Anal Carcinoma

Etiology

An increasing number of risk factors for anal carcinoma have been identified, with global social and cultural shifts over recent decades contributing to heightened exposure to these risk factors, which include:

• Human papillomavirus (HPV) infection: Persistent infection with HPV, a nonenveloped, double-stranded DNA virus that infects the squamous epithelium, is the most significant risk factor for anal squamous cell carcinoma (SCC). Chronic infection with high-risk HPV subtypes, particularly HPV-16 and HPV-18, is strongly associated with anogenital malignancies, including cervical, vaginal, vulvar, penile, and oropharyngeal cancers, as well as anal carcinoma. HPV is primarily transmitted through direct skin-to-skin contact, with sexual activity increasing the likelihood of exposure, although transmission can occur independently of sexual contact.[5]

• Age: The incidence of anal carcinoma increases with advancing age, with a median age at diagnosis of 62. While the disease is rare in individuals younger than 35, incidence rates are rising among younger adults. The highest prevalence is observed in women aged 75 to 79 and men aged 80 to 84. Age is also a critical factor in the progression to high-grade anal intraepithelial neoplasia, particularly in both HIV-positive and HIV-negative males. This trend is primarily attributed to the prolonged latency period associated with HPV-related carcinogenesis.[6]

• Gender: Anal carcinoma exhibits a higher prevalence in women than in men, though the underlying mechanisms for this gender disparity remain incompletely understood. The higher HPV infection rates among females and the anatomical proximity of the genital and anal regions, facilitating cross-site viral transmission, may contribute to this discrepancy. Additionally, preclinical models suggest that female sex hormones may influence HPV-independent anal SCC pathogenesis, with estrogen and progesterone withdrawal potentially exerting a protective effect against tumor development.[7]

• Human immunodeficiency virus (HIV): HIV-positive individuals face a markedly increased risk of anal carcinoma, with incidence rates up to 40 times higher than those observed in the general population. This population also demonstrates a heightened prevalence of anal dysplasia and invasive carcinoma, often with earlier age at diagnosis. The precise mechanisms by which HIV-related immunosuppression differentially affects specific HPV subtypes and their oncogenic potential remain unclear. However, studies have demonstrated a strong correlation between lower CD4+ T-cell counts (<200/mm³) or a low CD4 nadir and an increased risk of progression from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) or invasive anal carcinoma.[8]

• Sexual activity: Sexual behavior significantly influences the risk of anal carcinoma. Factors, eg, multiple lifetime sexual partners, early initiation of sexual activity, and engagement in receptive anal intercourse are associated with increased rates of anal HPV infection, thereby elevating the risk of malignant transformation.[9]

• Immunosuppression: Individuals with immunosuppressive conditions—including organ transplant recipients and patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, and ulcerative colitis—are at elevated risk for anal carcinoma. Long-term systemic corticosteroid therapy further contributes to this vulnerability. The increased incidence in immunosuppressed individuals is attributed to impaired immune surveillance, reducing the host’s ability to clear persistent HPV infections.[10]

• Smoking: Tobacco use is a significant independent risk factor for anal carcinoma, with risk escalating in direct correlation with the number of pack-years smoked. Smoking is believed to interfere with apoptotic pathways that facilitate the elimination of dysplastic or malignant cells. Furthermore, tobacco use may impair immune function, thereby diminishing the body’s capacity to clear persistent HPV infections and dysplastic anal epithelial cells.[11]

Epidemiology

Anal carcinoma is a relatively uncommon malignancy, comprising approximately 2.8% of all newly diagnosed digestive system cancers in the United States, with a female-to-male incidence ratio of 2.1:1. Each year, an estimated 10,000 new cases are identified in the United States, with over 50,000 cases reported globally. Despite its relative rarity, the incidence of anal carcinoma has been steadily increasing worldwide. The disease is infrequent in individuals younger than 35, with the majority of cases occurring in older adults, typically around the early 60s. Epidemiological data indicate a higher prevalence among White women and Black men. At the time of diagnosis, approximately 48% of cases remain localized to the primary site, 32% exhibit regional lymphatic involvement, and 13% present with distant metastases.[2][12][13]

