Anorectal mucosal melanoma

Abstract

Anorectal mucosal melanoma accounts for less than 1 % of all anorectal malignant tumors and a tendency for delayed diagnosis leads to advanced disease at presentation.^1,2 Due to the rarity of the disease, there are limited prospective trials exploring the optimal treatment strategies. Generally, tumors are surgically excised, with a preference for conservative management with wide local excision. In the past decade, there have been advances with immunotherapy and other targeted therapies. Multiple clinical trials continue exploring neoadjuvant/adjuvant combination treatments in the setting of advanced or unresectable disease.

Introduction

Melanoma arises from the melanocyte, a pigmented dendritic-like cell located in the base of the epidermis, the eye, the epithelia of the nasal cavity, oropharynx, anus, vagina, and urinary tract.³ Approximately 90 % of melanomas are cutaneous and associated with ultraviolet radiation exposure. The remaining are non-cutaneous melanomas consisting of uveal and mucosal melanoma.³ Mucosal melanomas arise from the mucosa of the head and neck (55 %), anorectum (24 %), and vagina (18 %) (Table 1).¹

Table 1.

Classification and staging.

Classification of Melanoma Subtypes
Staging System for Anorectal Melanoma Thickness	Disease	TNM Staging
	Local	I = T1, N0, M0
≤2.00 mm	Regional nodes	II = T2, 3, N0, M0
≥2.01 mm	Distant disease	IIIA = T4, N0, M0 or T1, 2, 3, N1, M0
		IIIB = T4, N1, M0 or T1, 2, 3, N2, M0
		IV = Any T, Any N, M1

Anorectal mucosal melanoma (ARMM) is an extremely rare tumor with a 5-year overall survival (OS) estimated between 10 and 20 %.^3–6 Unlike cutaneous melanomas, sun exposure is not a risk factor for mucosal melanomas. Human immunodeficiency virus may be a risk factor but otherwise the risk factors for ARMM are poorly understood.^1,6,7 The incidence of ARMM increases with age with the mean age of presentation being 55 years and the range being wide, 29 to 91 years old.^8,9 ARMM is seen more frequently in women, however women are more likely to undergo a perineal examination potentially confounding the observed female predilection.⁷ Additionally, the incidence of ARMM is 1.7-fold higher in Caucasians than African Americans.^10,11

The anorectum consists of the distal rectum, the transitional zone at the pectinate line, and the anal canal. Most (65 %) ARMMs are found in the anal canal or transition zone, with the other 35 % arising from the distal rectum.¹² Patients present with bleeding, discomfort, change in bowel habits, and/or an anal mass. Early diagnosis is difficult due to location, nonspecific symptoms, and the high rate of amelanotic lesions (seen in up to 20 % of tumors).^7,13 In a study of 142 patients, 60 % presented with localized disease, 19 % had regional lymph node involvement, and 20 % had distant disease at the time of diagnosis.⁴ The presence of melanin pigment, junctional changes, atypical epidermoid cells or pleomorphic spindle cells adjacent to the tumor focus aid the diagnosis.¹³ In scenarios of amelanotic tumors or those lacking junctional changes, histologic markers (S-100, melanoma antigen HMB-45, vimentin, cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen) aid in the diagnosis.^5,14–16

The lack of a consensus staging system

Two staging systems are used clinically. One is determined by the disease spread (Stage I is localized; Stage II involves lymph nodes; Stage III represents distant disease) and the other staging by American Joint Commission on Cancer (AJCC) system.¹³ The AJCC system uses the depth of the primary tumor and lymph node involvement (Table 1).³ Tumor thickness, determined by the Breslow classification, defined as the distance in millimeter (mm) from the surface of epithelium to deepest point of penetration by tumor, is associated with long term survival. Wanebo et al’s study of 26 patients with ARMM showed that patients with melanomas thicker than 2.0 mm had worse prognosis, with no patients living longer than 5 years after diagnosis. The 4 patients with <2.0 mm thick melanomas were alive 13 or more years after diagnosis.¹² Brady et al. showed that patients who presented with distant disease had worse OS than those who presented with locoregional disease only (0 % versus 20 % respectively, p<0.001).⁵ ARMM has the potential to metastasize to the inguinal lymph nodes, mesorectum, liver, lungs, bones, and brain.¹⁷ A retrospective review estimated that 5 year OS paralleled tumor stage: Stage I, 27 %; Stage II, 10 %; Stage III, 0 %.⁴

