A Revisit to AnorectalMalignant Melanoma (ARMM)

Joint Hospital Surgical Grand Round

8 Nov 2014

Dr Jessie Chan

Pamela Youde Nethersole Eastern Hospital

Outline

Introduction Epidemiology Presentation Investigations Staging Prognosis

Treatment Surgery Adjuvant therapy

Introduction

Rare neoplasm

First reported by Moore in 1857

Distinct biological and clinical entity from cutaneous melanoma with worse prognosis

No clear etiology elucidated

Arised from melanocytes distal to dentate line and extend proximally to rectum

Arised directly from melanocytes which present rarely in the mucosal epithelium of proximal anus or distal rectum

ARMM

<1% of all malignant melanomas

<4% of anal canal malignancies

Primary

Secondary Metastasis from cutaneous melanoma (2%)

Epidemiology

Median age at presentation: 55 (range 29-92)

Reported incidence: 0.04 – 1.19%

No adequate population-based studies to draw definite conclusions for racial and gender difference

Presentation

Non-specific symptoms PR bleeding Anal pain, anal mass Tenesmus, pruritus Change in bowel habit

Symptoms of metastatic disease Most common sites of metastases: inguinal / mesenteric /

hypogastric / para-aortic lymph nodes, liver, lung, skin, brain

Weight loss, groin mass, pelvic mass, bowel obstruction

Incidental finding

Presentation

80% lack obvious pigmentation

20% histologically amelanotic

Presentation

Up to 60% with locoregional lymphatic spread (mesorectal, pelvic side wall, inguinal lymph nodes)

Up to 40% with distant metastasis

Investigations

Endoscopy and biopsy

Staging Endoscopic ultrasound: role unclear CT: regional lymphadenopathy, distant metastasis PET scan: may be helpful

Staging

Cutaneous melanoma: AJCC TNM system

ARMM Clinical staging Stage I: local disease Stage II: local disease with regional lymph nodes Stage III: distant metastatic disease

Prognosis

Poor prognosis

Overall 5-year survival 3-22%

Survival <10 months with recurrent or metastatic disease

Prognosis

Good prognostic factors Tumour thickness <2mm

Poor prognostic factors Tumour thickness >3mm Tumour site above dentate line Lymphovascular / perineural invasion Necrosis

Wanebo HJ, Woodruff JM, Farr GH, et al. Anorectal melanoma. Cancer. 1981 Apr 1; 47(7):1891-900.Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum. 1995 Feb; 38(2):146-51.

Perez DR, Trakarnsanga A, Shia J, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol. 2013;20:2339-2344.

Treatment

Treatment

Surgery Wide local excision (WLE) Abdominoperineal resection (APR)

Regional lymph node Sentinel lymph node biopsy Lymphadenectomy

Treatment

Adjuvant therapy Systemic

Chemotherapy Biochemotherapy Interferon Vaccine / immunotherapy

Local Radiation therapy Electrochemotherapy

Surgery

Mainstay of treatment

Controversies

① APR vs local excision (LE) APR – en bloc excision with mesorectal lymph nodes ?oncological benefit

② Inguinal lymphadenectomy

Surgery

Meta-analysis by Akihisa Matsuda et al in Annals of Surgery 2014 31 studies 1006 patients APR vs LE

Overall survival Relapse-free survival Local recurrence rate

Akihisa Matsuda, Masao Miyashita, Satoshi Matsumoto, et al. Abdominoperineal Resection Provides Better Local Control But Equivalent Overall Survival to Local Excision of Anorectal Malignant Melanoma – A Systemic Review. Ann Surg. 2014; 00: 1-8.

APR vs LE

Overall survival – no difference (31 studies, N=1006)

APR vs LE

Recurrence-free survival – no difference (14 studies, N=328)

APR vs LE

Local recurrence rate – significantly lower in APR (13 studies)

Surgery

No survival benefit from APR over LE

Higher local recurrence from LE which could be managed by salvage surgery

Less complications and morbidities with LE Better body image Better urinary and sexual function Minimal impact on bowel function

Minimizing morbidities and maximizing quality of life merits consideration in such an aggressive disease

Inguinal lymphadenectomy

Locoregional lymph node metastasis – no significant prognostic implication

Perez DR, Trakarnsanga A, Shia J, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol. 2013;20:2339-2344.

Inguinal lymphadenectomy

Systemic dissemination with micrometastasis in distant organs occurs early with unfavourable prognosis

Prophylactic – no improvement in survival, increased risk of complications

Therapeutic – seems not to contribute to improvement of survival

Perez DR, Trakarnsanga A, Shia J, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol. 2013;20:2339-2344.

