Anal Neoplasms

Surg Clin N Am 82 (2002) 1233–1251

Anal neoplasms Harvey G. Moore, MDa, Jose´ G. Guillem, MD, MPHa,b,* a

Colorectal Surgery Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA b Cornell University Medical College, 525 East 68th Street, New York, NY 10021 USA

Perianal and anal canal neoplasms are relatively uncommon. Cancer of the anal canal constitutes 1.5% of gastrointestinal neoplasms in the United States, with approximately 3900 cases predicted for 2002 [1]. The varied histology of the anal canal and anal verge give rise to a wide spectrum of malignant and premalignant diseases. Fortunately, most are curable by either primary chemoradiation or local excision, allowing sphincter preservation in the majority of patients. Such is not the case for anorectal melanoma, which continues to have a guarded prognosis despite aggressive surgical therapy. The optimal treatment for other relatively rare anal neoplasms, such as anal adenocarcinoma, remains unclear. In this article, we review the various neoplasms that affect the anal canal and anal margin, focusing on diagnosis, therapy, and outcome.

Anatomy and histology of the anal canal A thorough understanding of anal canal anatomy is essential for accurate diagnosis and treatment of anal neoplasms. According to the traditional definition, the ‘‘surgical’’ anal canal extends from the anorectal ring (upper portion of the puborectalis/levator complex) at the floor of the pelvis to the anal verge. A variety of definitions, however, are used to define the anal canal, making comparison of distinct databases difficult. In an effort to standardize the reporting of anal neoplasms, the World Health Organization (WHO) has defined the anal canal as extending from the upper to the lower border of the internal anal sphincter, which approximates the above clinical definition.

* Corresponding author. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-1077, New York, NY 10021. E-mail address: [email protected] (J.G. Guillem). 0039-6109/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 3 9 - 6 1 0 9 ( 0 2 ) 0 0 0 5 7 - 9

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The lining of the anal canal is divided into three zones: the colorectal zone proximally, the anal transitional zone (ATZ, extending approximately 1 cm upward from dentate line), and the squamous zone (extending distally from the dentate line to the anal verge) [2]. The colorectal zone consists of columnar mucosa identical to the distal rectal mucosa. The ATZ contains many epithelial variants, including squamous and colorectal type mucosa as well as the ‘‘ATZ epithelium,’’ made up of four to nine cell layers including basal, columnar, and cuboidal cells. Melanocytes and endocrine cells are also occasionally found. The squamous zone consists of unkeratinized squamous mucosa without skin appendages. Melanocytes may also be present. The anal verge is the point at which modified squamous epithelium (anoderm) of the anal canal meets hair-bearing perianal skin. The perianal skin contains sweat, sebaceous, and apocrine glands, and is keratinized. The anal margin refers to the perianal skin extending approximately 5 cm to 6 cm from the anal verge. Essentially all skin cancers can affect the anal margin [2,3]. The lymphatic drainage of the anal canal is complex but important to understand when evaluating anal neoplasms. Drainage from the colorectal zone and the ATZ is primarily cephalad to the inferior mesenteric nodes via the superior rectal lymphatics. To a lesser degree, drainage may also occur via the inferior and middle rectal lymphatics to the internal iliac nodes. Lymphatic drainage of the anal canal between the dentate line and anal verge (squamous zone) is predominately to the inguinal lymph nodes. Secondary drainage can occur via the inferior rectal lymphatics to the ischioanal nodes and internal iliac nodes. Drainage from the perianal skin (anal margin) is entirely to the inguinal nodes [3]. Histologic typing and staging of rectal neoplasms The WHO has created guidelines for the classification of carcinoma of the anus (Box 1) [4]. Similarly, the American Joint Committee on Cancer (AJCC) has established the TNM staging system for anal carcinoma, which continues to be widely endorsed (Table 1) [5,6]. The primary tumor is staged according to clinical or pathological size and local extension (T stage). Regional lymph nodes (N stage) include the perirectal, internal iliac, and inguinal nodes (superficial and deep). All other nodal groups, as well as other organs, are considered distant metastases (M stage). Tumors of the anal margin are staged according to the system used for skin cancers [6]. Anal margin neoplasms Bowen’s disease Bowen’s disease (BD) of the perianal area is an intraepidermal squamous cell carcinoma (SCC), which likely represents the extreme end of a spectrum of epithelial dysplastic changes known as anal intraepithelial neoplasia (AIN). Whereas AIN generally refers to dysplastic changes of the anal canal

