- Email: [email protected]
Treatment and outcomes of anorectal melanoma
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Review
Treatment and outcomes of anorectal melanoma Anna Heeney*, Jurgen Mulsow, John M.P. Hyland Department of Colorectal Surgery, St. Vincent’s University Hospital, Dublin 4, Ireland
article info
abstract
Article history:
Introduction: Anorectal melanoma is an uncommon disease constituting less than 3% of all
Received 6 January 2010
melanomas. Due to its rarity, there are a lack of randomized control trials regarding
Received in revised form
appropriate management and current evidence is based mainly on retrospective studies.
12 July 2010
Methods: In view of the controversial surgical treatment of anorectal melanoma, we review
Accepted 12 July 2010
the most published literature in an attempt to elucidate its typical clinical features along
Available online 19 August 2010
with current thinking with respect to management approaches to this aggressive disease. Using the keywords “anorectal” and “malignant melanoma”, a medline search of all arti-
Keywords:
cles in English was performed and the relevant articles procured. Additional references
Anorectal melanoma
were retrieved by cross reference from key articles.
Outcomes
Results: Anorectal melanoma affects the elderly with a slight preponderance for females. It
Wide local excision
commonly presents disguised as benign disease with local bleeding or suspicion for hae-
Abdominoperineal resection
morrhoidal disease. There is no convincing evidence to indicate that radical resection of primary anorectal melanoma is associated with improvement in local control or survival, and local excision is an acceptable treatment option. Conclusion: Optimum management depends on several factors and the therapeutic goals should be to lengthen survival and preserve quality-of-life. Given that wide local excision is a more limited intervention with comparable survival it should be considered as the initial treatment choice. Unfortunately prognosis for patients with this disease remains poor despite choice of treatment strategy with overall five year disease-free survival less than twenty percent in most studies. ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Anorectal malignant melanoma was first reported by Moore et al. in 1857.1 Over 500 cases have been reported in the literature to date. It remains a relatively rare condition with a very poor prognosis. Nevertheless, the anorectum is the most common site for development of primary melanoma in the gastrointestinal tract with the anorectal region being the third most common site for melanoma overall
following the skin and retina.2,3 Malignant melanoma is also the most common tumour which metatasises to the GI tract, with most common sites of GI invasion being the small bowel, colon and anorectum.4 These tumours tend to present late and are often misdiagnosed as benign lesions early in their course. Optimal surgical treatment is widely debated while the response to radiotherapy and chemotherapy continues to be poor. This article serves to highlight current aspects in the treatment and outcomes of
* Corresponding author. Tel.: þ353 1 2214000; fax: þ353 1 2214001. E-mail address: [email protected] (A. Heeney). 1479-666X/$ e see front matter ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2010.07.007
28
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
primary anorectal melanoma based on the recent published literature.
Epidemiology Anorectal melanoma accounts for 0.2%e3% cases of melanoma, and 0.1%e4.6% of all malignant tumours of the rectum and anus.5e7 The disease appears to affect all ages, with a mean incidence of 64.3 yrs (58.1 yrse70.2 yrs). (Table 1) However, cases have been reported in patients younger than 30 yrs. There is a higher incidence in females; only two studies analysed showing a male preponderance. One study shows the disease is more common in caucasians.8 It has been reported that, as is the case in cutaneous melanoma, the incidence of anorectal malignant melanoma is increasing, with an almost doubling in incidence over the past twenty years.9
tumours in one study were found incidentally on clinical exam or colonoscopy.11 Unlike cutaneous melanomas, a significant proportion of lesions are not pigmented adding to diagnostic difficulties. (right hand side of the page) Likewise, if the lesion is polypoid and pigmented it can resemble a thrombosed haemorrhoid. In one major study, 8% of patients had their melanoma discovered on pathological review of haemorrhoidectomy specimens.12 Metastatic spread is via the lymphatic and haematogenous routes and it has been reported that up to 38% of patients have metastatic disease at the time of diagnosis.24 Liver and lungs are the most common sites of distant metastases. It is uncertain whether the pronounced tendency to metastasize implies a more aggressive tumour biology or is due to plentiful lymphatic and haematogenous channels of the anal canal.
Diagnosis Aetiology Although ultraviolet radiation is a recognised contribution to cutaneous melanoma, there are lilmited data regarding risk factors for anorectal melanoma. One recent study implicates human immunodeficiency virus as a risk factor in young, mostly male, patients.10
Clinical features Unfortunately, anorectal melanomas usually present at an advanced stage. Bleeding is the most common presenting symptom with 53e89% of patients reporting this as the predominant complaint. Other common presentations include suspicion of haemorrhoids, discomfort or pain, an anal mass, change in bowel habit, tenesmus or pruritis (Table 2). A smaller proportion of patients present with nodal disease and inguinal lymphadenopathy. Up to 11.7% of
Table 1 e Patient characteristics. Study
Year
No. of Males Females Age Mean patients range age
Malik et al.21 Homsi et al.35 Roumen et al.16 Thibault et al.7 Pessaux et al.17 Cagir et al.10 RagnarssonOlding et al.36 Moozar et al.11 Chute et al.37 Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39 Brady et al.12
2004 2007 1996 1997 2004 1999 2009
19 12 63 50 40 117 251
10 3 27 15 12 43 101
9 9 36 35 28 74 150
39e90 27e86 29e89 24e83 37e83 29e96 e
61.4 67 66 63 58.1 66 70.2
2003 2006 2003 2008 2003 2008 1995
14 17 15 40 19 79 85
5 8 6 19 10 34 46
9 9 9 21 9 45 39
e e 29e86 e 33e87 31e89 e
63.7 69.4 65 63 62 65.8 60
