Gross anatomy

There are three regions where anal cancers occur; the perianal skin or anal margin, the anal canal, and the lower rectum. The anal canal is 3–4 cm long and extends from the anal verge to the pelvic floor.¹ Cancers of the anal canal and the anal margin have different natural histories. The literature is confusing because of the various definitions of the anal canal and the anal margin. For example, some define the distal limit of the anal canal as the dentate line and all tumors below this as anal margin cancers,^{2, 3} others consider the distal extent of the anal canal as the anal verge,^{4, 5} while another definition of anal margin tumors are those tumors that arise within 5 cm of the anal verge.⁶

The incidence of anal margin and anal canal cancers is dependent on the anatomical boundaries. When the anal verge is defined as the distal margin of the anal canal, 15% of tumors arise from the anal margin, but this number increases to 30% when the dentate line is used as the distal limit. To clarify this issue, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contra le Cancer (UICC) formed a consensus that the anal canal extends from the anorectal ring (dentate line) to the anal verge.^{7, 8} These two organizations agree that anal margin tumors behave in a similar manner to skin cancers and therefore are classified and treated as skin tumors.

There is an extensive lymphatic system for the anus with many connections. The three main pathways include (1) superiorly from the rectum along the superior hemorrhoidal vessels to the inferior mesenteric lymph nodes, (2) from the upper anal canal and superior to the dentate line along the inferior and middle hemorrhoid vessels to the hypogastric lymph nodes, and (3) inferior from the anal margin and anal canal to the superficial inguinal lymph nodes.

Epidemiology

In the United States, cancers of the anal region account for 1–2% of all large bowel cancers and 4% of all anorectal carcinomas. Since 1997, the incidence of carcinoma in situ (CIS) and squamous cell cancer (SCC) anus have dramatically increased. However, more men are more likely to be diagnosed with CIS.⁹ In 2014, a total of 7210 cases of cancers of the anal region are estimated to occur in the United States, including 2660 men and 4550 women.¹⁰ It is estimated that there will be 950 deaths.

Etiology

Pathology

A variety of histologic cell types may occur in the anal area.³² The majority of these (75–80%) are squamous cell carcinomas³³ and 15% are adenocarcinomas. In addition to the more common types seen in Table 1, other rare histologic entities can arise, such as small cell carcinomas³⁵ and lymphoma. Melanomas constitute 1–2% of all anal cancers.³⁶

Source: Peters 1983,³⁴ Reproduced with permission of MacMillan Publishing Group.

Squamous tumors may arise from the entire length of the anal canal as well as from the anal margin. Basaloid carcinomas, which are a variant of squamous carcinoma, are commonly referred to as cloacogenic carcinomas. Adenocarcinomas arise from the glands at the dentate line. Small cell carcinomas are of neuroendocrine origin and are rare.

Tumors of the anal margin include squamous carcinoma, basal cell carcinoma, Bowen’s disease (squamous CIS), Paget’s disease (adenocarcinoma in situ), verrucous carcinoma, and Kaposi’s sarcoma. Malignant melanomas may arise from either location but more commonly from below the dentate line.

Squamous cell tumors are divided into those with and without keratinization,³⁷ and nonkeratinizing tumors are further subdivided into basosquamous, basaloid, and cloacogenic carcinomas. With the exception of melanoma and sarcoma, most clinicians conclude that prognosis is more dependent on stage rather than histology and treat all histologic varieties the same.^{38, 39} In contrast, using a multivariate analysis, Das and associates reported a higher distant metastasis rate for patients with basaloid histologies.⁴⁰

Studies of flow cytometric analysis are conflicting and have reported both high proliferative index but near-diploid peaks⁴¹ as well as an aneuploid pattern.⁴² In a multivariate analysis by Shepard et al, the depth of penetration, inguinal node involvement, and DNA ploidy were of independent prognostic significance.⁴³

Natural history

The most common route of spread is by local extension proximally to involve other organs in the pelvis. Hematogenous spread occurs more often from tumors that arise at or above the dentate line.⁴⁴ This pattern of spread allows tumor cells into the portal system resulting in liver and lung metastases in 5–8% of patients⁴⁴ and bone in 2%.⁴⁵ Distant metastases occur with equal frequency independent of the histologic cell type involved. Distant metastases are rarely seen with anal margin tumors.

Lymphatic spread is common and involves the inguinal, pelvic, and mesenteric nodes. Inguinal lymph nodes are positive in 15–63% of cases.^{46, 47} The incidence of synchronous positive inguinal nodes is 15%.^{44, 48} In a series of 96 patients, Metachronous positive inguinal nodes appeared in 25% with a median time to presentation of 12 months. Pelvic nodes are less commonly involved and mesenteric nodes are more likely to be involved if the tumors are proximal (50%) than distal (14%).⁴⁹ Positive mesenteric nodes in anal margin tumors are rare.