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Box 1. World Health Organization (WHO) Classification of Carcinoma of the Anus Anal Canal Malignant epithelial tumors Squamous cell (cloacogenic) carcinoma Large cell keratinizing Large cell non-keratinizing (transitional) Basaloid Adenocarcinoma Rectal type Anal gland type Associated with fistula-in-ano Small cell carcinoma Undifferentiated Anal Margin Malignant epithelial tumors Squamous cell carcinoma Giant condyloma (verrucous carcinoma) Basal cell carcinoma Others Bowen’s disease Paget’s disease Adapted from [4] Jass JR, Sobin LH. Histologic typing of intestinal tumors; World Health Organization. 2nd edition. New York: Springer-Verlag org; 1989. p. 41–7.

epithelium (see below), use of the term BD generally implies involvement of the perianal skin [7]. Human papillomavirus (HPV) is considered a potential etiological agent, with HPV 16 found in 60% to 80% of patients with perianal Bowen’s disease [8]. It is estimated that Bowen’s disease may progress to invasive SCC in approximately 2% to 5% of cases [9]. Although early reports suggested a strong connection between BD and subsequent development of other internal malignancies (which were reported in up to 68.5% of BD cases) [10], more recent studies have reported no significant association between BD and subsequent internal malignancy [9,11–14]. Bowen’s disease presents as an asymptomatic or mildly symptomatic scaly, erythematous rash of the perianal area. Pruritus and burning of the

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Table 1 TNM staging system for anal carcinoma of the American Joint Committee on Cancer (AJCC) Primary Tumor (T stage) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor
2 cm in greatest dimension T2 Tumor > 2 cm but not > 5 cm in greatest dimension T3 Tumor > 5 cm in greatest dimension T4 Tumor of any size invades adjacent organ(s), eg. vagina, urethra, bladder Regional lymph nodes (N stage) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in perirectal lymph nodes N2 Metastasis in unilateral internal iliac and/or inguinal lymph nodes N3 Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes Distant metastasis (M stage) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Stage Stage Stage

Groupings 0 Tis I T1 II T2 T3 Stage IIIA T1 T2 T3 T4 Stage IIIB T4 Any T Any T Stage IV Any T

N0 N0 N0 N0 N1 N1 N1 N0 N1 N2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Adapted from Fleming ID, Coopers JS, Henson DE, editors. AJCC manual for staging of cancer. 5th edition. Philadelphia: Lippincott-Raven; 1997.

skin are common complaints [9]. Alternatively, BD may be found incidentally on examination of tissue removed during other anorectal procedures [7]. Diagnosis is made by biopsy, and must be distinguished from other conditions of the perianal area, including Paget’s disease, melanoma, and other dermatoses. The histologic appearance is generally characteristic, with atypical epithelial cells involving the full thickness of the epidermis, producing sharp demarcation with the normal dermis. Also, cells with large haloed hyperchromatic nuclei, so-called ‘‘bowenoid cells,’’ are often seen [7]. A number of different therapies have been employed to treat BD, including cryosurgery, topical 5-fluorouracil (5-FU), argon laser therapy, CO2 laser ablation, and photodynamic therapy [9]. The treatment of choice for BD, however, remains wide local excision (WLE) with the goal of obtaining