Diagnosis begins with clinical exam and digital rectal examination provides us with information regarding size, location, fixation and ulceration of the tumour.13 Further visualization with proctosigmoidoscopy may give additional support to the diagnosis if pigmentation of the lesion is evident. It also allows histological sampling. Advanced imaging with endoluminal ultrasound, CT and MRI are currently being used in assessing the primary lesion and staging. The most common finding on CT is a bulky intraluminal fungating mass in the distal rectum, frequently with perirectal infiltration and enlarged lymph nodes.14 Magnetic Resonance Imaging and Endoscopic Ultrasound have also been used showing increased accuracy in early diagnosis.15
Tumour characteristics Tumours are most commonly located in the anal canal, followed by at the dentate line with fewer melanomas located in the rectum itself (Table 3). Size of the tumour on presentation is variable but published series report sizes in the range of 2.9e3.8 cms.16e18 At a molecular level, recent studies compared anorectal melanoma and cutaneous melanoma and identified presence of BRAF gene mutations suggesting that they are two separate entities which may have implications for future therapeutic approaches and gene therapy.19
Pathology Like cutaneous malignant melanoma, anorectal melanoma originates from melanocytes which are found in the anal canal, which have undergone malignant transformation. Microscopically, the tumour cells are arranged in nests and individual cells may be epithelioid or spindled. These clusters of tumour cells invade the overlying squamous mucosa in a pagetoid manner and are characterized by immunostaining specific for the melanosome protein, HMB-453.20
29
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
Table 2 e Clinical features. Study
Number of patients
Primary presenting complaint
Other symptoms
Time to diagnosis
Malik et al.21
19
Bleeding 89%,
P-26%
Homsi et al.35 Roumen et al.16
12 63
Haemorrhoids 50% Bleeding 71%
B-33%, P-8%, In-8% H-43%,P-35%, Ch-35%,I-13%, Pr-11%,U-8%,
Thibault et al.7 Pessaux et al.17
50 40
Bleeding 55% Bleeding 72.5%
Cagir et al.10 RagnarssonOlding et al.36 Moozar et al.11 Chute et al.37
117 251
M-34%,P-13%, Ch-11%, Pr-8%, T-3% M- 40%,T- 20%, H- 17.5%, I- 10%,IM- 10%, Pr- 7.5%, Ch- 7.5%, In- 5% e e
14 17
Bleeding Bleeding 53%
Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39
15 40 19 79
e Bleeding 55% Bleeding 58% Bleeding 69%
e e
M P-29%, Ch-17.6%, M-17.6%,H-11.7%, In-11.7% e H-12.5%, P-15%, IM-2.5% M-21%, Pr-15.8%, H-10.5% P-16.4%, M-15%, C-5%, In-7.5%
47% <1 mth, 37% : 1e3 mths, 10.5% >12 mths e 50.7% <3 mths, 17.4%: 3e6 mths, 9.5% >6mths, 22% unknown, 4.7% no symptoms Median 4 months Mean 6.1 months
e e e e e Median 5 months e e
Legend: B ¼ bleeding, P ¼ pain, M ¼ mass, Pr ¼ pruritis, H ¼ haemorrhoid, I ¼ incontinence, Ch ¼ change in bowel habit, C ¼ constipation, In ¼ incidental, U ¼ ulcer, T ¼ tenesmus, IM ¼ inguinal mass.
as N1 with disease in a single node, N2 with two to three nodes involved and N3 having four or more nodes involved.
Staging There are no separate staging criteria for anorectal melanoma and it is usually considered according to the AJCC TNM classification [AJCC Cancer Staging Sixth Edition]. T1 refers to tumours 1 mm, T2 are tumours 1e2 mm, T3 are tumours 3e4 mm and T4 are all lesions >4 mm. Nodal disease is classified
Treatment Management of patients with anorectal melanoma remains controversial. Owing to its low incidence, treatment is not
Table 3 e Tumour characteristics. Name of study
Number of patients
Location of tumour
Size of tumour
Depth
e
Malik et al.21
19
Above DL 47.3%; At DL 5.2%; Below DL 31.5%
Homsi et al.35 Roumen et al.16
12 63
e median 3.8 cm
Thibault et al.7 Pessaux et al.17
50 40
e Above DL 31.7%; At DL 22.2%; Below DL 38%; Too large 7.9% e Above DL 10%; At DL 57.5%; Below DL 25%; Too large 7.5% Above DL 35%; At DL 15.3%; Below DL 20.5%; Too large 29% Above DL 10%; At DL 24%; Below DL 25%; Unknown 11% e
8 ¼ 5e10 mm, 2 > 10 mm, 1 < 5 mm median 11.5 mm median 12 mm
e mean 2.9 cm
e mean 11 mm
Above DL 5.8%; At DL 76.4% e Above DL 10%; At DL 17.5%; Below DL 72.5% e e
1e6 cm
Cagir et al.10
117
RagnarssonOlding et al.36 Moozar et al.11
251 14
Chute et al.37 Bullard et al.23 Belli et al.38
17 15 40
Weyandt et al.18 Ishizone et al.39
19 79
DL ¼ Dentate Line.
e
e
e
e
e
e
e e
e
3.2 cm median e
10 mm median e
Stage Local 42.1%, Regional 26.3%, Distant 5.2% e Local 35%, Regional 7%, Distant 33% Stage 4 26% Local 60%, Regional 15%, Distant 25% Local 32.5%, Regional 28%, Distant 15.5% e Local 71.4%, Regional 21.4%, Distant 7.1% 1 (6), 2 (6), insufficient info in 5 e Local 42.5%, Regional 30%, Distant 27.5% Distant 31.5% Local 32.9%, Regional 43%, Distant 22.7%
30
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
Table 4 e Treatment. Name of study
Number of patients
Malik et al.22 Homsi et al.37 Roumen et al.16 Thibault et al.7 Pessaux et al.17 Moozar et al.11 Chute et al.39 Bullard et al.24 Belli et al.38 Weyandt et al.18 Ishizone et al.39
19 12 63 50 40 14 17 15 40 19 79
Purpose of treatment Curative Curative Curative Curative Curative N/A N/A N/A Curative Curative Curative
intent intent intent intent intent
APR
WLE
Other
7 5 21 26 9 4 8 4 9 5 63
10 6 18 11 21 10 5 11 18 8 14
2 1 24 0 10 0 4 0 13 0 2
14 11 42 37 24
intent 31 intent 13 intent 60
well defined since it is based on retrospective studies of limited numbers or over long time periods. Our review of the literature, found that in all patients treated with curative intent, the surgical options of abdominoperineal resection or wide local excision were adopted, with no approach being favoured in any study.11,12,16,21,22,24 Other options include palliative debulking or defunctioning colostomy. Abdominoperineal resection constituted 46.1% of procedures with local resection accounting for 37.8% of reported operations (Table 4). There is no evidence to support prophylactic bilateral inguinal lymphadenectomy as it does not appear to affect survival and there is clearly a significant morbidity attached.25,26
Outcomes Survival in anorectal melanoma is universally poor with five year survival between 6%e28.8% (Table 5). Even in patients who undergo potentially curative surgical resection, outcomes remain dismal. Survival is improved with earlier stage of disease with one study showing varying survival
between 28 months for stage 1 and 4 months for stage 3 disease.16 An association between poor survival and the presence of amelanotic melanoma has been observed.17 One study showed that tumour histological type is associated with recurrence, but not with survival with tumours showing pure epithelioid histology less likely to recur compared with tumours showing pure spindle cell or mixed histology.
