Clinical presentation, diagnosis, and staging of anal cancer

INTRODUCTION — Although anal cancer is an uncommon cancer, its incidence is increasing globally [1]. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer".)

This topic will discuss the clinical presentation, diagnosis, and staging of anal cancer. The management of anal cancer and anal squamous intraepithelial lesions is discussed separately.

●(See "Treatment of anal cancer".)

●(See "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment".)

DEFINITION

●Anal cancer – An anal cancer is clinically defined as a tumor that develops from any of the three types of mucosa located in the anal region (glandular, transitional, and squamous mucosa) and that cannot be visualized in its entirety while gentle traction is placed on the gluteal cheeks (buttocks) (figure 1) [2].

•For the purposes of this topic, the term "anal squamous cell carcinoma (SCC)" refers to an anal SCC arising within the transitional or nonkeratinized stratified squamous mucosa of the anal canal.

•Anal adenocarcinoma, which is rarer than anal SCC, arises from the glandular mucosa found in the anal canal. Anal adenocarcinoma presents and is staged similarly to anal SCC (table 1) but is treated as a rectal adenocarcinoma. (See "Treatment of anal cancer", section on 'Anal adenocarcinoma'.)

•Further details on the anatomy and classification of other types of anal canal tumors (table 2) are discussed separately. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Anatomy and terminology'.)

●Perianal cancer – Perianal cancers are clinically defined as tumors that arise in the hair-bearing skin within a 5 cm radius of the anal verge that can be seen in their entirety with gentle traction placed on the gluteal cheeks (buttocks) [2,3]. Perianal cancers are generally treated similarly to anal SCC. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Perianal skin cancers'.)

●Other skin lesions – Any lesion more than 5 cm from the anal verge is considered a skin lesion unrelated to anorectal pathology. (See "Approach to adult patients with anorectal complaints", section on 'Anatomy and terminology'.)

CLINICAL PRESENTATION

Symptoms — Most patients with anal cancer are identified based on locoregional symptoms from the primary tumor. The most common presenting symptoms include rectal or anal bleeding (45 percent) and anorectal pain or sensation of a rectal mass (30 percent) [4-6]. Of note, clinicians should not assume that anal bleeding is due to benign anorectal disease (eg, hemorrhoids), which may lead to a delayed or missed diagnosis of anal cancer or another intestinal malignancy. (See 'Endoscopy' below and "Approach to adult patients with anorectal complaints", section on 'Bleeding'.)

Other symptoms include rectal pruritus, urgency, pressure, anal discharge, and changes in bowel habits (eg, thinned stool caliber, stool incontinence). Patients may also present with inguinal lymphadenopathy, a common site of nodal metastases due to the pattern of lymphatic drainage from the primary anal tumor.

Patients with distant metastases may present with abdominopelvic pain or distension, cough, shortness of breath, enlarged lymph nodes at distant sites, bone pain, and/or constitutional symptoms (eg, unintentional weight loss, fatigue).

Approximately 20 percent of patients with anal cancer are asymptomatic at presentation. Such patients are usually diagnosed incidentally, such as on digital rectal examination (DRE) for other medical conditions, during gynecologic examination, during screening colonoscopy, or on diagnostic imaging studies. In rare circumstances, patients may present with anal cancer as part of the evaluation for a squamous cell carcinoma (SCC) of unknown primary, often involving the inguinal lymph nodes. (See "Squamous cell carcinoma of unknown primary site", section on 'Inguinal lymph nodes'.)

Sites of disease — Most patients with anal cancer present with locally advanced disease. Approximately 41 percent of patients present with early-stage disease without lymph node involvement; approximately 36 percent present with regional invasion to locoregional lymph nodes (inguinal, mesorectal, superior rectal, internal iliac, obturator, external iliac) or adjacent organs; and approximately 14 percent present with distant metastatic disease [7,8].

DIAGNOSTIC EVALUATION — The diagnosis of anal cancer is suspected in the adult patient with an anal mass, particularly those who are symptomatic (eg, anorectal bleeding or pain) or have specific risk factors for anal cancer. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Risk factors'.)

Given that anal cancer can present similarly to other conditions, further clinical assessment is necessary including history and physical examination, endoscopic evaluation, and confirmation of the diagnosis with biopsy and histopathologic analysis of the suspicious mass. (See 'Differential diagnosis' below and "Approach to adult patients with anorectal complaints".)

History — The clinician should elicit a history of common symptoms related to anal cancer and prior endoscopic studies. (See 'Clinical presentation' above.)