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negative microscopic margins. In the largest single-institution report of BD to date, 27 patients were treated with ‘‘radical resections,’’ including 26 that underwent a WLE (defined as excision based on preoperative disease mapping with frozen section evaluation of biopsy specimens, and >1 cm of microscopic disease clearance) and one that underwent an abdominoperineal resection (APR). These patients were compared with 20 undergoing conservative procedures, including local excision in 15 (defined as 0.5 cm of macroscopic clearance) and laser vaporization in 5. At a median follow-up of 104 months, local recurrence occurred in 23% of patients treated with radical excision and in 60% of patients treated with conservative procedures (P ¼ 0.002). Multiple recurrences were also much less common in the radical excision group than in the conservative group (0% versus 45%, P < 0.001). In addition, invasive SCC occurred in 3 of 20 conservatively treated patients and in none in the radical excision group (P ¼ .034) [9]. Small defects resulting from WLE can be closed primarily or covered by split-thickness skin grafts. Larger defects may require the use of V-Y, S-shaped, or house-shaped advancement anoplasty [7,15]. Careful clinical follow-up of longer than five years is required, as local recurrence has been reported as late as 111 months after surgery [9]. Squamous cell cancer Squamous cell cancer of the anal margin accounts for less than 15% of anal cancers and resembles those occurring elsewhere on the skin [16]. These cancers generally have rolled edges with an ulcerated center. They are generally well differentiated, and demonstrate keratinization [3]. Any suspicious, nonhealing ulcer of the anal margin should be biopsied to rule-out SCC. Determining the optimal treatment of SCC of the anal margin is complicated by the fact that anal margin and anal canal tumors have been lumped together in many clinical trials. Nevertheless, small (<3 cm), superficial, well-differentiated lesions appear to be adequately treated by WLE with a 1 cm margin [16,17]. However, a WLE may be difficult even for small tumors located close to the anal canal. Following an incomplete local excision or local failure, chemoradiation may be an option. Larger and deeper, less favorable lesions (T2–4 or N1) have been treated successfully with primary radiation (40–70 Gy) with or without chemotherapy. In general, radiation to the inguinal nodes is given prophylactically for T2–4, N0 patients [18–22]. Node positivity [21] and T stage [22] have been found to be significant predictors of outcome, as with SCC of the anal canal. Salvage therapy for treatment failures may include local excision, APR, and additional radiation with or without chemotherapy. Five-year cancer-specific survival and local control in these series, which included locally advanced and node-positive lesions, is reported to be 70% to 89% and 69% to 87%, respectively. Sphincter preservation is reported in approximately 67% to 84% of patients [18,20–22].

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Paget’s disease Extramammary Paget’s disease (PD) may involve the axilla and anogenital region, including the perianal skin. Perianal PD is rare, with fewer than 200 cases reported in the literature between 1966 and 1995 [23]. Histologically, PD represents an intraepithelial adenocarcinoma, the origin of which remains unclear. The preponderance of immunohistochemical evidence and the propensity of extramammary PD to involve anatomic areas possessing apocrine glands, suggest that Paget’s cells are of apocrine origin [24]. In contrast to PD of the nipple, which is uniformly associated with an underlying invasive or preinvasive breast cancer, perianal PD may or may not be associated with an underlying invasive adenocarcinoma. Perianal PD may best be thought of as either primary (in situ or with an invasive component, no separate underlying malignancy), or secondary (essentially downward ‘‘Pagetoid’’ extension from an established adenocarcinoma) [25]. The incidence of synchronous visceral carcinomas has been reported to be approximately 50%, underscoring the importance of a thorough large bowel investigation, including the anal canal, in any patient with perianal PD [23,26]. Clinically, perianal PD presents as a slowly enlarging, eczematous, erythematous, scaly rash that is often sharply demarcated. The rash may ooze and pruritus is common [26]. Perianal PD must be distinguished from a variety of other perianal conditions, including idiopathic pruritus ani, Bowen’s disease, melanoma, SCC, hidradenitis suppurativa, and perianal Crohn’s disease. Biopsy is generally diagnostic. Histologically, distinctive Paget’s cells (large round cells with pale vacuolated cytoplasm and reticular nucleus) that stain positive for periodic acid-Schiff and mucicarmine are seen [25,26]. Additional staining with S-100 protein, carcinoembryonic antigen, and cytokeratins may help distinguish Paget’s disease from melanoma and BD [26]. Recently, Cytokeratin 7 has emerged as a valuable immunohistochemical stain [27]. In the absence of an invasive component, the treatment of choice for perianal PD is WLE [26]. As with Bowen’s disease, the recommended technique is preoperative or intraoperative four-quadrant mapping encompassing the lesion, with frozen section analysis of biopsy specimens, including the dentate line, anal verge, and perineum [23]. Extensive disease may require a circumferential excision of the perianal skin. The resulting skin defect can be left open to granulate and close by secondary intention. Alternatively, it may be covered with split-thickness skin grafts or sliding flaps [3,15,28]. Radiation therapy with or without chemotherapy has been used in the treatment of perianal PD, either as primary therapy or as an adjunct to surgery, with mixed results; however, the small sample size precludes conclusions about the role of radiation therapy in PD [29–31]. Although local recurrence with in situ disease is common (61% in one series), it can generally be managed with repeat WLE [26,30]. The importance of obtaining negative microscopic margins is highlighted by one study in