Discussion Anal tumours, in general, are rare and account for 4% of all cancers of the lower gastrointestinal tract with melanoma making up a very small percentage of these.28 As diagnosis is commonly delayed, suggestions proposed to reduce the significant morbidity and likely mortality from this aggressive disease include histopathological sampling of anal lesions atypical for haemorrhoids and to always include anorectal melanoma in the differential diagnosis of rectal bleeding in adults. Prognostic factors have been studied in several series with varying results. Locally advanced disease along with diffuse
Table 5 e Outcomes. Name of study
Number of patients
Malik et al.21 Homsi et al.35 Roumen et al.16
19 12 63
Thibault et al.7 Pessaux et al.17 Cagir et al.10 Ragnarsson-Olding et al.36 Moozar et al.11 Chute et al.37 Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39
50 40 117 251 14 17 15 40 19 79
OS ¼ Overall Survival, DF ¼ Disease-free survival.
5 year survival
Primary recurrence location
Median survival (months)
21% n/a 6%
31.6% Distant Mets 33.3% Liver 39.6% Lung
22% OS, 16% DF 17% OS, 14%DF 14.90% 14% n/a n/a n/a 20.8%DF(WLE), 15.4%DF(APR) n/a 28.80%
16% Lung/Nodal n/a n/a n/a n/a 47% Nodal mets n/a n/a
n/a n/a 28 mths stage 1, 16 mths stage 2, 4 mths stage 3. n/a 17 OS, 10 DF n/a 12.2 12 13 18 (14 forapr, 19 forwle) 17 for curative, 6 for palliative
21% Liver/Lung/Nodal n/a
25 22
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
metastases at diagnosis undoubtedly lead to unfavourable outcomes. Yeh et al. found that tumour necrosis, perineural invasion and, less significantly, spindle cell histology and larger diameter were associated with poor outcome.27 Brady et al. found that survival was higher among females.12 Wanebo et al. showed that patients with tumours less than 2 mm in depth had increased survival26 and it has been shown that patients with tumours less than 2 cm in diameter had significantly longer survival.5 There is no clear evidence to advocate prophylactic lymph node excision despite the important role of lymph node involvement as a prognostic factor in primary cutaneous melanoma.29 Definitive therapeutic modalities have yet to be clearly outlined due to a paucity of evidence in the literature. Most studies have not found significant differences in survival or disease-free interval between APR and local excision. Many institutions are evolving towards the use of local excision if feasible27 as this approach is more favourable to the patient with preservation of continence. Although it is argued that a more radical approach decreases the rate of local recurrence, the patient does not appear to benefit from a longer survival as a local recurrence is usually accompanied by a relapse at multiple sites with distant metastases. Abdominoperineal resection is not without its own inherent risks and is a technically demanding procedure with a considerable post-operative morbidity. With present staging modalities such as endoluminal ultrasound and positron emission tomography, APR may be recommended for only those lesions with potential curability. APR can sometimes lead to better results in the palliative setting if a patient is very symptomatic with discomfort, pain and incontinence. The role of adjuvant therapy has not been clearly defined and there is limited literature on chemoradiotherapy with its use being mainly confined to the palliative setting.25,30 Chemotherapeutic agents used are based on drugs developed for advanced cutaneous melanoma including cisplatin, vinblastine, dacarbazine, INF and interleukin-2.31 Sentinel lymph node mapping is an integral part of the management in cutaneous melanoma, however there has been minimal research into its use in its anorectal counterpart. From several case reports it is technically possible and without changing prognosis it gives information that may prevent unnecessary lymphandenectomy.32e34 Cutaneous malignant melanoma is widely appreciated as an aggressive malignancy and its anorectal counterpart is no different. It is difficult to elicit accurate figures regarding estimated survival however, as studies to date vary in exclusion criteria and those with seemingly better outcomes may only take into account patients treated with curative intent.
Conclusion It is important to consider the diagnosis of anorectal melanoma as a differential diagnosis in patients complaining of non-specific symptoms in the anorectal region, especially in older women. In the absence of metastatic disease, potentially curative surgical resection is indicated.
