Case report
Anal melanoma. Case report and literature review
Ana Clara Ortega,1Ignacio Pitaco,2 Eduardo Gómez,3 Ángel M. Minetti.4
Sanatorio de la Trinidad. Quilmes, Provincia de Buenos Aires
1 Trainee of the Coloproctology Specialist University Course, School of Medicine, Universidad de Buenos Aires.
2 Staff of the General Surgery Service and the Coloproctology Sector.
3 Head of the General Surgery Service.
2 Adjunct Professor of Surgery, School of Medicine, Universidad de Buenos Aires; Head of the Coloproctology Sector.
The authors declare no conflicts of interest.
Ana Clara Ortega
anaclaraortega@gmail.com
Ana Clara Ortega: https://orcid.org/0000-0002-4733-3844
Ignacio Pitaco: https://orcid.org/0000-0002-8450-0488
Eduardo Gómez: https://orcid.org/0000-0002-9639-976X
Ángel M. Minetti: https://orcid.org/0000-0003-1235-6904
ABSTRACT
Anal melanoma is a malignant neoplasm of low incidence, with an unfavorable prognosis and non-specific symptoms. Its early diagnosis is essential for patient survival. A case of melanoma of the anal margin with unilateral inguinal metastasis is presented. Wide local resection and delayed inguinal lymphadenectomy, without adjuvant treatment, was performed. At 18-month follow-up, there was no evidence of local and/or distant recurrence.
Key words: Anal melanoma, Mucosal melanoma, Anal cancer
INTRODUCTION
Neoplasms of the anal canal and perianal skin are rare entities, constituting 2-4% of anorectal malignancies.1-3 Melanoma of the anus comprises 1-3% of all melanomas. It affects people between 60 and 80 years old, with a female predominance. Its prevalence is so low that it does not allow the development of randomized prospective trials to develop guidelines, which prevents having an optimal management protocol. Its non-specific form of presentation, the delay in diagnosis and the poor response to multimodal treatment lead to a poor prognosis. The best results are obtained in the initial cases treated by surgery.
CASE
A 73-year-old white male presented with proctorrhagia of 10 months' duration, with mucosanguinous discharge and a perianal tumor that had doubled in the last 5 months. He has no relevant personal or family history.
Physical examination: 6x5 cm tumor in the hemicircumference of the left perianal skin and internal limit in the mucocutaneous line. It is broad-based, smooth, hard-elastic, bluish-brown in color and partially mobile. Digital rectal examination and anoscopy show an uninvolved anal canal (Fig. 1). In the left inguinal region, a 1.5 cm node was palpable, painless and mobile.
Figure 1. A. Nodular tumor that limits internally with the mucocutaneous line and extends towards the perianal skin on the left side. B. The internal margin of the lesion is observed at the level of the dentate line (arrow).
Complementary tests: Normal laboratory.
Presumptive diagnosis: Melanoma vs. squamous or connective tissue tumor.
In order to improve the severe local symptoms and confirm the diagnosis, complete resection with surgical safety margins is proposed.
Surgical procedure: Spinal anesthesia. Lithotomy position. Border marking with electrocautery 2 cm from the lesion on the inner side and 5 cm in the rest of the contour. Dissection up to the muscular plane of the sphincter, resecting some of its fibers and the perianal fat. Excision of the specimen (Fig. 2) and closure of the defect with a sliding skin flap (Fig. 3).
Figure 2. Incision on the perianal skin.
Figure 3. A. Surgical bed after resection. B. Final appearance after flap reconstruction.
Discharge at 48 hours. On the seventh day, partial wound dehiscence that heals by secondary intention.
Histopathology: 4.8 x 2.5 cm mucosal, nodular, invasive melanoma, in vertical growth phase, with ulceration. It invades the submucosa of the distal anal canal. Maximum tumor thickness (Breslow): 7 mm. Mitotic index: 3 mitoses/mm2. Macroscopic satellite nodules, tumor-infiltrating lymphocytes, tumor regression, microsatellite disease, or neurotropism were not identified. Lymphovascular invasion. (Fig. 4A). Resection margins free of neoplasia: closest lateral margin is 0.2 cm (hour 3) and deep margin is 1.2 cm. Pathologic staging (pTNM): not available for mucosal melanoma of the anal canal.
Immunostaining: CKAE1A3: negative in neoplastic cells. S100: cytoplasmic positive in neoplastic cells. HMB45: cytoplasmic positive in neoplastic cells. Melan-A: cytoplasmic positive in neoplastic cells (Fig. 4B).
Figure 4. Melanoma. A. Hematoxylin and eosin staining. B. Positive Melan-A immunostaining.
With the definitive histological diagnosis, the patient was staged by positron emission tomography, which defined a hypermetabolic nodular image in the left inguinal region of 23.7 mm (SUV 4.4). No pathological findings in the rest of the study (Fig. 5).