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which local recurrence occurred in five out of six patients treated by resection of all macroscopic disease only and in only one out of five patients in whom negative microscopic margins were assured [26]. In the setting of a deeply invasive component, and especially an associated anorectal adenocarcinoma, APR is recommended. The long-term prognosis for in situ perianal PD is excellent. In patients with an invasive component, however, prognosis is guarded despite APR, as many of these patients present with distant metastases at the time of diagnosis [26,30]. Careful long-term follow-up with biopsy of any suspicious lesions is necessary, because local recurrence of PD has been reported as long as nine years after WLE [26]. Basal cell carcinoma Basal cell carcinoma (BCC) of the anal margin accounts for less than 1% of anorectal neoplasms [32]. They are generally between 1 cm and 2 cm in size, although larger lesions of over 10 cm have been reported. Large tumors may also extend into the anal canal. Basal cell carcinoma has a characteristic appearance, with a central ulceration and raised edges. Despite this fact, BCCs are often misdiagnosed as hemorrhoids and anal fissures. Histologic confirmation is important in order to distinguish true basal cell carcinomas from the basaloid variant of SCC, which requires more aggressive treatment. In a recent review of 19 documented cases of BCC of the anal margin (defined as within 3 cm of the anal verge), all patients were treated by local procedures, including local excision to macroscopically clear margins in 17. All patients were free of recurrence at a mean follow-up of 72 months [32]. Others have reported a local recurrence rate of 29% [33]. In this series, seven of eight local recurrences were treated by either repeat local excision (six patients) or radiation therapy, with one patient requiring APR. No deaths in either series were attributable to BCC. Thus it appears that local excision to clear macroscopic margins is adequate therapy for BCC. The use of splitthickness skin grafts may be required for larger lesions. Rarely, APR may be required for local control of advanced recurrent tumors no longer amenable to local procedures. Verrucous carcinoma Also commonly referred to as ‘‘giant condyloma acuminatum’’ and ‘‘Buschke-Lowenstein tumor,’’ verrucous carcinoma is a large, locally invasive warty growth with a cauliflower-like appearance. Verrucous carcinomas range in size from 1.5 cm to 30 cm [34]. Histologically, the lesions resemble condyloma acuminata. Large tumors may also include an invasive component of SCC, and verrucous carcinoma may represent the midpoint of a spectrum of disease leading from condyloma acuminata to invasive SCC.

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Evidence supports sexual transmission with HPV types 6 and 11 as a possible etiological factor. These lesions do not metastasize, but may invade local structures, including the anal sphincters. Treatment is generally by WLE with a 1 cm margin. APR may be required for advanced cases. Anecdotal cases report success with radiation therapy alone, as well as combined modality therapy [3,34].

Anal canal neoplasms Squamous cell cancer of the anal canal Due to the varied histology of the anal canal mucosa, especially the ATZ, there are a number of different tumor types that may arise in the anal canal. Most common is squamous cell carcinoma, accounting for approximately 75% to 80% of malignant anal tumors [35,36]. Variants of SCC include cloacogenic, transitional, and basaloid tumors, collectively known as epidermoid carcinomas. According to the WHO classification, these variants are now referred to as large-cell keratinizing, large-cell nonkeratinizing (transitional), and basaloid [4]. Because these variants all appear to have similar behavior and response to treatment, they will be considered together in this discussion as SCC. Like Bowen’s disease, invasive SCC of the anal canal likely represents the end-stage of AIN. The management of AIN is controversial, and beyond the scope of this discussion. In both anal SCC and AIN, however, evidence strongly implicates HPV 16 infection as a causative factor [37]. Other risk factors for anal SCC include a history of sexually transmitted disease; a history of anoreceptive intercourse; multiple sexual partners; immunosuppresion; a history of cervical, vaginal, or vulvar cancer; and possibly HIV infection. All of these are likely secondary to the increased prevalence of persistent HPV infection associated with these conditions [38]. Squamous cell carcinoma generally presents with a history of minor perianal bleeding, pain, and a mass. Other signs and symptoms may include discharge, disturbances in continence, and a change in bowel habits. Workup includes digital rectal examination, rigid proctoscopy with biopsy, and careful examination of the inguinal lymph nodes. Computed tomography (CT) scan is generally used to evaluate nodal involvement and systemic spread of disease. A colonoscopy should also be performed to rule out more proximal disease. Endorectal ultrasound (ERUS) may be helpful in establishing depth of tumor invasion, as well as in postoperative follow-up [39]. Until the mid-1970s, APR with or without adjuvant chemoradiation was the standard treatment for advanced SCC of the anal canal. Despite this aggressive surgical approach, local recurrence occurred in up to 40% of cases, and overall five-year survival ranged between 40% and 70% [40–43]. The pioneering work of Nigro et al at Wayne State University introduced the use of combined modality therapy (CMT)—radiation therapy (XRT)