Patients should also be asked about risk factors specific to anal cancer, which include (see "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Risk factors'):

●Sexual history, including number of sexual partners, history of receptive anal intercourse (table 3), and prior or current history of sexually transmitted infections, including human papillomavirus (HPV) infection. (See "Screening for sexually transmitted infections", section on 'Sexual history'.)

●Prior or current history of other HPV-associated cancers (eg, cervical cancer in females, penile cancer in males, head and neck cancer). (See "Virology of human papillomavirus infections and the link to cancer".)

●Tobacco use.

●Prior human immunodeficiency virus (HIV) infection. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

●Chronic immunosuppression (eg, organ transplant recipients, autoimmune disease, chronic corticosteroid use).

Physical examination — The physical examination for a patient with suspected anal cancer includes:

●A complete physical examination, including palpation for all lymph nodes (especially bilateral inguinal lymph nodes, which are a common site of nodal metastasis for anal cancer).

●A complete anorectal examination, including inspection, digital rectal examination (DRE), and endoscopy (proctoscopy/anoscopy, flexible sigmoidoscopy, or colonoscopy). (See "Approach to adult patients with anorectal complaints", section on 'Complete anorectal examination' and 'Endoscopy' below.)

Endoscopy — A proctoscopy/anoscopy is performed to evaluate for suspicious masses in the anal canal and/or the distal rectum. Anoscopy has the advantage of being a quick, relatively painless, inexpensive procedure that can be performed in the office setting in an unprepped patient. Clinical findings of anal cancer on endoscopy include polypoid or ulcerative mass (picture 1). Further details on the approach to anoscopy or proctoscopy in the patient with anorectal complaints are discussed separately. (See "Approach to adult patients with anorectal complaints", section on 'Anoscopy or proctoscopy'.)

However, more extensive endoscopic evaluation (such as flexible sigmoidoscopy or colonoscopy) should also be discussed with patients who have symptoms of anal cancer that overlap with symptoms of colorectal cancer, such as anorectal bleeding, changes in bowel habits, abdominopelvic pain and distension, or other systemic symptoms. Further details on when to obtain an endoscopy evaluation in the patient with anorectal complaints is discussed separately. (See "Approach to adult patients with anorectal complaints", section on 'Endoscopy' and "Approach to adult patients with anorectal complaints", section on 'Bleeding'.)

Biopsy (diagnosis) — The diagnosis of anal cancer is typically confirmed on biopsy of visualized anal masses suspected to be anal cancer and histopathologic evaluation of the obtained tissue sample. Biopsy can be obtained either during anorectal examination or during proctoscopy/anoscopy or other endoscopic evaluation. For some patients with a squamous cell carcinoma (SCC) of unknown primary involving the inguinal lymph nodes, a biopsy of the lymph nodes may also lead to the diagnosis of anal cancer. (See "Squamous cell carcinoma of unknown primary site", section on 'Inguinal lymph nodes'.)

The histopathologic findings of anal cancer, including evaluation for HPV on the tumor sample, is discussed separately. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Histopathology' and "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'Human papillomavirus infection'.)

Differential diagnosis — The differential diagnosis for anal cancer includes both benign and malignant etiologies. These different conditions can be distinguished on histopathology.

●Primary rectal SCC – Primary rectal SCC, which is rare, is staged and treated as an anal SCC. (See "Treatment of anal cancer", section on 'Rectal squamous cell cancers'.)

●Colorectal adenocarcinoma – The clinical presentation and diagnosis of colorectal cancer is discussed separately. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation'.)

●Other perianal tumors – Other tumors of the perianal skin, such as cutaneous SCC in situ (Bowen disease), perianal intraepithelial adenocarcinoma (Paget disease), or melanoma or neuroendocrine tumors, may present with anal pruritus or a bleeding, erythematous eczematoid plaque. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Approach to the patient with anal pruritus", section on 'Dermatologic diseases'.)

●Benign anorectal disease – Benign anorectal disease (eg, hemorrhoids) can also present with bleeding or other symptoms similar to those seen with anal cancer. (See "Hemorrhoids: Clinical manifestations and diagnosis".)

Of note, clinicians should not assume during the initial diagnostic evaluation that anal bleeding is due to benign anorectal disease (eg, hemorrhoids), which may lead to a delayed or missed diagnosis of anal cancer or another intestinal malignancy. (See 'Diagnostic evaluation' above and "Approach to adult patients with anorectal complaints", section on 'Bleeding'.)