Figure 5. PET scan, showing abnormal uptake in a left inguinal node (arrow).
Reoperation: Two months later, left inguinal lymphadenectomy (Fig. 6).
Figure 6. Sectioned lymphadenectomy specimen, showing the metastatic node.
Postoperative follow-up: Partial dehiscence of the wound with necrosis of the margin and lymphorrhagia. Healing by secondary intention. Histopathology: Lymphadenectomy showing p.V600E mutation in Exon 15 of the BRAF gene.
In a multidisciplinary conference, clinical control and total body tomography every 3 months are decided, along with MRI of the pelvis.
Long-term follow-up: No evidence of local and/or distant recurrence at 18 months.
DISCUSSION
The prevalence of anal melanoma is between 0.6 and 1.6%, ranking third after skin and retina.2 It affects people between the sixth and eighth decade of life and is 1.6 to 2.3 times higher in females.3,4 It has increased in recent years, however the specific cause is unknown since it is not related to areas exposed to radiation such as cutaneous melanoma.3
The clinical signs and symptoms are not very specific and can simulate benign anal conditions, delaying the diagnosis.3The most frequent are bleeding, mucosanguinous discharge, anal tumor, pruritus and pain. In cases of rectal involvement, there is tenesmus and change in bowel habits (constipation or diarrhea).3,4 The time elapsed between the onset of symptoms and diagnosis is estimated at 3 to 8 months. Sixty-seven percent of patients present distant metastases at the time of diagnosis, which is associated with an unfavorable prognosis and a median overall survival of between 8 and 18.6 months.4
In 2018, the World Health Organization classified cutaneous, uveal and mucosal melanoma into nine histological variants: melanoma associated with cumulative sun damage and those not associated, including mucosal melanoma. The nodular form has the worst prognosis.5 Lesions may or may not be pigmented; in the anorectal region, the non-pigmented ones comprise between 10 and 87%.4 The definitive diagnosis is obtained by immunohistochemistry, positive for protein S100, HMB 45 and Melan-A and negative for CEA, Cytokeratin and epithelial membrane antigen.2, 3 ,7
Methods for local, regional, and systemic staging include digital rectal examination, anoscopy, sigmoidoscopy, colonoscopy, and anorectal ultrasound. Total body tomography and/or magnetic resonance imaging together with positron emission tomography are useful for systemic evaluation.
Unlike skin melanoma, mucosal melanoma does not have TNM staging.9 In 2013, Falch et al.4 proposed the following staging for anorectal melanoma: Stage I, locally disseminated tumor, without infiltration of the muscle layer; Stage II, locally disseminated tumor, with infiltration of the muscular layer; Stage III, regionally disseminated tumor and/or nodal metastases; Stage IV, disseminated tumor.
The most frequent distant metastases are in the liver, lung, and bone.4,8 Submucosal infiltration is associated with 44% lymph node metastasis and lower survival,4,9 although it is controversial since there is literature that does not support it.12
Treatment consists of surgery through two variants: abdominoperineal resection (APR) or extended local resection (LR) with the addition of simultaneous or delayed inguinal lymphadenectomy. Adjuvant treatment is performed by radiotherapy (RT), chemotherapy (CTX) and immunotherapy (IMT).
In a systematic review of 1006 patients, Matsuda et al.10 concluded that the APR in relation to the LR allows better local control, but no benefits in 5-year overall survival and disease-free survival (LR 18% vs. APR 19.9%). Reasonably, LR had lower morbidity and mortality and better quality of life. Furthermore, it was found that most of the time local recurrence, both after APR and LR, is accompanied by distant metastasis. Recurrence after LR can be treated with APR, or with a new LR when possible and there are no risks of severe incontinence.14,10 The data seem to show a preference for LR, however it should be noted that the decision to perform APR or sphincter-sparing surgery is linked to several factors such as: the location of the tumor (rectal, anal or cutaneous), its size, and especially for the LR, a high risk of incontinence.
Lymphadenectomy as part of treatment is another controversial issue. A retrospective study by Pérez et al.12 reports the experience of the Memorial Sloan-Kettering Cancer Center with 65 patients with anorectal melanoma treated with curative intent, between 1985 and 2010. APR was performed in 25 (39%) patients and LR in 40 (61%) patients. In 18 (26%) patients different forms of adjuvant therapy (CTX, RT and IMT) were performed. In the APR group, only 7 of 65 patients had positive nodes in the mesorectum, which did not influence disease-free or overall survival. The location of the tumor (above or below the dentate line) and the depth of invasion were also not related. There was no association between tumor location above or below the dentate line and the pattern of lymphatic spread to the mesorectum or groin. In 32 of the 65 patients, positive inguinal nodes were found; however, although there was a tendency to a lower overall survival in them, it was not statistically significant. Mesorectal or inguinal lymphatic dissemination was not associated with a worse prognosis. Sentinel node biopsy, performed only in 9 patients in the RL group, was positive in 7, although it had no influence on overall and disease-free survival.