31
Although most series report no benefit of APR vs WLE with regards to overall survival, many centres are now favouring local excision with negative margins, which clearly has benefits of a less invasive procedure and preservation of continence. There is unlikely to be a prospective study comparing the two approaches so the decision on surgical approach must depend on individual cases taking into account quality-of-life issues and current evidence from available data. Prognosis of this disease is poor, irrespective of surgical treatment performed. Early diagnosis and treatment is vital to improve survival in patients with this rare condition.
references
1. Moore WD. Recurrent melanosis of the rectum, after previous removal from the verge of the anus, in a man aged sixty-five. Lancet 1857;1:290. 2. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664e78. 3. Quan SHQ. Anal cancers. Squamous and melanoma. Cancer 1992;70:1384e9. 4. Blecker D, Abraham S, Furth E, Kochman M. Melanoma in the Gastrointestinal tract. Am J Gastroenterol 1999 Dec;94(12): 3427e33. 5. Goldman S, Glimelius B, Pahlman L. Anorectal malignant melanoma in Sweden. Report of 49 patients. Dis Colon Rectum 1990;33:874e7. 6. Weinstock MA. Epidemiology and prognosis of anorectal melanoma. Gastroenterology 1993;104:174e8. 7. Thibault C, Sagar P, Nivatvongs S, Ilstrup DM, Wolff BG. Anorectal melanomaean incurable disease? Dis Colon Rectum 1997;40:661e8. 8. Cooper PH, Mills SE, Allen MS. Malignant melanoma of the anus: report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 1982;25:693e703. 9. Cote´ TR, Sobin LH. Primary melanomas of the esophagus and anorectum: epidemiologic comparison with melanoma of the skin. Melanoma Res 2009;19(1):58e60. 10. Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiology of anorectal melanoma. Dis Colon Rectum 1999;42:1203e8. 11. Moozar KL, Wong CS, Couture J. Anorectal malignant melanoma: treatment with surgery or radiation therapy, or both. Can J Surg 2003;46:345e9. 12. Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Centre. Dis Colon Rectum 1995;38:146e51. 13. Stoidis CN, Spyropoulos BG, Misiakos EP, Fountzilas CK, Paraskeva PP. Fotiadis CI.Diffuse anorectal melanoma; review of the current diagnostic and treatment aspects based on a case report. World J Surg Oncol 2009;11(7):64. 14. Kim KW, Ha HK, Kim AY, et al. Primary malignant melanoma of the rectum: CT findings in eight patients. Radiology 2004; 232:181e6. 15. Sashiyama H, Takayama W, Miyazaki S, et al. The diagnostic value of endoscopic ultrasonography and magnetic resonance imaging for anorectal malignant melanoma: report of a case. Surg Today 2003;33:209e13. 16. Roumen RM. Anorectal melanoma in the Netherlands: a report of 63 patients. Eur J Surg Oncol 1996;22:598e601.
32
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17. Pessaux P, Pocard M, Elias D, Duvillard P, Avril MF, Zimmerman P, Lasser P. Surgical management of primary anorectal melanoma. Br J Surg 2004;91(9):1183e7. 18. Weyandt GH, A0 Eggert, Houf M, et al. Anorectal melanoma. Surgical management guidelines according to tumour thickness. Br J Cancer 2003;89(11):2019e22. 19. Helmke BM, Mollenhauer J, Herold-Mende C, Benner A, Thome M, Gassler N, et al. BRAF mutations distinguish anorectal from cutaneous melanoma at the molecular level. Gastroenterology 2004;127(6):1815e20. 20. Rodrigues Gabriel, Kudva Annappa, Kudva Ranjini. Primary anal malignant melanoma. Internet J Surg 2003;4(1). 21. Malik A, Hull TL, Floruta C. What is the best surgical treatment for anorectal melanoma? Int J Colorectal Dis 2004;19:121e3. 22. Antoniuk PM, Tjandra JJ, Webb BW, et al. Anorectal Melanoma has a poor prognosis. Int J Colorectal Dis 1993;8:81e6. 23. Bullard KM, Tuttle TM, Rothenberger DA, et al. Surgical therapy for anorectal melanoma. J Am Coll Surg 2003;196:206e11. 24. Podnos YD, Tsai NC, Smith D, Joshua DI. Factors affecting survival in patients with anal melanoma. Am Surg 2006;72:917e20. 25. Rosseti C, Koukouras D, Eboli M, Andreola S, Bertario L. Primary anorectal melanomas: an institutional experience. J Exp Clin Cancer Res 1997;16:81e5. 26. Chiu YS, Uni KK, Beart Jr RW. Malignant melanoma of anorectum. Dis Colon Rectum 1980;23:122e4. 27. Yeh JJ, Shia J, Hwu WJ, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. Ann Surg 2006;244(6):1012e7. 28. Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol 2004;5(3):149e57. 29. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622e34.
30. Slingluff Jr CL, Vollmer RT, Seigler HF. Anorectal melanoma; clinical characteristics and results of surgical management in twenty-four patients. Surgery 1990;107:1e9. 31. Eton O, Leggha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 2002;20:2045e52. 32. Olsha O, Mintz A, Gimon Z, Gold Deutch R, Rabin I, Halevy A, et al. Anal melanoma in the era of sentinel lymph node mapping: a diagnostic and therapeutic challenge. Tech Coloproctol 2005;9:60e2. 33. Mariolis-Sapsakos T, Malamitsi J, Yakoumakis E, Orfanos F. Is sentinel node mapping useful in anorectal melanoma? Hell J Nucl Med 2008;11(1):39e42. 34. Duport C, Tiffet O, Perrot JL, Pre´vot N, Rey Y, Cambazard F. Sentinel node mapping in anorectal melanoma. Ann Chir 2006;131(9):550e2. 35. Homsi J, Garrett C. Melanoma of the anal canal: a case series. Dis Colon Rectum 2007;50:1004e10. 36. Ragnarsson-Olding BK, Nilsson PJ, Olding LB, Nilsson BR. Primary ano-rectal malignant melanomas within a population-based national patient series in Sweden during 40 years. Acta Oncol 2009;48(1):125e31. 37. Chute DJ, Cousar JB, Mills SE. Anorectal malignant melanoma: morphologic and immunohistochemical features. Am J Clin Pathol 2006;126(1):93e100. 38. Belli F, Gallino GF, Lo Vullo S, Mariani L, Poiasina E, Leo E. Melanoma of the anorectal region: the experience of the National Cancer Institute of Milano. Eur J Surg Oncol 2009;35 (7):757e62. 39. Ishizone S, Koide N, Karasawa F, Akita N, Muranaka F, Uhara H, et al. Surgical treatment for anorectal malignant melanoma: report of five cases and review of 79 Japanese cases. Int J Colorectal Dis 2008;23(12):1257e62.