●Condylomata acuminata (anogenital warts) – Among patients with anal SCC, anorectal condylomata acuminata (anogenital warts) are present in approximately 50 percent of men who have sex with men (MSM) and less than 30 percent of heterosexual males and females [9]. These lesions are typically associated with lower risk types of HPV (HPV 6 and 11), although coinfection with high-risk types of HPV (HPV 16) associated with anal SCC are common. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Association with malignancy'.)

POSTDIAGNOSTIC EVALUATION

Imaging studies — For patients with a confirmed diagnosis of anal cancer or squamous cell carcinoma (SCC) of the perianal skin, we obtain staging imaging studies using contrast-enhanced computed tomography (CT) of the chest and abdomen. Pelvic imaging is obtained using either a contrast-enhanced CT or magnetic resonance imaging (MRI) of the pelvis with gadolinium contrast. Such imaging studies are used to detect potential disease involvement of locoregional lymph nodes, invasion of adjacent structures, and/or distant metastases.

Fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT from skull base to midthigh is an additional option for staging imaging but it is not mandatory and should not replace a diagnostic CT scan, as high-quality evidence supporting its exclusive use as a definitive staging modality are limited [10-14].

Biopsy of inguinal lymph nodes — We biopsy any clinically palpable lymph nodes or locoregional lymph nodes noted on diagnostic imaging that are concerning for disease involvement. If the biopsy is positive for disease, this permits appropriate modification of treatment, particularly radiation fields to fully encompass regional disease in the lymph nodes. Options for lymph node sampling include fine needle aspiration or core needle biopsy. Inguinal lymph nodes that demonstrate positive FDG uptake on PET imaging are classified as having clinical disease involvement.

Staging system — All carcinomas (squamous cell, adenocarcinoma) that arise within any of the mucosal surfaces of the anal canal or the perianal skin are staged similarly. The ninth version of the joint American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) Tumor, Node, Metastasis (TNM) staging system for anal cancers (table 1) is based on tumor size, invasion of adjacent structures, and the presence or absence of nodal and distant metastases [15].

The eighth edition of the AJCC staging system for anal cancer was based on tumor (T) and nodal (N) staging where nodal (N) disease was classified as higher stage than was tumor (T) stage, but this approach lacked hierarchical staging for overall survival. For example, clinical stage IIIA (node positive) disease had a better prognosis than stage IIB disease (larger tumors without associated nodal invasion), indicating that T stage appeared to have more impact on overall outcome. In the ninth version of the AJCC staging system for anal cancer (table 1), stage IIB disease has been revised (previously T3N0M0 to T1-2N1M0); stage IIIA disease has been revised (previously T1-2N1M0 to T3N0-1M0); and stage IIIC has been revised (previously T3-4N1M0 to T4N1M0). The term Tis has also been omitted altogether.

Additionally, in the ninth version of the AJCC staging system for anal cancer, metastases in the inguinal, mesorectal, internal, superior rectal, internal iliac, and/or obturator nodes are classified as N1a nodes; external iliac lymph nodes are classified as N1b nodes; and N1c is designated as a combination of N1a plus N1b (table 1). Lymph node involvement is far more common in cancers that originate in the anal canal than those originating on the perianal skin.

Both tumor size (T stage) and nodal status (N stage) are important prognostic factors for patients with anal cancer [16-19]. Further details are discussed separately. (See "Treatment of anal cancer", section on 'Prognosis'.)

Metastatic disease (M) can either be confirmed clinically on imaging studies (cM1) or on biopsy (pM1).

PRETREATMENT EVALUATION — Patients with a confirmed diagnosis of anal cancer undergo the following evaluations prior to initiating therapy. (See "Treatment of anal cancer".)

Laboratory testing — For patients with a confirmed diagnosis of anal cancer, we obtain a baseline complete blood count with differential, a chemistry panel, and liver function testing. Additional laboratory testing includes:

HIV testing — We obtain HIV testing for all individuals with newly diagnosed anal cancer and an unknown HIV status. We do not routinely test for HIV status in patients with anal adenocarcinoma, unless the individual patient's history suggests that screening may be warranted. (See "Screening and diagnostic testing for HIV infection in adults".)

For patients with anal cancer and a known diagnosis of HIV or acquired immunodeficiency syndrome (AIDS), the pretreatment assessment includes a thorough history, including infectious diseases and use of antiretroviral therapy (ART); review of HIV serology; cluster of differentiation 4 (CD4) count and percentage; viral load; and screening for coinfections, including viral hepatitis. (See "Initial evaluation of adults with HIV".)

Although infection with HIV is a risk factor for anal squamous cell carcinoma (SCC), anal SCC is not an AIDS-defining illness. (See "Anatomy, pathology, epidemiology, and risk factors of anal cancer", section on 'HIV infection' and "The natural history and clinical features of HIV infection in adults and adolescents", section on 'AIDS-defining conditions'.)