Adjuvant Therapy

Chemotherapy

Role remains unclear ?Adjuvant ?Palliative

Dacarbazine, cisplatin, vinblastine, vincristine, nimustine, bacillus Calmette-Guérin, levamisole, temozolomide

Single or combination – poor results

Interferon

Interferon alpha Combination of direct activities and indirect immune-

mediated effects Parenteral route / intratumoural injection No standard regimen established Insufficient data

Biochemotherapy

Biologic agent (interferon, interleukin) + traditional cytotoxic chemotherapeutic agent

Longer disease-free and median survival in metastatic ARMM when compared with chemotherapy alone

Kim K B, Sanguino A M, Hodges C, et al. Biochemotherapy in patients with metastatic anorectal mucosal melanoma. Cancer. 2004;100:1478–1483.

Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul; 17(7):2105-16.

Biochemotherapy

Role Best available adjuvant therapy after surgery Considered in advanced or metastatic ARMM

Vaccine / Immunotherapy

Immunize against melanoma cell antigen

BRAF and cKIT mutations

Insufficient data

Area of significant research effort and may play an important part of the non-operative treatment of melanoma in the future

Radiation Therapy

Locoregional disease control Primary lesion, inguinal and pericolic lymph nodes

Utility unclear, evidence conflicting

Radiation Therapy

Ballo et al Local excision + post-op RT

Local control rate comparable with APR 5-year local control rate: 74%

No improvement in survival

Moozar et al Pre-op RT little effect on tumour burden Post-op RT did not change local recurrence No survival benefit

Moozar KL, Wong CS, Couture J. Anorectal malignant melanoma: treatment with surgery or radiation therapy, or both. Can J Surg. 2003 Oct; 46(5):345-9.

Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002 Dec 1; 20(23):4555-8.

Electrochemotherapy

Injection of chemotherapy directly into the lesions, followed by application of electric pulses using a needle electrode

Electrical stimulation to the tissues creating a transient permeabilization of the plasma membrane

Allows direct access of the chemotherapeutic agents into the cytosol of tumor cells

Known to provide effective local control for cutaneous melanoma

Electrochemotherapy

Convert APR to sphincter-preserving local excision

Overall success rate unclear

Snoj M, Rudolf Z, Cemazar M, et al. Successful sphincter-saving treatment of anorectal malignant melanoma with electrochemotherapy, local excision and adjuvant brachytherapy. Anticancer Drugs. 2005 Mar; 16(3):345-8.

Summary

ARMM is a rare and highly malignant disease

Survival predicted by status of regional and distant metastasis but not method of surgery for local control

Minimizing surgical morbidities and maximizing quality of life should be the major consideration in formulating the treatment plan

Role of all adjuvant therapies is still unclear

References

P Carcoforo, M.T Raiji, G.M Palini, et al. Primary Anorectal Melanoma: An Update. J Cancer. 2012; 3:449-453. doi:10.7150/jca.5187.

Marc Singer and Matthew G. Mutch. Anal Melanoma. Clin Colon Rectal Surg. May 2006; 19(2): 78–87.

Akihisa Matsuda, Masao Miyashita, Satoshi Matsumoto, et al. Abdominoperineal Resection Provides Better Local Control But Equivalent Overall Survival to Local Excision of Anorectal Malignant Melanoma – A Systemic Review. Ann Surg. 2014; 00: 1-8.

Perez DR, Trakarnsanga A, Shia J, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol. 2013;20:2339-2344.

Wanebo HJ, Woodruff JM, Farr GH, et al. Anorectal melanoma. Cancer. 1981 Apr 1; 47(7):1891-900.

Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum. 1995 Feb; 38(2):146-51.

References

Kim K B, Sanguino A M, Hodges C, et al. Biochemotherapy in patients with metastatic anorectal mucosal melanoma. Cancer. 2004;100:1478–1483.

Ulmer A, Metzger S, Fierlbeck G. Successful palliation of stenosing anorectal melanoma by intratumoral injections with natural interferon-β. Melanoma Res. 2002;12:395–398.

Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul; 17(7):2105-16.

Snoj M, Rudolf Z, Cemazar M, et al. Successful sphincter-saving treatment of anorectal malignant melanoma with electrochemotherapy, local excision and adjuvant brachytherapy. Anticancer Drugs. 2005 Mar; 16(3):345-8.

Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002 Dec 1; 20(23):4555-8.

Moozar KL, Wong CS, Couture J. Anorectal malignant melanoma: treatment with surgery or radiation therapy, or both. Can J Surg. 2003 Oct; 46(5):345-9.

Thank You