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Review
Treatment and outcomes of anorectal melanoma Anna Heeney*, Jurgen Mulsow, John M.P. Hyland Department of Colorectal Surgery, St. Vincent’s University Hospital, Dublin 4, Ireland
article info
abstract
Article history:
Introduction: Anorectal melanoma is an uncommon disease constituting less than 3% of all
Received 6 January 2010
melanomas. Due to its rarity, there are a lack of randomized control trials regarding
Received in revised form
appropriate management and current evidence is based mainly on retrospective studies.
12 July 2010
Methods: In view of the controversial surgical treatment of anorectal melanoma, we review
Accepted 12 July 2010
the most published literature in an attempt to elucidate its typical clinical features along
Available online 19 August 2010
with current thinking with respect to management approaches to this aggressive disease. Using the keywords “anorectal” and “malignant melanoma”, a medline search of all arti-
Keywords:
cles in English was performed and the relevant articles procured. Additional references
Anorectal melanoma
were retrieved by cross reference from key articles.
Outcomes
Results: Anorectal melanoma affects the elderly with a slight preponderance for females. It
Wide local excision
commonly presents disguised as benign disease with local bleeding or suspicion for hae-
Abdominoperineal resection
morrhoidal disease. There is no convincing evidence to indicate that radical resection of primary anorectal melanoma is associated with improvement in local control or survival, and local excision is an acceptable treatment option. Conclusion: Optimum management depends on several factors and the therapeutic goals should be to lengthen survival and preserve quality-of-life. Given that wide local excision is a more limited intervention with comparable survival it should be considered as the initial treatment choice. Unfortunately prognosis for patients with this disease remains poor despite choice of treatment strategy with overall five year disease-free survival less than twenty percent in most studies. ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Anorectal malignant melanoma was first reported by Moore et al. in 1857.1 Over 500 cases have been reported in the literature to date. It remains a relatively rare condition with a very poor prognosis. Nevertheless, the anorectum is the most common site for development of primary melanoma in the gastrointestinal tract with the anorectal region being the third most common site for melanoma overall
following the skin and retina.2,3 Malignant melanoma is also the most common tumour which metatasises to the GI tract, with most common sites of GI invasion being the small bowel, colon and anorectum.4 These tumours tend to present late and are often misdiagnosed as benign lesions early in their course. Optimal surgical treatment is widely debated while the response to radiotherapy and chemotherapy continues to be poor. This article serves to highlight current aspects in the treatment and outcomes of
* Corresponding author. Tel.: þ353 1 2214000; fax: þ353 1 2214001. E-mail address: [email protected] (A. Heeney). 1479-666X/$ e see front matter ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2010.07.007
28
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
primary anorectal melanoma based on the recent published literature.
Epidemiology Anorectal melanoma accounts for 0.2%e3% cases of melanoma, and 0.1%e4.6% of all malignant tumours of the rectum and anus.5e7 The disease appears to affect all ages, with a mean incidence of 64.3 yrs (58.1 yrse70.2 yrs). (Table 1) However, cases have been reported in patients younger than 30 yrs. There is a higher incidence in females; only two studies analysed showing a male preponderance. One study shows the disease is more common in caucasians.8 It has been reported that, as is the case in cutaneous melanoma, the incidence of anorectal malignant melanoma is increasing, with an almost doubling in incidence over the past twenty years.9
tumours in one study were found incidentally on clinical exam or colonoscopy.11 Unlike cutaneous melanomas, a significant proportion of lesions are not pigmented adding to diagnostic difficulties. (right hand side of the page) Likewise, if the lesion is polypoid and pigmented it can resemble a thrombosed haemorrhoid. In one major study, 8% of patients had their melanoma discovered on pathological review of haemorrhoidectomy specimens.12 Metastatic spread is via the lymphatic and haematogenous routes and it has been reported that up to 38% of patients have metastatic disease at the time of diagnosis.24 Liver and lungs are the most common sites of distant metastases. It is uncertain whether the pronounced tendency to metastasize implies a more aggressive tumour biology or is due to plentiful lymphatic and haematogenous channels of the anal canal.
Diagnosis Aetiology Although ultraviolet radiation is a recognised contribution to cutaneous melanoma, there are lilmited data regarding risk factors for anorectal melanoma. One recent study implicates human immunodeficiency virus as a risk factor in young, mostly male, patients.10
Clinical features Unfortunately, anorectal melanomas usually present at an advanced stage. Bleeding is the most common presenting symptom with 53e89% of patients reporting this as the predominant complaint. Other common presentations include suspicion of haemorrhoids, discomfort or pain, an anal mass, change in bowel habit, tenesmus or pruritis (Table 2). A smaller proportion of patients present with nodal disease and inguinal lymphadenopathy. Up to 11.7% of
Table 1 e Patient characteristics. Study
Year
No. of Males Females Age Mean patients range age
Malik et al.21 Homsi et al.35 Roumen et al.16 Thibault et al.7 Pessaux et al.17 Cagir et al.10 RagnarssonOlding et al.36 Moozar et al.11 Chute et al.37 Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39 Brady et al.12
2004 2007 1996 1997 2004 1999 2009
19 12 63 50 40 117 251
10 3 27 15 12 43 101
9 9 36 35 28 74 150
39e90 27e86 29e89 24e83 37e83 29e96 e
61.4 67 66 63 58.1 66 70.2
2003 2006 2003 2008 2003 2008 1995
14 17 15 40 19 79 85
5 8 6 19 10 34 46
9 9 9 21 9 45 39
e e 29e86 e 33e87 31e89 e
63.7 69.4 65 63 62 65.8 60