Pathophysiology

The pathophysiology of anal SCC is strongly associated with chronic inflammatory processes triggered by persistent HPV infection. HPV preferentially targets the squamocolumnar transition zone within the anal canal, where viral particles infect the basal epithelial cells. This leads to the expression of early viral oncoproteins, eg, E6 and E7, which drive cellular proliferation, disrupt tumor suppressor pathways, and promote malignant transformation. Persistent infection with high-risk HPV serotypes, particularly HPV-16 and HPV-18, is a well-established precursor to anal intraepithelial neoplasia (AIN), a premalignant condition characterized by dysplastic changes in the squamous epithelium. AIN is classified into grades AIN 1, AIN 2, and AIN 3, based on the extent of epithelial abnormalities, mitotic activity, and nuclear atypia. Progression from AIN to invasive SCC occurs in approximately 10% to 11% of cases, with a significantly higher malignant transformation risk in HIV-positive individuals due to impaired immune surveillance.[1]

Molecular profiling of anal SCC has identified recurrent mutations in the PI3K/AKT/mTOR signaling pathway, as well as alterations in chromatin-modifying genes MLL2 and MLL3, which may contribute to tumor initiation and progression. Additionally, genetic alterations in key tumor suppressor genes, including TP53 and CDKN2A, have been observed, with CDKN2A mutations being more prevalent in HPV-negative tumors, which are associated with worse clinical outcomes. Furthermore, programmed death-ligand 1 (PD-L1) expression is detected in approximately 30% of HPV-positive and 40% of HPV-negative anal SCC cases. This suggests a potential role for immune checkpoint dysregulation in tumor pathogenesis, which may have therapeutic implications, particularly in the setting of immunotherapy-based treatment strategies.[14][15][16]

Histopathology

Premalignant Lesions

The WHO classification includes low- and high-grade intraepithelial neoplasia or dysplasia, Bowen disease, and perianal squamous intraepithelial neoplasia. Other systems, eg, the American Joint Commission on Cancer (AJCC), use terms like carcinoma in situ, high-grade squamous intraepithelial lesion (HSIL), and AIN grades 2 to 3.[17]

LSIL-AIN 1 is characterized by the proliferation of metaplastic squamous cells with nuclear irregularities confined to the lower third of the epithelium or by koilocytotic alterations in a papillary structure. In contrast, HSIL-AIN 2-3 is identified by a thickened epithelial layer containing atypical cells with disrupted nuclear polarity, significant nuclear pleomorphism, a high nuclear-to-cytoplasmic ratio, pronounced nuclear hyperchromatism, and elevated mitotic activity.[18]

Malignant Tumors

Types of malignancies associated with anal cancer include:

• Squamous cell carcinoma: The most common anal malignancy (85%), SCC typically arises at the transformation zone between squamous and columnar epithelium. The cells may exhibit large, pale, eosinophilic squamous features, with or without regions of keratinization. Alternatively, tumor-cell clusters may display prominent nuclear palisading. These cells can form tumor nests, and well-differentiated tumors might show peripheral nuclear palisading or central areas of keratinization.
• Verrucous carcinoma: Known as the Buschke-Löwenstein tumor, this locally aggressive lesion resembles condyloma but has destructive potential.
• Adenocarcinoma: Originating in mucosa or anal glands, adenocarcinoma may be associated with Paget or Crohn’s disease.
• Melanoma: Rare and aggressive, anal melanomas resemble cutaneous melanomas but are associated with poor prognosis.
• Neuroendocrine tumors: Accounting for 1% of anal cancers, these rapidly growing tumors are diagnosed with immunohistochemical markers like chromogranin and synaptophysin.[19][1]

Other Rare Tumors

Less common types include lipomas, Kaposi sarcoma, leiomyosarcomas, and basal cell carcinomas, which are often limited to the anal skin.[19]