Treatment

Surgery

There is limited evidence on which to base decisions regarding optimal surgical management of ARMM. The typical treatment involves wide local excision or a more radical abdominoperineal resection (APR). Several studies have shown no difference in OS between APR and local excision.^4,18–21 However, APR is associated with a lower risk of recurrence in some reviews.⁵ Additionally, APR is preferred for large, advanced, resectable, nonmetastatic melanomas that are not amenable to local excision.⁴ Patients with localized disease should undergo local excision whenever possible as this technique minimizes morbidity from radical surgery and maximizes quality of life.²² Local recurrence is more common following wide local excision, but this is not associated with inferior OS compared to APR.²³ The most important prognostic factor with regard to surgery is achieving microscopically clear margins.²⁴ Unfortunately, most patients will develop distant disease regardless of the initial surgical approach..

The high incidence of inguinal lymph node involvement likely contributes to postoperative recurrence. In a retrospective study of 208 patients, lymph node metastasis played an important prognostic role, however lymphadenectomy was not associated with improved OS.²⁵ Perez et al. argue against the use of prophylactic lymphadenectomy in clinically node negative patients as locoregional lymphadenectomy does not affect outcome for occult nodal metastasis, as it does for cutaneous melanoma.²⁶ The role of sentinel lymph node biopsy remains undefined, but may have a role in disease diagnosis and treatment.²⁷ The shift towards a preference for local excision, when feasible, is to prioritize a patient’s quality of life and minimize morbidity. Palliative surgery (e.g., diverting colostomy) is recommended in patients with large primary tumors or in the presence of distant metastasis.²⁸

Adjuvant or systemic therapy

Radiation therapy (RT)

Literature on the merits of radiation with or without surgery are limited in ARMM, and radiation is currently not the standard of care. Konstadoulakis et al. demonstrated a local control rate similar to APR when radiation therapy was administered after wide local excision. However, there was no difference in OS.²⁹ This is supported by findings in Kelly et al., which showed that a combination of wide local excision and hypo-fractionated radiation therapy resulted in a crude local recurrence rate of only 17 % and was associated with a high rate of sphincter preservation and generally good sphincter function.³⁰ A large, prospective phase III trial studied the role of adjuvant radiation in patients with clinically at-risk lymph nodes after therapeutic lymphadenectomy in cutaneous melanoma. The risk of lymph node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (Hazard Ratio [HR]: 0.56, 95 %, Confidence Interval [CI], 0.32–0.98), but no differences were noted for OS (HR: 1.37, 95 % CI, 0.94–2.01).³¹ These findings support the role of radiation therapy for patients with cutaneous melanoma, however it remains unclear if the benefit remains for patients with mucosal melanoma and should be evaluated on a case-by-case basis in the context of a multidisciplinary team discussion.

Chemotherapy

Literature on the benefits of adjuvant chemotherapy in mucosal melanoma are sparse. Dacarbazine is part of the National Comprehensive Cancer Network (NCCN) guidelines for metastatic melanoma inducing objective responses in some patients.³² Yi et al. retrospectively reviewed 28 patients with non-cutaneous melanoma receiving dacarbazine-based chemotherapy and reported a similar objective response rate between non-cutaneous and cutaneous melanoma of 20 % and 30 %, respectively.³³ A retrospective study of metastatic anorectal melanoma patients yielded a response rate of 44 % when treated with combinations of cisplatin, vinblastine, dacarbazine, interferon alpha-2b, and interleukin 2.³⁴ These findings are further supported by Flaherty et al., reporting findings that therapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN-a, and G-CSF showed significant improvements in relapse-free survival (median, 4.0 vs 1.9 years; p = 0.03) in high-risk stage III melanoma.³⁵ More recently, a prospective trial of 114 patients with untreated advanced mucosal melanoma demonstrated improved progression-free survival (PFS) in patients who received carboplatin/paclitaxel/bevacizumab compared to carboplatin/paclitaxel (4.8 vs 3.0 months, HR; 0.46). Objective response rates were 20 % and 13 %, respectively (p = 0.38).³⁶ Lastly, a phase II randomized trial with 189 stage II/III mucosal melanoma patients examined the effect of adjuvant high-dose IFN-α2b and temozolomide plus cisplatin. The groups for comparison were Group A, observation only, Group B, high dose interferon, and Group C, temozolomide plus cisplatin. Median relapse free survival was 5.4, 9.4, and 21 months for group A, B, and C, respectively. Estimated median OS for group A, B, and C was 21, 40, and 49 months, respectively. Patients treated with temozolomide plus cisplatin showed significant improvements in relapse free survival (p< 0.001) and OS (p< 0.01).³⁷ The NCCN currently recommends carboplatin and paclitaxel or single agent temozolomide as preferred cytotoxic agents for cutaneous melanoma. Overall, there are small retrospective studies and few prospective trials that explore the benefit of chemotherapy for patients with mucosal melanoma. It is clear that further research is needed in this disease space.