Diagnosis begins with clinical exam and digital rectal examination provides us with information regarding size, location, fixation and ulceration of the tumour.13 Further visualization with proctosigmoidoscopy may give additional support to the diagnosis if pigmentation of the lesion is evident. It also allows histological sampling. Advanced imaging with endoluminal ultrasound, CT and MRI are currently being used in assessing the primary lesion and staging. The most common finding on CT is a bulky intraluminal fungating mass in the distal rectum, frequently with perirectal infiltration and enlarged lymph nodes.14 Magnetic Resonance Imaging and Endoscopic Ultrasound have also been used showing increased accuracy in early diagnosis.15
Tumour characteristics Tumours are most commonly located in the anal canal, followed by at the dentate line with fewer melanomas located in the rectum itself (Table 3). Size of the tumour on presentation is variable but published series report sizes in the range of 2.9e3.8 cms.16e18 At a molecular level, recent studies compared anorectal melanoma and cutaneous melanoma and identified presence of BRAF gene mutations suggesting that they are two separate entities which may have implications for future therapeutic approaches and gene therapy.19
Pathology Like cutaneous malignant melanoma, anorectal melanoma originates from melanocytes which are found in the anal canal, which have undergone malignant transformation. Microscopically, the tumour cells are arranged in nests and individual cells may be epithelioid or spindled. These clusters of tumour cells invade the overlying squamous mucosa in a pagetoid manner and are characterized by immunostaining specific for the melanosome protein, HMB-453.20
29
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
Table 2 e Clinical features. Study
Number of patients
Primary presenting complaint
Other symptoms
Time to diagnosis
Malik et al.21
19
Bleeding 89%,
P-26%
Homsi et al.35 Roumen et al.16
12 63
Haemorrhoids 50% Bleeding 71%
B-33%, P-8%, In-8% H-43%,P-35%, Ch-35%,I-13%, Pr-11%,U-8%,
Thibault et al.7 Pessaux et al.17
50 40
Bleeding 55% Bleeding 72.5%
Cagir et al.10 RagnarssonOlding et al.36 Moozar et al.11 Chute et al.37
117 251
M-34%,P-13%, Ch-11%, Pr-8%, T-3% M- 40%,T- 20%, H- 17.5%, I- 10%,IM- 10%, Pr- 7.5%, Ch- 7.5%, In- 5% e e
14 17
Bleeding Bleeding 53%
Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39
15 40 19 79
e Bleeding 55% Bleeding 58% Bleeding 69%
e e
M P-29%, Ch-17.6%, M-17.6%,H-11.7%, In-11.7% e H-12.5%, P-15%, IM-2.5% M-21%, Pr-15.8%, H-10.5% P-16.4%, M-15%, C-5%, In-7.5%
47% <1 mth, 37% : 1e3 mths, 10.5% >12 mths e 50.7% <3 mths, 17.4%: 3e6 mths, 9.5% >6mths, 22% unknown, 4.7% no symptoms Median 4 months Mean 6.1 months
e e e e e Median 5 months e e
Legend: B ¼ bleeding, P ¼ pain, M ¼ mass, Pr ¼ pruritis, H ¼ haemorrhoid, I ¼ incontinence, Ch ¼ change in bowel habit, C ¼ constipation, In ¼ incidental, U ¼ ulcer, T ¼ tenesmus, IM ¼ inguinal mass.
as N1 with disease in a single node, N2 with two to three nodes involved and N3 having four or more nodes involved.
Staging There are no separate staging criteria for anorectal melanoma and it is usually considered according to the AJCC TNM classification [AJCC Cancer Staging Sixth Edition]. T1 refers to tumours 1 mm, T2 are tumours 1e2 mm, T3 are tumours 3e4 mm and T4 are all lesions >4 mm. Nodal disease is classified
Treatment Management of patients with anorectal melanoma remains controversial. Owing to its low incidence, treatment is not
Table 3 e Tumour characteristics. Name of study
Number of patients
Location of tumour
Size of tumour
Depth
e
Malik et al.21
19
Above DL 47.3%; At DL 5.2%; Below DL 31.5%
Homsi et al.35 Roumen et al.16
12 63
e median 3.8 cm
Thibault et al.7 Pessaux et al.17
50 40
e Above DL 31.7%; At DL 22.2%; Below DL 38%; Too large 7.9% e Above DL 10%; At DL 57.5%; Below DL 25%; Too large 7.5% Above DL 35%; At DL 15.3%; Below DL 20.5%; Too large 29% Above DL 10%; At DL 24%; Below DL 25%; Unknown 11% e
8 ¼ 5e10 mm, 2 > 10 mm, 1 < 5 mm median 11.5 mm median 12 mm
e mean 2.9 cm
e mean 11 mm
Above DL 5.8%; At DL 76.4% e Above DL 10%; At DL 17.5%; Below DL 72.5% e e
1e6 cm
Cagir et al.10
117
RagnarssonOlding et al.36 Moozar et al.11
251 14
Chute et al.37 Bullard et al.23 Belli et al.38
17 15 40
Weyandt et al.18 Ishizone et al.39
19 79
DL ¼ Dentate Line.
e
e
e
e
e
e
e e
e
3.2 cm median e
10 mm median e
Stage Local 42.1%, Regional 26.3%, Distant 5.2% e Local 35%, Regional 7%, Distant 33% Stage 4 26% Local 60%, Regional 15%, Distant 25% Local 32.5%, Regional 28%, Distant 15.5% e Local 71.4%, Regional 21.4%, Distant 7.1% 1 (6), 2 (6), insufficient info in 5 e Local 42.5%, Regional 30%, Distant 27.5% Distant 31.5% Local 32.9%, Regional 43%, Distant 22.7%
30
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
Table 4 e Treatment. Name of study
Number of patients
Malik et al.22 Homsi et al.37 Roumen et al.16 Thibault et al.7 Pessaux et al.17 Moozar et al.11 Chute et al.39 Bullard et al.24 Belli et al.38 Weyandt et al.18 Ishizone et al.39
19 12 63 50 40 14 17 15 40 19 79
Purpose of treatment Curative Curative Curative Curative Curative N/A N/A N/A Curative Curative Curative
intent intent intent intent intent
APR
WLE
Other
7 5 21 26 9 4 8 4 9 5 63
10 6 18 11 21 10 5 11 18 8 14
2 1 24 0 10 0 4 0 13 0 2
14 11 42 37 24
intent 31 intent 13 intent 60
well defined since it is based on retrospective studies of limited numbers or over long time periods. Our review of the literature, found that in all patients treated with curative intent, the surgical options of abdominoperineal resection or wide local excision were adopted, with no approach being favoured in any study.11,12,16,21,22,24 Other options include palliative debulking or defunctioning colostomy. Abdominoperineal resection constituted 46.1% of procedures with local resection accounting for 37.8% of reported operations (Table 4). There is no evidence to support prophylactic bilateral inguinal lymphadenectomy as it does not appear to affect survival and there is clearly a significant morbidity attached.25,26
Outcomes Survival in anorectal melanoma is universally poor with five year survival between 6%e28.8% (Table 5). Even in patients who undergo potentially curative surgical resection, outcomes remain dismal. Survival is improved with earlier stage of disease with one study showing varying survival
between 28 months for stage 1 and 4 months for stage 3 disease.16 An association between poor survival and the presence of amelanotic melanoma has been observed.17 One study showed that tumour histological type is associated with recurrence, but not with survival with tumours showing pure epithelioid histology less likely to recur compared with tumours showing pure spindle cell or mixed histology.