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with 5-FU and mitomycin C (MMC) as primary treatment for SCC of the anal canal [44,45]. Although originally intended as neoadjuvant therapy prior to APR, the unexpected finding of a complete pathologic response in the majority of patients led to the use of APR only for patients with biopsy-proven residual disease at the completion of therapy. Treatment modifications of the Nigro protocol with higher radiation doses (30–60 Gy) subsequently reported three- to five-year local control and survival ranging between 80% to 97% and 58% to 90%, respectively. A complete response to chemoradiation was reported in 74% to 93% of patients in these series [35,46–53]. Others reported comparable results for treatment of anal canal SCC with radiation alone [54–56]. The results of a phase II trial [57] and two randomized phase III trials, however, established the benefit of chemotherapy and radiation versus radiation alone in the treatment of SCC of the anal canal [58,59]. These studies demonstrated that local control and disease-specific survival were significantly improved with the addition of chemotherapy versus radiation alone. Furthermore, colostomy-free survival was improved by up to 32% [59]. Also of note, late toxicity was not significantly different between radiation only and radiation plus chemotherapy regimens. Overall survival, however, was not significantly prolonged by the addition of chemotherapy. Subsequent randomized evaluation of CMT with and without MMC demonstrated that the addition of MMC significantly improved results. At four years, colostomy-free survival, disease-free survival, and locoregional control were 71%, 73%, and 84%, respectively in the MMC arm, versus 59%, 51%, and 66% without MMC. Toxicity was greater, however, in the MMC arm [60,61]. CMT has become the treatment of choice for SCC of the anal canal, despite never being compared with surgery alone in a prospective, randomized trial. Subsequent research has focused on determining the optimal CMT regimen by modulating chemotherapeutic agents and total radiation dose. The use of cisplatin in combination with 5-FU and radiation therapy as primary treatment of SCC of the anal canal has produced encouraging results, with complete response rates of 68% to 94% and colostomy-free survival of up to 86% reported [62,63]. In one study, the complete response rate noted with cisplatin/5-FU in combination with radiation was similar to a previous experience with 5-FU/MMC and radiation. In addition, local recurrence was decreased (6% versus 24%), yet overall toxicity did not appear to be significantly different [62]. Current studies have focused on the efficacy of induction chemotherapy, including platinum-based chemotherapies, as well as higher doses of radiation. One study reported a complete response rate of 94% in patients treated with three cycles of induction 5-FU and carboplatin followed by 46 Gy to 48 Gy of radiation [64]. The final results of a French phase II study of a novel regimen including two cycles of induction 5-FU and cisplatin followed by concomitant radiation (45 Gy plus 15–20 Gy boost after a one- or twomonth gap) with an additional two cycles of 5-FU and cisplatin, have

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recently been reported. The complete response rate at the completion of CMT was 67%. Three-year overall, colostomy-free, and disease-free survival rates were 86%, 73%, and 67%, respectively (Table 2) [65]. This trial has prompted a French intergroup randomized trial to further evaluate the role of induction chemotherapy, as well as higher-dose radiation boosts. A randomized phase III trial (RTOG 98-11) aimed to compare the efficacy of 5-FU and MMC concurrently with radiation to induction 5-FU and cisplatin followed by concomitant 5-FU/cisplatin and radiation. Another promising avenue is the modification of radiation delivery. Although analysis of previous trials suggests that local control improves with escalating radiation doses (up to 60 Gy) [66,67], a split-dose regimen (treatment break of one to two weeks) is generally required to reduce toxicity to an acceptable level. However, preliminary results from the RTOG 98-02 trial demonstrated a marked increase in the need for permanent colostomy with a split-dose XRT regimen (60 Gy) as compared with the RTOG 87-04 trial using identical chemotherapy but a lower total dose of radiation (40–50.4 Gy) given without a split [68]. This issue of increased permanent colostomy rate noted with the split-dose regimen approach has been addressed by the use of high-dose brachytherapy (6 Gy) interposed during the one- to two-week treatment break of split-dose radiation (50.4 Gy). Although innovative, the five-year disease-specific survival, locoregional control, and colostomy-free survival rates from this approach (76%, 76%, and 73%, respectively) are not dramatically different from those obtained with similar chemotherapy combined with lower-dose, continuous radiation therapy [69] (Table 2). Finally, some have questioned the need for chemotherapy with early stage tumors. In one study, local control and disease-specific survival were 91% and 88% to 100%, respectively, for 13 T1-2, N0 patients treated with 55 Gy to 60 Gy of radiation alone [70]. Other studies have shown no improvement in local control with the addition of chemotherapy for T1 tumors [46]. Thus, radiation alone may be adequate treatment for T1N0, and perhaps T2N0 tumors. The optimal mode of salvage for patients with persistent disease following chemoradiation or local recurrence appears to be APR. The fact that over half of treatment failures are isolated to the pelvis makes them potentially amenable to APR with curative intent [71,72]. A number of studies have reported the outcome of patients undergoing salvage APR for residual disease following chemoradiation therapy or for locally recurrent disease. Successful salvage has been reported in 19% to 100% of patients, with threeto five-year survival rates of 44% to 100% [35,67,71,73–76]. Results following APR for residual disease appear to be better than after local recurrence. In one series, overall survival at five years was 60% following APR for residual disease versus 0% for APR following local recurrence [75]. Others have reported the use of salvage chemotherapy (cisplatin) and radiation for residual disease following primary chemoradiation, with successful salvage in up