Historic surgical series report survivals of 0–20% following lymph node dissection with synchronous positive nodes.^{50, 51} Modern CMT has substantially improved this. Patients who undergo lymph node dissection for metachronous lesions have more favorable survivals with rates as high as 83%.^{50, 52} The majority of these recurrences occur by 2 years but may present as late as 8 years.⁴⁹

Diagnosis

The initial and most common symptom is bleeding, which occurs in over 50% of patients. Other common symptoms include pain, tenesmus, pruritus, change in bowel habits, abnormal discharge, and less commonly, inguinal lymphadenopathy.^{49, 53, 54} Most of these symptoms are associated with benign conditions of the anus including fissure, fistula-in-ano, hemorrhoids, anal pruritus, and anal condyloma. Benign perianal conditions may coexist in 60% of anal margin tumors and in 6% of anal canal tumors.⁵⁵

The most common physical finding is an intraluminal mass that can be misdiagnosed as a hemorrhoid.^{45, 46} Endoscopically, the tumors may appear as flat or slightly raised lesions, as raised lesions with indurated borders, or as polypoid lesions (Figure 1). The use of transrectal ultrasound is required and allows for the determination of depth of penetration and involvement of adjacent organs.⁵⁶

An incisional biopsy is recommended for diagnosis. Excisional biopsies should be limited to small superficial lesions. Clinically palpable inguinal lymphadenopathy should be aspirated for cytological examination. A formal inguinal lymph node dissection is not recommended owing to the associated morbidity, failure to have an impact on outcome, and the high control rates with CMT. In a report by Garcia and associates of 46 HIV+ patients, anal brush cytology was more sensitive and specific for external compared with internal lesions.⁵⁷ High-resolution anoscopy is helpful in detecting both high-grade intraepithelial and invasive lesions in HIV+⁵⁸ and HIV− patients.⁵⁹

Although a metastatic work-up is commonly negative, it includes computed tomography (CT) of the abdomen and pelvis to evaluate the primary tumor and exclude liver metastases. A chest X-ray or chest CT is required.

Most studies reveal a benefit of positron emission tomography (PET) for staging.^60–63 In a series of 41 patients, ¹⁸flourodeoxyuridine glucose positron emission tomography (¹⁸FDG-PET) detected 91% of nonexcised primaries compared with 59% with CT alone.⁶⁴ In addition, 17% of inguinal nodes negative by CT and physical exam were positive by PET. Sveistrup et al.⁶² performed a retrospective analysis of 28 patients with SCC and found that compared with transrectal ultrasound, PET/CT upstaged disease in 14% and changed the treatment plan in 17%. Bannas et al.⁶⁵ reported that compared with either PET or CT alone, radiation field design was changed in 23% of patient who underwent a combined PET-CT.

Although feasible, the benefit of sentinel inguinal lymph node biopsy is variable and its role remains controversial.^66–68

Staging

A common staging system was developed in 1997 by the AJCC and the UICC. This staging system accounts for the fact that anal canal carcinoma is primarily treated by CMT and abdominoperineal resection (APR) is reserved for treatment failure. The TNM classification is clinical. The primary tumor is assessed for size and for invasion of local structures such as the vagina, urethra, or bladder. The seventh edition of the AJCC staging system is seen in Table 2.⁶⁹

Prognostic factors

As with most gastrointestinal cancers, the most important prognostic factors in anal cancer are T and N stage. In patients treated with radiation with or without chemotherapy, the most striking difference in results is seen when comparing T1-2 primary cancers (≤5 cm) versus T3-4 primary cancers (>5 cm). The local failure rates with T3-4 primary cancers are approximately 50% following CMT. When a complete response is achieved, the local failure rate is 25%.

Peiffert et al.⁷⁰ reported an increase in local failure with T-stage (T1: 11%, T2: 24%, T3: 45%, and T4: 43%) and a corresponding decrease in 5-year survival (T1: 94%, T2: 79%, T3: 53%, and T4: 19%). A similar decrease in 5-year colostomy-free survival with T1-2 tumors versus T3-4 tumors was reported by Gerard et al.⁷¹ (T1: 83% and T2: 89% vs T3: 50% and T4: 54%).

In contrast to T stage, the impact of positive lymph nodes is less clear. Unlike rectal cancer, inguinal lymph nodes in anal cancer are considered nodal (N) metastasis rather than distant (M) metastasis and patients should be treated in a potentially curative manner. Cummings et al reported that patients with negative nodes who received CMT had a higher 5-year cause specific survival compared with those with positive nodes (81% vs 57%).⁷²

The RTOG 87-04 trial (Table 3) reported a higher colostomy rate (which is an indirect measurement of local failure) in N1 versus N0 patients (28% vs 13%).⁷³ In node negative and possibly node positive patients, the addition of mitomycin-C decreased the overall colostomy rates. The EORTC randomized trial (Table 3) of 45 Gy ± 5-FU/mitomycin-C also reported that patients with positive nodes experienced significantly higher local failure (p = 0.035) and lower survival (p = 0.038) rates compared to those with negative nodes.⁷⁶

CFS, Colostomy free survival; *, statistically significant (p ≤ 0.05); MMC, Mitomycin-C; CDDP, cisplatin; LN+, lymph node positive; CR, complete response; PFS, progression free survival; EBRT, external beam radiation therapy. The ACT I trial included 23% anal margin cancers.

^a Biopsy at 6 weeks.

^b Biopsy at 8 weeks.

Allal et al. reported that, by multivariate analysis, the only variable for which there was a possible impact was overall treatment time (p = 0.09).⁸⁰ In the EORTC randomized trial, multivariate analysis identified that positive nodes, skin ulceration, and male gender were independent negative prognostic factors for local control and survival.⁷⁶ Goldman et al.⁸¹

Related posts:

Aberrant signaling pathways in cancer Disparities in cancer care Monoclonal serotherapy Tumor suppressor genes Neoplasms of the small intestine, vermiform appendix, and peritoneum and carcinoma of the colon and rectum Infections in patients with cancer

Stay updated, free articles. Join our Telegram channel

Join