Discussion Anal tumours, in general, are rare and account for 4% of all cancers of the lower gastrointestinal tract with melanoma making up a very small percentage of these.28 As diagnosis is commonly delayed, suggestions proposed to reduce the significant morbidity and likely mortality from this aggressive disease include histopathological sampling of anal lesions atypical for haemorrhoids and to always include anorectal melanoma in the differential diagnosis of rectal bleeding in adults. Prognostic factors have been studied in several series with varying results. Locally advanced disease along with diffuse
Table 5 e Outcomes. Name of study
Number of patients
Malik et al.21 Homsi et al.35 Roumen et al.16
19 12 63
Thibault et al.7 Pessaux et al.17 Cagir et al.10 Ragnarsson-Olding et al.36 Moozar et al.11 Chute et al.37 Bullard et al.23 Belli et al.38 Weyandt et al.18 Ishizone et al.39
50 40 117 251 14 17 15 40 19 79
OS ¼ Overall Survival, DF ¼ Disease-free survival.
5 year survival
Primary recurrence location
Median survival (months)
21% n/a 6%
31.6% Distant Mets 33.3% Liver 39.6% Lung
22% OS, 16% DF 17% OS, 14%DF 14.90% 14% n/a n/a n/a 20.8%DF(WLE), 15.4%DF(APR) n/a 28.80%
16% Lung/Nodal n/a n/a n/a n/a 47% Nodal mets n/a n/a
n/a n/a 28 mths stage 1, 16 mths stage 2, 4 mths stage 3. n/a 17 OS, 10 DF n/a 12.2 12 13 18 (14 forapr, 19 forwle) 17 for curative, 6 for palliative
21% Liver/Lung/Nodal n/a
25 22
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
metastases at diagnosis undoubtedly lead to unfavourable outcomes. Yeh et al. found that tumour necrosis, perineural invasion and, less significantly, spindle cell histology and larger diameter were associated with poor outcome.27 Brady et al. found that survival was higher among females.12 Wanebo et al. showed that patients with tumours less than 2 mm in depth had increased survival26 and it has been shown that patients with tumours less than 2 cm in diameter had significantly longer survival.5 There is no clear evidence to advocate prophylactic lymph node excision despite the important role of lymph node involvement as a prognostic factor in primary cutaneous melanoma.29 Definitive therapeutic modalities have yet to be clearly outlined due to a paucity of evidence in the literature. Most studies have not found significant differences in survival or disease-free interval between APR and local excision. Many institutions are evolving towards the use of local excision if feasible27 as this approach is more favourable to the patient with preservation of continence. Although it is argued that a more radical approach decreases the rate of local recurrence, the patient does not appear to benefit from a longer survival as a local recurrence is usually accompanied by a relapse at multiple sites with distant metastases. Abdominoperineal resection is not without its own inherent risks and is a technically demanding procedure with a considerable post-operative morbidity. With present staging modalities such as endoluminal ultrasound and positron emission tomography, APR may be recommended for only those lesions with potential curability. APR can sometimes lead to better results in the palliative setting if a patient is very symptomatic with discomfort, pain and incontinence. The role of adjuvant therapy has not been clearly defined and there is limited literature on chemoradiotherapy with its use being mainly confined to the palliative setting.25,30 Chemotherapeutic agents used are based on drugs developed for advanced cutaneous melanoma including cisplatin, vinblastine, dacarbazine, INF and interleukin-2.31 Sentinel lymph node mapping is an integral part of the management in cutaneous melanoma, however there has been minimal research into its use in its anorectal counterpart. From several case reports it is technically possible and without changing prognosis it gives information that may prevent unnecessary lymphandenectomy.32e34 Cutaneous malignant melanoma is widely appreciated as an aggressive malignancy and its anorectal counterpart is no different. It is difficult to elicit accurate figures regarding estimated survival however, as studies to date vary in exclusion criteria and those with seemingly better outcomes may only take into account patients treated with curative intent.
Conclusion It is important to consider the diagnosis of anorectal melanoma as a differential diagnosis in patients complaining of non-specific symptoms in the anorectal region, especially in older women. In the absence of metastatic disease, potentially curative surgical resection is indicated.