Immunohistochemistry and Molecular Features

SCC typically exhibits markers including CK5/6, CK13/19, and p63. In contrast, CK7 is generally present in adenocarcinoma but is usually absent in SCC, except in cases with adenoid cystic patterns, where CK7 may be expressed. Neuroendocrine tumors are characterized by positive staining for classic neuroendocrine markers, melanomas by melanocytic markers, and lymphomas by a specific panel of lymphoid markers. For primary perianal Paget disease, CK and gross cystic disease fluid protein 15 (GCDFP15) are commonly expressed. However, in cases involving pagetoid extension from colorectal or urothelial adenocarcinoma, the pagetoid cells often coexpress CK20 and lack GCDFP-15.[20]

History and Physical

Clinical History

Assessing a patient for suspected anal carcinoma begins with a thorough clinical history and physical examination. Clinicians should obtain detailed information regarding the duration, progression, and nature of symptoms, including rectal bleeding, unexplained weight loss, fecal incontinence, and anal or perirectal pain. Anal carcinoma most commonly presents with rectal or anal bleeding in nearly 50% of cases, followed by anal pain and the presence of a palpable mass. Additional symptoms may include pruritus, tenesmus, mucopurulent discharge, changes in stool caliber, and alterations in bowel continence. Some patients may exhibit clinical features resembling benign anorectal conditions, eg, anal fissures or fistulas, whereas others remain asymptomatic until the disease has reached an advanced stage.[21][22]

The duration of symptoms does not generally correlate with prognosis, except in cases where symptoms persist for less than 1 month, which has been associated with improved outcomes. The type of presenting symptom is more strongly correlated with the tumor's T stage rather than its duration. A comprehensive history should also include an assessment of prior or current HPV and HIV infections, as both are significant risk factors for anal carcinoma.[23]

Physical Examination

A digital rectal examination (DRE) and an evaluation for inguinal and femoral lymphadenopathy are essential. The precise location of the lesion should be identified, differentiating between the following:

• Skin lesions: Located >5 cm from the anal verge and visible without the need for traction.
• Perianal lesions: Found within 5 cm of the anus, fully visible with gentle traction.
• Anal canal lesions: Wholly or partially nonvisible even with traction, requiring DRE for identification.

In women, performing a vaginal exam and evaluating the cervix to rule out HPV related cervical pathology, which can coexist, is essential.[23] 

During staging assessment, tumor size, mobility, and rectal tone should be carefully documented. Advanced disease may present with inguinal or femoral lymphadenopathy, particularly in cases where the tumor is distal to the dentate line. Lymph node involvement is a critical prognostic indicator, as nodal metastasis significantly reduces survival rates in locally advanced disease.[23]

Evaluation

Anal carcinoma evaluation comprises several laboratory, imaging, and histologic studies for initial diagnosis as well as posttreatment monitoring.

Laboratory Studies

The following laboratory studies are recommended in the evaluation of anal carcinoma:

• HIV testing as anal cancer has a strong association with HPV and is more common in HIV-positive patients.
• Complete blood count (CBC) to assess for anemia or other hematologic abnormalities.
• Liver function to evaluate for possible liver metastases.
• High-risk HPV subtypes (HPV-16, HPV-18) are implicated in most cases of anal squamous cell carcinoma. Testing for p16 protein (a surrogate marker for HPV-related cancer) may provide prognostic information.[24]

Gynecologic and Fertility Assessment

Infertility risks and fertility preservation counseling should be discussed before treatment begins.[24]

Imaging Studies

Imaging plays a pivotal role in staging, treatment planning, and response assessment in anal cancer, predominantly squamous cell carcinoma. The primary objectives include defining tumor extent (T-staging), assessing nodal involvement (N-staging), and detecting distant metastases (M-staging).

