of the Anus in the US JAMA Oncol 2022 8 1 3
179 Wei F Alberts CJ Albuquerque A Clifford GM Impact of Human Papillomavirus Vaccine Against Anal Human Papillomavirus Infection, Anal Intraepithelial Neoplasia, and Recurrence of Anal Intraepithelial Neoplasia: A Systematic Review and Meta-analysis J Infect Dis 2023 228 1496 1504 37257044
180 Jácome AA Morris VK Eng C The Role of Immunotherapy in the Treatment of Anal Cancer and Future Strategies Curr Treat Options Oncol 2022 23 1073 1085 35666353
181 Rogers JE Ohinata A Silva NN Mehdizadeh A Eng C Epidermal growth factor receptor inhibition in metastatic anal cancer Anticancer Drugs 2016 27 804 808 27272412
182 Rogers JE Jácome AAA Ohinata A Wolff R Morris VK Johnson B Mehdizadeh A Rothschild ND Ahmed SU Guerra JL Eng C Outcomes with anti-EGFR monoclonal antibodies in metastatic and recurrent anal squamous cell carcinoma Expert Rev Anticancer Ther 2020 20 901 908 32799569
183 Kim DW Byer J Kothari N Mahipal A Chang YD Kim RD EGFR Inhibitors in Patients with Advanced Squamous Cell Anal Carcinomas: A Single-Institution Experience Oncology 2017 92 190 196 28152526
184 Waldmann TA Dubois S Miljkovic MD Conlon KC IL-15 in the Combination Immunotherapy of Cancer Front Immunol 2020 11 868 32508818
185 Hanna G Kaczmar J Zandberg D Wong D Yilmaz E Sherman E Hernando-calvo A Sacco A Raben D Odogwu L Bohr D Salazar R Reiners R Chung C Updated Dose Expansion Results of a Phase 1/1b Study of the Bifunctional EGFR/TGFβ Inhibitor BCA101 with Pembrolizumab in Patients with Recurrent, Metastatic Head and Neck Squamous Cell Carcinoma Int J Radiat Oncol Biol Phy 2024 118 e88
186 Rebucci-Peixoto M Vienot A Adotevi O Jacquin M Ghiringhelli F de la Fouchardière C You B Maurina T Kalbacher E Bazan F Meynard G Clairet AL Fagnoni-Legat C Spehner L Bouard A Vernerey D Meurisse A Kim S Borg C Mansi L A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 T(H)1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study Front Oncol 2022 12 957580 35928870
187 Spindler KL NOAC9 - Circulating Tumor DNA Guided Follow-Up in Anal Cancer. [accessed 2024 Jan 25]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://ichgcp.net/clinical-trials-registry/nct05572801 ClinicalTrials.gov Identifier: NCT05572801