The treatment of anal cancer in patients living with HIV is discussed separately. (See "Treatment of anal cancer", section on 'Patients living with HIV'.)

What is the role of tumor markers? — We do not routinely assay for tumor markers prior to treatment in patients with localized anal cancer, as there are none that are consistently elevated in this disease. As an example, serum carcinoembryonic antigen (CEA) can be found in 20 to 39 percent of patients with anal SCC [20-22].

Gynecologic examination — For female patients with a diagnosis of anal cancer, a gynecologic examination should be performed before initiating treatment. Such patients should also be screened for cervical cancer, which is also caused by human papillomavirus (HPV), a risk factor for anal SCC. (See "The gynecologic history and pelvic examination", section on 'Pelvic examination' and "Screening for cervical cancer in resource-rich settings" and "Screening for cervical cancer in resource-limited settings".)

Fertility preservation and reproductive counseling — We offer fertility preservation and reproductive counseling to all patients with anal cancer who are planning treatment. Treatments for anal cancer (chemotherapy, radiation therapy) may be gonadotoxic or impair the ability for future fertility. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Anal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical terminology

•Anal cancer – An anal cancer is clinically defined as a tumor that develops from any of the three types of mucosa located in the anal region (glandular, transitional, and squamous mucosa) and cannot be visualized in its entirety while gentle traction is placed on the gluteal cheeks (buttocks) (figure 1). (See 'Definition' above.)

•Perianal cancer – Perianal cancers are clinically defined as tumors that arise in the hair-bearing skin within a 5 cm radius of the anal verge that can be seen in their entirety with gentle traction placed on the gluteal cheeks (buttocks).

●Clinical presentation – The most common presenting symptoms of anal cancer include rectal or anal bleeding, anorectal pain, or the sensation of a rectal mass. Other symptoms include rectal pruritus, urgency, pressure, anal discharge, and changes in bowel habits. Some individuals are asymptomatic at presentation and are diagnosed incidentally. (See 'Clinical presentation' above.)

●Diagnostic evaluation – The diagnosis of anal cancer is suspected in the adult patient with an anal mass, particularly those who are symptomatic (eg, anorectal bleeding or pain) or have specific risk factors for anal cancer. Diagnostic evaluation includes (see 'Diagnostic evaluation' above):

•History – A history of common symptoms related to anal cancer, prior endoscopic studies, and risk factors specific to anal cancer (multiple sexual partners, receptive anal intercourse, sexually transmitted infections, other human papillomavirus (HPV)-associated cancers, tobacco use, prior HIV infection, and chronic immunosuppression). (See 'History' above.)

•Physical examination – A complete physical examination, including palpation for all lymph nodes (especially bilateral inguinal lymph nodes). (See 'Physical examination' above.)

•Anorectal examination and endoscopy – A complete anorectal examination including inspection, digital rectal examination (DRE), and endoscopy (proctoscopy/anoscopy, flexible sigmoidoscopy, or colonoscopy). (See 'Endoscopy' above and "Approach to adult patients with anorectal complaints", section on 'Anoscopy or proctoscopy'.)

●Biopsy – The diagnosis of anal cancer is typically confirmed on biopsy of visualized anal masses suspected to anal cancer and histopathologic evaluation of the obtained tissue sample. (See 'Biopsy (diagnosis)' above.)

●Imaging studies – For patients with a confirmed diagnosis of anal cancer or squamous cell carcinoma (SCC) of the perianal skin, we obtain staging imaging studies using contrast-enhanced CT of the chest and abdomen. Pelvic imaging is obtained using either a contrast-enhanced CT or MRI of the pelvis with gadolinium contrast. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT from skull base to midthigh is an additional option for staging imaging but it is not mandatory and should not replace a diagnostic CT scan. (See 'Imaging studies' above.)

●Staging system – All carcinomas (eg, squamous cell, adenocarcinoma) that arise within any of the mucosal surfaces of the anal canal or the perianal skin are staged similarly using the joint American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) Tumor, Node, Metastasis (TNM) staging system for anal cancers (table 1). (See 'Staging system' above.)

●Pretreatment evaluation – Pretreatment evaluation includes a baseline complete blood count with differential, a chemistry panel, liver function testing, HIV testing (for those with an unknown HIV status), a gynecologic examination in female patients, and fertility preservation and reproductive counseling. (See 'Pretreatment evaluation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David P Ryan, MD, who contributed to earlier versions of this topic review.