>4 cm and/ or LNþ

29 mos.

31 mos.

9.8 yrs.

40 mos.

48 mos.

Followup

5-FU, CIS

5-FU, MMC or CIS for tumors >3 cm (N ¼ 26) 5-FU, MMC for tumors >3 cm (N ¼ 28)

5-FU, MMC

5-FU, MMC

Chemotherapy

Abbreviations: NG, not given; CIS, Cisplatin; LN, lymph node. * 5-year overall survival. ** 5-year disease-specific survival. *** 3-year overall survival.

80

Peiffert [65] (2001)

T1–4, N0-2, M0

Stage I–IIIB

49

39

Stage I–IV

30

Kapp [69] (2001)

T1–4

122

Klas [35] (1999) Faynsod [74] (2000) Mitchell [70] (2001)

Stage

N

Study

Table 2 Results of recent trials of chemoradiation for SCC of the anal canal

Split-dose 50.4 Gy with 6 Gy brachytherapy 45 Gy + 15–20 Gy boost

45–60 Gy + 10–15 Gy boost

45–55 Gy

35–45+ Gy

Radiation

67%

80%

T1–2 74% T3–4 33%

94%

NG

73% (3-yr)

73%

81%

NG

NG

Survival

Stage I 62%* Stage II 68% Stage IIIA 100% Stage IIIb 70% 76%**

74%*

57%*

84% (3-yr) 86%***

76%

85%

64%

NG

Complete response Colostomy- Local free survival control

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to 50% of patients [48,49,61]. Therefore, close follow-up with digital rectal examination and proctoscopic examination are recommended every three to six months following completion of CMT. However, an unanswered question is the timing for performing an examination under anesthesia (EUA) and biopsy of suspicious lesions, as it appears that on subsequent follow-up a number of initially suspicious findings resolve. This may be due to resolution of radiation-induced changes in tissue fibrosis or prolonged effects of CMT on tumor ablation. Local excision has been utilized by some for small (
2 cm), mobile lesions without evidence of nodal metastases. Two studies reported five-year survival of 100% for 21 patients with mobile,
2 cm tumors treated with local excision [41,43]. In a more recent series, 19 patients with early-stage tumors (T1, <2.5 cm) managed with local excision alone had a five-year survival of 60% and a 23% recurrence rate [35]. These results, which are inferior to those from patients with more advanced anal SCC treated with CMT, suggest that local excision may not be optimal therapy for these early lesions. SCC found incidentally after resection of a benign appearing polyp or in a hemorrhoidectomy specimen may also be treated with chemotherapy and radiation, perhaps with lower radiation doses [77]. The prognosis for patients with disseminated disease is dismal, with a median survival of approximately nine months. The most common sites of distant metastases include the liver, lung, and bone [3]. The role of chemotherapy is unclear, and conservative surgery should be used to achieve local control in carefully selected patients with both local and distal disease. Some response to therapy has been reported using cisplatin-based chemotherapy for the treatment of metastases from anal SCC [78,79]. Anorectal melanoma Anorectal melanoma is a rare tumor, accounting for less than 1% of all colorectal malignancies [80,81]. Although only 2% of all melanomas occur in the anorectum, it is the third most common site after cutaneous and ocular. A recent report based on data from the Surveillance, Epidemiology and End Results (SEER) database noted a rising trend in overall incidence over the last two decades, especially in young males in the San Francisco area, indirectly implicating HIV infection as a potential risk factor [80]. As with most anorectal neoplasms, pain, rectal bleeding, and a perianal mass are the most common presenting signs and symptoms [81,82]. Physical examination may reveal a pigmented, polypoid lesion that can appear to be a benign anal polyp or thrombosed hemorrhoid [83]. It is important to remember, however, that 30% to 70% of anorectal melanomas are amelanotic, making clinical and histologic diagnosis more difficult [82,84,85]. Overall five-year survival has been reported to be approximately 17% to 22% [81,84]. Distant metastases have been reported at the time of diagnosis in between 16% and 57% of patients, accounting in large part for the dismal