31
Although most series report no benefit of APR vs WLE with regards to overall survival, many centres are now favouring local excision with negative margins, which clearly has benefits of a less invasive procedure and preservation of continence. There is unlikely to be a prospective study comparing the two approaches so the decision on surgical approach must depend on individual cases taking into account quality-of-life issues and current evidence from available data. Prognosis of this disease is poor, irrespective of surgical treatment performed. Early diagnosis and treatment is vital to improve survival in patients with this rare condition.
references
1. Moore WD. Recurrent melanosis of the rectum, after previous removal from the verge of the anus, in a man aged sixty-five. Lancet 1857;1:290. 2. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664e78. 3. Quan SHQ. Anal cancers. Squamous and melanoma. Cancer 1992;70:1384e9. 4. Blecker D, Abraham S, Furth E, Kochman M. Melanoma in the Gastrointestinal tract. Am J Gastroenterol 1999 Dec;94(12): 3427e33. 5. Goldman S, Glimelius B, Pahlman L. Anorectal malignant melanoma in Sweden. Report of 49 patients. Dis Colon Rectum 1990;33:874e7. 6. Weinstock MA. Epidemiology and prognosis of anorectal melanoma. Gastroenterology 1993;104:174e8. 7. Thibault C, Sagar P, Nivatvongs S, Ilstrup DM, Wolff BG. Anorectal melanomaean incurable disease? Dis Colon Rectum 1997;40:661e8. 8. Cooper PH, Mills SE, Allen MS. Malignant melanoma of the anus: report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 1982;25:693e703. 9. Cote´ TR, Sobin LH. Primary melanomas of the esophagus and anorectum: epidemiologic comparison with melanoma of the skin. Melanoma Res 2009;19(1):58e60. 10. Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiology of anorectal melanoma. Dis Colon Rectum 1999;42:1203e8. 11. Moozar KL, Wong CS, Couture J. Anorectal malignant melanoma: treatment with surgery or radiation therapy, or both. Can J Surg 2003;46:345e9. 12. Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Centre. Dis Colon Rectum 1995;38:146e51. 13. Stoidis CN, Spyropoulos BG, Misiakos EP, Fountzilas CK, Paraskeva PP. Fotiadis CI.Diffuse anorectal melanoma; review of the current diagnostic and treatment aspects based on a case report. World J Surg Oncol 2009;11(7):64. 14. Kim KW, Ha HK, Kim AY, et al. Primary malignant melanoma of the rectum: CT findings in eight patients. Radiology 2004; 232:181e6. 15. Sashiyama H, Takayama W, Miyazaki S, et al. The diagnostic value of endoscopic ultrasonography and magnetic resonance imaging for anorectal malignant melanoma: report of a case. Surg Today 2003;33:209e13. 16. Roumen RM. Anorectal melanoma in the Netherlands: a report of 63 patients. Eur J Surg Oncol 1996;22:598e601.
32
t h e s u r g e o n 9 ( 2 0 1 1 ) 2 7 e3 2
17. Pessaux P, Pocard M, Elias D, Duvillard P, Avril MF, Zimmerman P, Lasser P. Surgical management of primary anorectal melanoma. Br J Surg 2004;91(9):1183e7. 18. Weyandt GH, A0 Eggert, Houf M, et al. Anorectal melanoma. Surgical management guidelines according to tumour thickness. Br J Cancer 2003;89(11):2019e22. 19. Helmke BM, Mollenhauer J, Herold-Mende C, Benner A, Thome M, Gassler N, et al. BRAF mutations distinguish anorectal from cutaneous melanoma at the molecular level. Gastroenterology 2004;127(6):1815e20. 20. Rodrigues Gabriel, Kudva Annappa, Kudva Ranjini. Primary anal malignant melanoma. Internet J Surg 2003;4(1). 21. Malik A, Hull TL, Floruta C. What is the best surgical treatment for anorectal melanoma? Int J Colorectal Dis 2004;19:121e3. 22. Antoniuk PM, Tjandra JJ, Webb BW, et al. Anorectal Melanoma has a poor prognosis. Int J Colorectal Dis 1993;8:81e6. 23. Bullard KM, Tuttle TM, Rothenberger DA, et al. Surgical therapy for anorectal melanoma. J Am Coll Surg 2003;196:206e11. 24. Podnos YD, Tsai NC, Smith D, Joshua DI. Factors affecting survival in patients with anal melanoma. Am Surg 2006;72:917e20. 25. Rosseti C, Koukouras D, Eboli M, Andreola S, Bertario L. Primary anorectal melanomas: an institutional experience. J Exp Clin Cancer Res 1997;16:81e5. 26. Chiu YS, Uni KK, Beart Jr RW. Malignant melanoma of anorectum. Dis Colon Rectum 1980;23:122e4. 27. Yeh JJ, Shia J, Hwu WJ, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. Ann Surg 2006;244(6):1012e7. 28. Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol 2004;5(3):149e57. 29. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622e34.
30. Slingluff Jr CL, Vollmer RT, Seigler HF. Anorectal melanoma; clinical characteristics and results of surgical management in twenty-four patients. Surgery 1990;107:1e9. 31. Eton O, Leggha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 2002;20:2045e52. 32. Olsha O, Mintz A, Gimon Z, Gold Deutch R, Rabin I, Halevy A, et al. Anal melanoma in the era of sentinel lymph node mapping: a diagnostic and therapeutic challenge. Tech Coloproctol 2005;9:60e2. 33. Mariolis-Sapsakos T, Malamitsi J, Yakoumakis E, Orfanos F. Is sentinel node mapping useful in anorectal melanoma? Hell J Nucl Med 2008;11(1):39e42. 34. Duport C, Tiffet O, Perrot JL, Pre´vot N, Rey Y, Cambazard F. Sentinel node mapping in anorectal melanoma. Ann Chir 2006;131(9):550e2. 35. Homsi J, Garrett C. Melanoma of the anal canal: a case series. Dis Colon Rectum 2007;50:1004e10. 36. Ragnarsson-Olding BK, Nilsson PJ, Olding LB, Nilsson BR. Primary ano-rectal malignant melanomas within a population-based national patient series in Sweden during 40 years. Acta Oncol 2009;48(1):125e31. 37. Chute DJ, Cousar JB, Mills SE. Anorectal malignant melanoma: morphologic and immunohistochemical features. Am J Clin Pathol 2006;126(1):93e100. 38. Belli F, Gallino GF, Lo Vullo S, Mariani L, Poiasina E, Leo E. Melanoma of the anorectal region: the experience of the National Cancer Institute of Milano. Eur J Surg Oncol 2009;35 (7):757e62. 39. Ishizone S, Koide N, Karasawa F, Akita N, Muranaka F, Uhara H, et al. Surgical treatment for anorectal malignant melanoma: report of five cases and review of 79 Japanese cases. Int J Colorectal Dis 2008;23(12):1257e62.