High-resolution anoscopy

High-resolution anoscopy (HRA) enhances an anoscope with a high-magnification colposcope, offering a more detailed imaging approach for identifying precancerous squamous cell changes. A large, multicenter randomized controlled trial (ANCHOR) found that detecting HSIL through biopsy and treating with local ablation, topical fluorouracil, or topical imiquimod significantly reduces the risk of developing anal cancer, thereby highlighting the advantages of early detection and intervention.[23][25]

Magnetic resonance imaging 

Magnetic resonance imaging (MRI) with high-resolution T2-weighted (T2WI), diffusion-weighted (DWI), and dynamic contrast-enhanced (DCE) sequences is the preferred modality for T and N staging. It provides superior soft-tissue contrast, allowing precise delineation of tumor invasion into the sphincters, levator ani, and adjacent structures. The sensitivity for primary tumor detection approaches 95%, with specificity for distinguishing viable tumors from fibrosis postchemoradiation reaching 85% to 90%.MRI criteria for nodal involvement include size >10 mm, irregular borders, central necrosis, and restricted diffusion. The sensitivity and specificity for detecting metastatic lymph nodes are 85% and 78%, respectively. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology, and European Society for Medical Oncology guidelines endorse MRI as the primary staging modality.[24][26][27]

Computed tomography

Contrast-enhanced CT (CECT) of the chest, abdomen, and pelvis is essential for M-staging, particularly for the lungs and liver, which are common metastatic sites. Sensitivity for pulmonary metastases is 80% to 90%, while for liver metastases, it ranges from 85% to 95%. Although inferior to MRI in local staging, CT is often used when MRI is unavailable or contraindicated.

Positron emission tomography-computed tomography 

FDG positron emission tomography-computed tomography (PET-CT) is highly sensitive for nodal metastases (90% to 95%) and superior to CT for distant disease detection, with a specificity of 85% to 90%. PET-CT benefits small, borderline lymph nodes and distant metastases undetected by MRI or CT (see Image. Anal Squamous Cell Carcinoma). PET-CT plays a crucial role in posttreatment response assessment, distinguishing viable tumor from radiation-induced fibrosis, where MRI alone has limitations.NCCN recommends PET-CT in cases of suspected metastases, particularly in T3/T4 or node-positive disease.[24][28][29]

Endoanal ultrasound

For early-stage (T1-T2) tumors, endoanal ultrasound provides high-resolution visualization of tumor depth and sphincter invasion, with a sensitivity of 85% to 95% and specificity of 75% to 85%. However, endoanal ultrasound is operator-dependent and limited in larger or locally advanced tumors, where MRI is superior.[30]

Inguinal lymph node ultrasound with fine-needle aspiration

Ultrasound-guided fine-needle aspiration is critical for inguinal lymph node evaluation, particularly when MRI or CT findings are indeterminate. Hypoechoic texture, loss of fatty hilum, and irregular margins characterize suspicious lymph nodes. Fine-needle aspiration confirms metastases with a diagnostic accuracy of 90% and is recommended by the NCCN when inguinal adenopathy is present.[24]

Imaging in Treatment Response and Surveillance

MRI remains the modality of choice for posttreatment assessment, though postradiation fibrosis versus residual disease remains a challenge (specificity ~80%). With its ability to detect metabolic activity, PET-CT improves accuracy in distinguishing recurrence, mainly when conventional imaging is inconclusive.[31]

Treatment / Management

Historically, the treatment for anal cancer involved surgical resection via abdominoperial resection, which achieved a cure rate of approximately 50% but was associated with significant morbidity. Today, the standard treatment for localized anal cancer has shifted to a combination of chemotherapy and radiation, which offers improved outcomes with reduced morbidity.[32]

The diagnostic evaluation and workup for anal canal cancer and perianal cancer are similar; however, treatment strategies differ based on the stage and anatomical location of the disease. For SCC of the anal canal, chemoradiation is the primary treatment, with surgery typically reserved for cases of persistent or recurrent disease. In contrast, early-stage perianal SCC (T1N0 and select T2N0 cases) can often be treated effectively with local excision, while more advanced stages usually require chemoradiation.[33]