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overall prognosis. Common sites include the inguinal lymph nodes, the liver, lung, and bone [81,82,84]. The prognosis in patients with incidentally discovered melanoma may also be poor. In one study, five patients with anorectal melanoma discovered incidentally at hemorrhoidectomy all underwent further WLE or APR with microscopically negative margins. All five developed distant metastases and died of disease at a mean of 29 months [81]. Other studies, however, have shown a significant five-year survival advantage in patients presenting without distant metastases (20% versus 0%) [84]. The treatment of anorectal melanoma is primarily surgical, as these tumors do not respond to radiation or chemotherapy. However, the optimal treatment approach remains unclear. The two largest series in the literature do not demonstrate a statistically significant difference in survival between patients treated by APR versus WLE [81,84]. In addition, a meta-analysis of 428 patients did not reveal a significant disease-free survival advantage of APR over WLE (13% versus 8%, P ¼ .30). In the series from Memorial Sloan-Kettering Cancer Center, however, there was a trend toward improved disease-free survival (DFS) in patients with APR versus those with WLE (27% versus 13%, P ¼ 0.34) [84]. In addition, nine out of ten long-term survivors (most of whom had early stage (<2 mm) or incidentally discovered melanoma) had undergone APR, suggesting that some patients with superficially invasive anal melanomas may benefit from APR. Tumor thickness has been shown to correlate with disease-free survival in anorectal melanoma, with all patients in one series with tumors <2 mm free of disease, whereas all patients with tumors 2 mm in thickness died of recurrent disease [86]. Thus, it appears that the stage of the tumor, rather than the surgical approach employed, is the strongest determinant of outcome. Furthermore, local recurrence is relatively rare in these series, and generally occurs in combination with distant metastases. WLE does not appear to compromise local control compared to APR. Thus, WLE as an initial approach is probably reasonable if local control can be obtained and continence maintained, especially in the case of disseminated disease. APR can be reserved for cases in which local control is not possible with WLE, or for salvage local control in selected patients with an isolated local recurrence [81]. Anal adenocarcinoma Anal adenocarcinoma makes up between 3% and 19% of all tumors arising in the anal canal [16,35,36,87]. The WHO classifies anal adenocarcinoma into three types based on presumed origin: rectal type, anal gland and duct type, and those arising in chronic anorectal fistulas (Box 1) [4]. Tumors arising from the colorectal mucosa lining the proximal anal canal behave as distal rectal cancers, and are not discussed further here. The anal glands are lined by mucin secreting, stratified columnar epithelium, and open into the anal canal via the anal ducts at the level of the dentate line [88]. Tumors originating from the anal glands are often located in the