The use of the sentinel node to decide lymphadenectomy has not been established in this location.4,6 A retrospective study by Bleicher et al.13 in a cohort of 24 patients showed no significant difference in survival between patients with or without identification of the sentinel node. Patients with a positive sentinel node received adjuvant systemic therapy.
The impact of adjuvant therapy on survival is currently unknown. Regarding non-surgical therapy, there is currently no gold standard in management, since the therapeutic strategy is still unclear. The different therapies (RT, CTX, and IMT) did not show benefits over each other. The median survival was 18.8 months, with zero overall survival at 5 years. Excluding patients with distant disease at diagnosis, the median overall survival was 19.9 months.
A retrospective study conducted by Naqvi et al.14 in 398 patients, the majority with nodal or metastatic disease, compared four groups of therapies: surgery alone, surgery + RT, surgery + CT/IMT and RT ± IMT/CT. The highest overall survival was obtained by the surgery + RT group (32.3 months). Survival with surgery alone was 22.9 months and with RT ± IMT/QT 5.1 months. In patients with lymph node involvement, surgery alone had a survival of 3.9 months, while surgery + CT/IMT had a survival of 10.8 months, highlighting the need for systemic treatment in advanced stages of the disease.
Despite any treatment, anal melanoma has a very high mortality, with a 5-year survival of less than 20%. Obtaining an R0 in surgery allows better survival.11 Although there are few studies that compare the different therapeutic options, it is clear that the stage of the disease when deciding to implement an appropriate strategy is crucial for survival.
Subsequent follow-up, the indicated studies and the management of recurrence, are still issues to be evaluated.
In conclusion, the main objective of treatment for anal melanoma is resection, preferably local when possible and there are no risks of incontinence, since it has better quality of life and morbidity and mortality and similar long-term results compared to abdominoperineal resection. Adjuvant therapies have not shown better effects.
The reported patient, treated with local resection and inguinal lymphadenectomy without other therapy, is free of disease after 18 months of follow-up.
REFERENCES
1. Wietfeldt ED, Thiele J. Malignancies of the anal margin and perianal skin. Clin Colon Rectal Surg. 2009; 22:127-35.
2. Leonard D, Beddy D, Dozois EJ. Neoplasms of anal canal and perianal skin. Clin Colon Rectal Surg. 2011; 24:54-63.
3. Meguerditchian AN, Meterissian SH, Dunn KB. Anorectal melanoma: diagnosis and treatment. Dis Colon Rectum. 2011; 54:638-44.
4. Falch C, Stojadinovic A, Hann-von-Weyhern C, Protic M, Nissan A, Faries MB, et al. Anorectal malignant melanoma: extensive 45-year review and proposal for a novel staging classification. Am Coll Surg. 2013; 217:324-35
5. Elder DE, Bastian BC, Cree IA, Massi D, Scolyer RA. The 2018 World Health Organization classification of cutaneous, mucosal, and uveal melanoma: detailed analysis of 9 distinct subtypes defined by their evolutionary pathway. Arch Pathol Lab Med. 2020; 144: 500-22.
6. Iddings DM, Fleisig AJ, Chen SL, Faries MB, Morton DL. Practice patterns and outcomes for anorectal melanoma in the United States; is more extensive surgical resection beneficial in all patients? Ann Surg Oncol. 2010; 17: 40-4.
7. Fuertes L, Santonja C, Kutzner H, Requena L. Inmunohistoquímica en dermatopatología: revisión de los anticuerpos utilizados con mayor frecuencia (parte I). Actas Dermosifiliogr. 2013; 104:99-127.
8. Efron J. Expert commentary on anal melanoma: a rare perianal tumor with a poor prognosis. Dis Colon Rectum. 2020; 63: 576-77.
9. 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;83:1664-78.
10. Matsuda A, Miyashita M, Matsumoto S, Takahashi G, Matsutani T, Yamada T, et al. Abdominoperineal resection provides better local control but equivalent overall survival to local excision of anorectal malignant melanoma: a systematic review. Ann Surg. 2015; 261:670-77.
11. Fields AC, Goldberg J, Senturk J, Saadat LV, Jolissaint J, Shabat G, et al. Contemporary surgical management and outcomes for anal melanoma: A National Cancer Database Analysis. Ann Surg Oncol. 2018; 25:3883-88.
12. Pérez DR, Trakarnsanga A, Shia J, Nash GM, Temple LK, Paty PB, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol. 2013; 20:2339-44.