Close posttreatment surveillance is essential to monitor the response to therapy after chemoradiation. Anal cancers tend to regress slowly over time, with complete responses often taking up to 26 weeks. Progressive disease during or after this period should be evaluated with a biopsy, and salvage surgical resection should be considered when necessary. For patients with metastatic disease, treatment is palliative and includes chemotherapy regimens such as fluorouracil, mitomycin-C, cisplatin, and paclitaxel. Additionally, ongoing clinical trials are exploring the role of immunotherapy in the management of anal SCC, offering potential new avenues for treatment.[34][35](B3)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating anal carcinoma include:

• Condylomata acuminatum
• Hemorrhoid
• Skin tag
• Anal fissure/fistula
• Chancroid
• Psoriasis

Surgical Oncology

Early-Stage Anal Cancer

Local excision is a therapeutic option for superficially invasive squamous cell carcinoma (SISCCA), which meets specific histopathologic criteria: tumor invasion of ≤3 mm into the basement membrane and a horizontal spread of ≤7 mm (T1, NX). SISCCA is frequently detected incidentally during the biopsy or excision of lesions presumed to be benign, eg, condylomas, hemorrhoids, or anal skin tags.

In cases where the carcinoma is completely excised with histologically confirmed negative margins, local excision may suffice as definitive treatment, as long as the site is surveyed closely. Close follow-up is essential, as studies indicate a 74% incidence of HSIL following local excision (see Image. Anal High-Grade Squamous Intraepithelial Lesions). A retrospective study of 17 patients with completely excised invasive anal carcinoma, including 7 with SISCCA, demonstrated excellent outcomes, reporting a 5-year overall survival (OS) rate of 100% and recurrence-free survival of 87% after a median follow-up of 45 months.[36]

Local excision is also a potential treatment modality for select perianal carcinomas, specifically T1, N0 or well-differentiated T2, N0 tumors that do not involve the anal sphincter complex. A surgical margin of at least 1 cm is recommended in these cases. However, thorough evaluation for anal canal involvement is necessary, as many patients with T1 or select T2 perianal carcinomas also harbor HSIL within the anal canal, a factor that must be considered when opting for conservative management.[24]

Locally Advanced and Recurrent Anal Cancer

Chemo-radiotherapy (chemoRT) remains the standard first-line treatment for anal carcinoma; however, locoregional failure rates range from 10% to 30%. Risk factors for tumor recurrence following chemoRT include higher T-stage and nodal metastasis (N-stage). If disease progression is suspected based on DRE findings, further biopsy and imaging (eg, CT or PET/CT) assessment is warranted. In patients with biopsy-confirmed locally progressive disease, radical surgical resection via abdominoperineal resection (APR) may be considered.

For select patients with locally advanced or recurrent disease, immunotherapy with nivolumab or pembrolizumab may be an alternative to surgery. However, mature clinical data to support this approach are not yet available.[24][37]

Radiation Oncology

Radiation doses for anal cancer treatment are derived from the RTOG 98-11 trial, which established dosing protocols tailored to tumor size, stage, and risk of nodal involvement. These doses are individualized based on individual factors. Additional radiation fractions are often prescribed for high-risk areas or involved nodal basins to ensure adequate tumor control while minimizing radiation-induced toxicity.

Intensity-modulated radiation therapy (IMRT) has become the preferred technique over 3-dimensional conformal radiation therapy (3D-CRT) due to its ability to optimize tumor coverage, reduce radiation exposure to adjacent normal tissues, and lower treatment-related toxicity. IMRT also allows for dose painting, where different regions receive customized radiation intensities, improving local tumor control and reducing adverse effects such as dermatitis, proctitis, and enteritis.[38]

A standard radiation protocol typically includes a minimum dose of 45 Gy to the primary tumor across all disease stages, ensuring adequate coverage of the gross tumor volume (GTV) and areas at risk for microscopic disease. The initial phase of treatment delivers 30.6 Gy, encompassing the pelvis, anus, perineum, and inguinal lymph nodes, as these areas are at high risk for subclinical disease. Patients with T2-T4 tumors or clinically positive lymph nodes require an additional boost of 9 to 14 Gy, further escalating the total dose to approximately 54 to 59 Gy in high-risk regions. In cases of persistent or recurrent disease, dose escalation beyond 59 Gy may be considered. Concurrent chemotherapy with radiation is typically used to increase efficacy.[24][39]