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ischioanal space, without involvement of the overlying anal mucosa. Anal adenocarcinomas have also been reported to arise in the setting of chronic fistula-in-ano, although the origin of these tumors may also be from the anal glands [89,90]. Although anal gland origin may be established in early tumors by demonstration of dysplastic or malignant changes in the anal glands, in advanced tumors with secondary involvement of the anoderm and distal rectal mucosa, distinction from a distal rectal cancer is impossible [91]. Common presenting symptoms include perianal pain, perianal mass, and rectal bleeding. Because these are nonspecific and are similar to common benign anorectal conditions, accurate diagnosis is often delayed. In advanced cases, other common findings include involvement of inguinal lymph nodes and the presence of an associated fistula in up to 50% of patients [92]. In one of the largest series published to date, 21 cases of anal adenocarcinoma were reported, with a five-year survival of 4.8% [90]. A subsequent study reported ten patients with a median survival of 29 months [93]. However, more recent reports have demonstrated five-year survival of up to 93%, including some patients managed with wide local excision (WLE) [35,92,94]. In previous reports, APR has been the most commonly performed procedure for anal adenocarcinoma [92,93]. In one study, 77% of patients underwent APR, either as a primary procedure or following failed WLE [92]. Survival was similar between patients undergoing APR and those undergoing WLE. Others have used WLE alone for selected, early-staged tumors with encouraging results [35,94]. However, until more data is available on the long-term outcome of WLE, APR remains the surgical procedure of choice for locally advanced disease. The role of radiation and chemotherapy in the primary treatment of anal adenocarcinoma has yet to be defined. Encouraged by the success of Nigro’s protocol for epidermoid cancers of the anal canal, several investigators have used similar chemoradiation protocols as primary treatment for anal adenocarcinoma. In one series of 6 patients with anal adenocarcinoma treated with CMT (5-FU/MMC, 45–60 Gy XRT) alone, no patient had suffered a relapse at a median follow-up of 6.6 years [95]. Others have reported similar results [96]. The role of adjuvant chemoradiation is also unclear. In previous reports, adjuvant therapy has either not been used [90] or has not demonstrated significant benefit [92]. In a recent series of 36 surgically treated patients, 14 patients with tumors >5 cm received either pre- or postoperative adjuvant chemoradiation. Five-year survival for the entire group was 63%, but no comparison was made between the adjuvant therapy and no adjuvant therapy groups [35]. Small-cell and undifferentiated carcinoma Small-cell adenocarcinoma of the anal canal is extremely rare, and is similar in histology and behavior to small-cell carcinoma of the lung. Small-cell carcinoma is often disseminated at diagnosis. Undifferentiated carcinomas

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are also very rare, with no evidence of glandular structure histologically. Both of these tumors are treated as adenocarcinomas. Prognosis is generally poor for both lesions [3,4]. Summary A common theme in most anal neoplasms appears to be a delay in diagnosis due to confusion with more common, benign conditions. Thus, the clinician must maintain a high index of suspicion when evaluating lesions of the anal canal and margin. The use of primary chemoradiation for SCC of the anal canal has resulted in equivalent, if not superior, local control and survival compared with radical surgery, and results in sphincter preservation in over two thirds of cases. Nevertheless, abdominoperineal resection still plays an important role in salvage of treatment failures, and also for patients who are unlikely to tolerate chemoradiation or have pre-existing impaired continence. Recent studies indicate that variations in chemotherapeutic agents and radiation technique might potentially produce even better results. The prognosis for anorectal melanoma, as well as for small cell and undifferentiated tumors, continues to be poor. Fortunately, these are relatively rare tumors. References [1] Jemal A, Thomas A, Murray T et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52: 23–47. [2] Fenger C. Anal canal. In: Sternberg SS, editor. Histology for pathologists. New York: Raven Press, Ltd.; 1992. p. 607–23. [3] Gordon PH, Nivatvongs S. Principles and practice of surgery for the colon rectum and anus. 2nd edition. St. Louis: Quality Medical Publishing; 1999. p. 3–39. [4] Jass JR, Sobin LH. Histologic typing of intestinal tumors: World Health Organization. 2nd edition. New York: Springer-Verlag; 1989. p. 41–7. [5] AJCC Manual for Staging of Cancer. 5th Edition. Philadelphia: Lippincott Raven; 1997. p. 91–3. [6] Rickert RR, Compton CC. Protocol for the examination of specimens from patients with carcinomas of the anus and anal canal: a basis for checklists. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 2000;124(1):21–5. [7] Cleary RK, Schaldenbrand JD, Fowler JJ, et al. Perianal Bowen’s disease and anal intraepithelial neoplasia: review of the literature. Dis Colon Rectum 1999;42(7):945–51. [8] Siegel JF, Mellinger BC. Human papillomavirus in the male patient. Urol Clin North Am 1992;19(1):83–91. [9] Marchesa P, Fazio VW, Oliart S, et al. Perianal Bowen’s disease: a clinicopathologic study of 47 patients. Dis Colon Rectum 1997;40(11):1286–93. [10] Graham JH, Helwig EB. Bowen’s disease and its relationship with with systemic cancer. Arch Dermatol 1961;83:315–27. [11] Sarmiento JM, Wolff BG, Burgart LJ, et al. Perianal Bowen’s disease: associated tumors, human papillomavirus, surgery, and other controversies. Dis Colon Rectum 1997;40(8): 912–8. [12] Arbesman H, Ransohoff DF. Is Bowen’s disease a predictor for the development of internal malignancy? A methodological critique of the literature. JAMA 1987;257(4):516–8.

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