13. Bleicher RJ, Essner R, Foshag LJ, Wanek LA, Morton DL. Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas. J Clin Oncol. 2003; 21:1326-31.
14. Naqvi J, Lee A, Lederman A, Kavi A, Osborn VW, Schreiber D. Patterns of care and survival outcomes in the treatment of anal melanoma. J Gastrointest Cancer. 2020; 51:211-16.
COMMENT
The relevance of this case report lies in the fact that it alerts the reader to a very rare disease, allowing its suspicion to reach an early diagnosis that will be essential for its prognosis.
Since the first case of anorectal melanoma described by Moore in 1857, there have been multiple publications on the subject; however, most have been case reports or small series with very low-quality evidence.
More than 67% of patients present metastases at the time of diagnosis, associated with a survival between 8 and 18 months. One of the largest series that includes 85,000 patients showed that mucocutaneous melanoma corresponds to 1.3% and only 24% of these are of the type presented in this case. Even in centers of reference in oncologic pathology, no more than 2 cases are treated per year,1
It should be noted that the pathophysiology of this neoplasia is not related to that known for cutaneous melanoma, since it does not occur in areas of the body exposed to ultraviolet rays and therefore there is no racial predilection.
As well described in the article, the prognosis of anal melanoma depends on its early diagnosis and the difficulty lies in the non-specificity of its symptoms (bleeding, pain, mass) associated with the fact that more than 87% are usually amelanotic.1
Regarding staging, there is currently no classification according to the TNM system. The recommendation is based on Ballantyne's description in 1970,3 which includes stages (I local, II regional, III disseminated). Falch et al.1 subdivide stage 1 according to whether or not there is muscle involvement, which is relevant for proper treatment.
According to Kelly et al.,2 90% of patients with positive nodes at the time of diagnosis will develop distant metastases. Patients treated with curative intent have shown a subsequent dissemination rate of 59 and 72% at 2 and 5 years, respectively, denoting the importance of close and prolonged follow-up given the insidious nature of this disease. Fortunately, in the case presented, after 1 year of follow-up there was no evidence of disease.
Regarding surgical treatment, it is interesting to cite the article by Smith et al.,3 a systematic review and meta-analysis that includes 27 studies and concludes that the most radical treatment (abdominoperineal resection) does not offer a significant difference in survival. They recommend wide local resection associated with close follow-up as the optimal treatment.
Regarding multimodal treatment, although new strategies have been incorporated into the therapeutic arsenal,4 none have been able to prolong survival over the past three decades. I recommend reading the article "Anorectal mucosal melanoma in the era of immune checkpoint inhibition: should we change our surgical management paradigm?" published in May, 2021.5
To end the comment, I recommend reading the United Kingdom guidelines for melanoma of the anal-uro-genital mucosa,6 the only guide available to standardize the diagnosis, treatment and follow-up of mucosal melanomas, although the levels of recommendation cannot be high due to the level of evidence.
In conclusion, given the lack of level I evidence, decision-making must maintain a balance between the possibility of cure and the morbidity associated with the treatment of a highly relapsing and high-mortality disease. Its early diagnosis and close follow-up are fundamental pillars to improve its prognosis.
Federico Carballo
Hospital Pirovano, Buenos Aires
1. Falch C, Stojadinovic A, Hann-von-Weyhern C, Protic M, Nissan A, Faries MB, et al. Anorectal malignant melanoma: extensive 45-year review and proposal for a novel staging classification. J Am Coll Surg. 2013;217:324-35.
2. Kelly P, Zagars GK, Cormier JN, Ross MI, Guadagnolo BA. Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: a 20-year experience. Cancer. 2011; 15;117:4747-55.
3. Smith HG, Glen J, Turnbull N, Peach H, Board R, Payne M, Gore M, Nugent K, Smith MJF. Less is more: A systematic review and meta-analysis of the outcomes of radical versus conservative primary resection in anorectal melanoma. Eur J Cancer. 2020; 135:113-20.
4. Jutten E, Kruijff S, Francken AB, Lutke Holzik MF, van Leeuwen BL, van Westreenen HL, et al. Surgical treatment of anorectal melanoma: a systematic review and meta-analysis. BJS Open. 2021; 5:zrab107.
5. Adileh M, Yuval JB, Huang S, Shoushtari AN, Quezada-Diaz F, Pappou EP, Weiser MR, et al. Anorectal mucosal melanoma in the era of immune checkpoint inhibition: should we change our surgical management paradigm? Dis Colon Rectum. 2021; 64:555-62.
6. Smith HG, Bagwan I, Board RE, Capper S, Coupland SE, Glen J, et al. Ano-uro-genital mucosal melanoma UK national guidelines. Eur J Cancer. 2020; 135:22-30.