Medical Oncology

Nonmetastatic Disease

The current standard protocol consists of 5-fluorouracil (5-FU)-based chemotherapy combined with mitomycin-C (MMC) and concurrent radiation (RT). The approach known as the Nigro regimen revolutionized anal cancer treatment by showing that chemoradiation (5-FU + MMC + RT) could achieve high cure rates without surgery. This regimen used 5-FU (1,000 mg/m²/day, continuous infusion on days 1 to 4 and 29 to 32) and MMC (10 to 15 mg/m², single dose on day 1) with RT. Later trials refined the regimen, confirming MMC (10 mg/m² capped at 20 mg, day 1 and 29) + 5-FU (1,000 mg/m²/day, days 1 to 4 and 29 to 32) + RT as the gold standard for locally advanced anal cancer. Complete tumor regression was seen in 80% to 90% of cases, significantly outperforming radiation therapy alone, with a response rate of 45% to 56%. The best outcomes are observed in patients with T1/T2 tumors and no nodal involvement.[40][41][24]

Capecitabine, an oral alternative to 5-FU, has been investigated and demonstrated similar clinical outcomes but lower hematologic toxicity in retrospective studies, particularly reduced rates of neutropenia. However, nonhematologic toxicities, eg, hand-foot syndrome and gastrointestinal adverse effects, may be more frequent with capecitabine. The NCCN panel recommends mitomycin/capecitabine plus RT as an alternative for stages I to III.[42][43]

Cisplatin has been studied as a substitute for 5-FU or mitomycin. The ACT II Trial found no significant difference between 5-FU + MMC + RT and 5-FU + cisplatin + RT regarding complete response, colostomy-free survival, or overall survival, confirming no advantage of cisplatin over MMC. However, the RTOG 98-11 trial showed that 5-FU + MMC + RT had superior 5-year overall survival (78% versus 70%) and lower locoregional failure rates compared to 5-FU + cisplatin + RT, establishing MMC as the preferred agent.[40][41] Studies also suggest no added benefit from induction chemotherapy or radiation dose boosts in chemoRT protocols for localized anal cancer.

Emerging treatments include biologics like PD-1 inhibitors and EGFR-targeting therapies, eg, cetuximab. While promising, cetuximab has shown significant toxicity in trials, limiting its applicability. For older or less fit patients unable to tolerate mitomycin, options such as cisplatin-based regimens, capecitabine, or RT alone are under consideration, though data remain insufficient for definitive recommendations.[44][24]

Metastatic Disease

Metastatic anal cancer most commonly spreads to the liver, lungs, and extrapelvic lymph nodes. Although this type of cancer is rare, with only 10% to 20% of cases presenting as metastatic outside the pelvis, systemic therapy has demonstrated potential benefits. Palliative chemoRT to the primary tumor site can be considered for local control in symptomatic, bulky tumors following initial chemotherapy. Data from the National Cancer Database indicate that combining chemotherapy with definitive pelvic RT is associated with longer median OS than chemotherapy alone (21.3 versus 15.9 months). Additionally, retrospective studies suggest that surgical removal or ablation of liver metastases may improve long-term outcomes, although this strategy is not yet included in standard guidelines.[45]

First-Line Chemotherapy

The phase II InterAACT trial identified carboplatin combined with paclitaxel as the preferred first-line regimen for metastatic anal cancer due to its favorable toxicity profile compared to cisplatin and 5-FU. While response rates were similar (approximately 59%), carboplatin plus paclitaxel demonstrated longer progression-free survival (PFS) and OS (8.1 and 20 months, respectively) compared to cisplatin and 5-FU (5.7 and 12.3 months, respectively). Other treatment options include FOLFCIS (5-FU, Leucovorin, Cisplatin), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and modified DCF (Docetaxel, Cisplatin and 5-FU) regimens, each showing varying efficacy and safety profiles. For instance, FOLFOX is noted for manageable safety, while modified DCF shows promise but comes with higher toxicity concerns.[46]

Ongoing research is exploring the integration of immune checkpoint inhibitors to enhance treatment outcomes. The phase III POD1UM-303/InterAACT 2 trial is evaluating the addition of retifanlimab to carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal. Preliminary results indicate a significant improvement in progression-free survival with the inclusion of retifanlimab. EA2176 trial is a Phase III clinical study evaluating the addition of nivolumab to the chemotherapy regimen of carboplatin and paclitaxel for patients with metastatic anal cancer.[47]

Second-Line Chemotherapy

Checkpoint inhibitors have shown promise for patients with refractory metastatic anal cancer. Trials of nivolumab and pembrolizumab demonstrated response rates of 24% and 17%, respectively, with manageable toxicity. Pembrolizumab also showed benefits in a microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) cancer cohort, with an objective response rate of 11%. Further research is underway, including trials evaluating nivolumab alone or in combination with ipilimumab and other novel agents. Current guidelines recommend PD-1 inhibitors like nivolumab and pembrolizumab as preferred second-line therapies for patients who have progressed on initial chemotherapy.[48][49]

Staging

Anal cancer staging established by the AJCC ninth edition uses the following tumor, node, metastasis criteria: 

• T (tumor) stage 
  • TX Primary tumor not assessed
  • T0 No evidence of primary tumor
  • Tis high-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II to III, high-grade anal intraepithelial neoplasia)
  • T1 Tumor ≤2 cm
  • T2 Tumor >2 cm but ≤5 cm
  • T3 Tumor >5 cm
  • T4 Tumor of any size invading adjacent organs, eg, the vagina, urethra, or bladder
• N (node) stage
  • 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 (N1b) and any N1a nodes
• M (metastasis) stage:
  • M0 No distant metastasis
  • cM1 Distant metastasis
  • pM1 microscopic confirmation of distant metastasis [24]

Prognosis

The prognosis of anal carcinoma is primarily determined by tumor size and the presence of lymph node metastases. At the time of diagnosis, approximately 50% of patients present with localized disease (T1-T2, N0), which is associated with a 5-year OS rate of 80%. However, 29% of patients exhibit regional lymph node involvement (N1-N3), which reduces the 5-year survival rate to 60% due to the increased risk of locoregional recurrence and distant dissemination. Approximately 12% of cases present with distant metastases (M1), leading to a reduced 5-year survival rate of 30.5%.[21]

A comprehensive analysis of over 600 patients from the RTOG 98-11 trial reinforced the prognostic significance of tumor and nodal classification in predicting OS, disease-free survival, and colostomy-free survival. The study highlighted that patients with T4, N0 disease and T3-T4, N+ disease had the poorest outcomes, demonstrating higher rates of treatment failure, locoregional recurrence, and the need for colostomy.[50][24]

Complications

Treatment-related toxicities are a well-documented consequence of chemoradiation for anal SCC. These complications, which can involve both superficial and deep pelvic structures, often have a profound impact on patients' quality of life. In some cases, they necessitate planned or unplanned interruptions in therapy, potentially compromising treatment outcomes. Research indicates that up to 80% of patients require treatment breaks due to these toxicities.[51][33]

Radiation-induced toxicities are given the following classifications of acute if they occur within 3 months of treatment or late if they arise beyond this period:

• Acute toxicity complications (< 3 months posttreatment): Anoproctitis, bleeding, cystitis, diarrhea, dehydration, enteritis, neutropenia, pelvic/perineal pain, and perineal dermatitis. 
• Late toxicity complications (>3 months posttreatment): Anorectal or perineal pain, bowel obstructions, decreased sexual desire, fecal incontinence, fistulas, impotence, non-healing wounds, osteomyelitis, osteonecrosis, pelvic fractures, stricture, urinary incontinence, and vaginal stenosis. 

Encouragingly, several quality-of-life studies have demonstrated that symptoms associated with acute toxicities often improve or resolve within 3 months following the completion of therapy.[32]