Current literature

Key molecular genes

The research into molecular pathways of melanoma has moved the field forward with immunotherapies and other targeted therapies for unresectable Stage III and Stage IV melanoma. A better characterization of the molecular pathogenesis of mucosal melanomas would aid in the development of systemic therapies. The following describes key mutations in ARMM.

Receptor tyrosine kinase: kit

KIT is a type III transmembrane tyrosine kinase involved in normal melanocyte development.³⁸ Binding of ligand stem cell factor leads to activation of downstream signaling pathways implicated in regulating cell processes including cell proliferation, survival, and migration (Fig. 1).^39,40 Mucosal melanomas commonly have amplifications or activating mutations.^41,42 Gong et al. reviewed 5224 patients and reported a positive association with KIT and mucosal melanoma (Odds Ratio [OR]: 1.36, 95 % CI,1.09–1.70) in addition to subtypes of cutaneous melanoma.⁴³ Prospective trials have studied KIT inhibitors in KIT+ mucosal, acral, and/or cutaneous melanoma. Studies have shown the benefit of imatinib in melanomas with kit alterations with response rates ranging from 16 %–23 %.^44,45 Hodi et al. noted a 50 % disease control rate which was significantly related to KIT mutational status (77 % mutated versus 18 % amplified, p = 0.01).⁴⁶ Imatinib has been included in NCCN guidelines for KIT+ melanoma since 2013. Other KIT inhibitors such as dasatinib,^47,48 sunitinib,⁴⁹ sorafenib,⁵⁰ and nilotinib^51,52 have demonstrated response in KIT+ melanomas.

Fig. 1.

Melanoma US Food and Drug Administration approved targeted therapies

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Source: Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021 Sep 5;10(9):2320. doi: 10.3390/cells10092320. PMID: 34,571,969; PMCID: PMC8469294.

BRAF

BRAF is a serine/threonine kinase involved in signal transduction in the mitogen-associated protein kinase (MAPK) pathway which regulates pathways such as cell proliferation and differentiation.⁵³ BRAF is mutated in an estimated 50 % of melanomas.⁵⁴ The most frequent BRAF mutation is V600E (80 % of BRAF mutated melanomas) followed by V600K (15 %) and V600R/M/D/G (5 %).⁵⁵ Unlike cutaneous melanoma, mucosal melanoma has a lower frequency of BRAF-V600 mutations. Nassar et al. performed a meta-analysis of 4009 patients from 65 studies and showed that BRAF is mutated in an estimated 4 % of lower mucosal melanomas (lower gastrointestinal tract, anorectum, genital).⁵³ One study of 1339 patients with mucosal melanomas demonstrated that BRAF mutations are less frequent in mucosal melanoma (8 % of mucosal melanomas), cutaneous melanomas present with BRAF-V600 mutations (about 90 %), while mucosal melanomas have a high prevalence of non-V600 mutations (Fig. 2D).⁵⁶

Fig. 2.

Mutational profiles of mucosal melanoma https://www.ncbi.nlm.nih.gov/pmc/about/copyright/.

Source: Nassar KW, Tan AC. The mutational landscape of mucosal melanoma. Semin Cancer Biol. 2020 Apr;61:139–148. doi: 10.1016/j.semcancer.2019.09.013. Epub 2019 Oct 23. PMID: 31,655,118; PMCID: PMC7078020.

Although the BRAF mutational profile is different in cutaneous versus mucosal melanomas, it remains a clinically relevant target. The presence of BRAF mutations in nevi supports the hypothesis that the RAF/MEK pathway is activated early in melanoma pathogenesis (Fig. 1).⁵⁷ Two BRAF kinase inhibitors, Vemurafenib and Dabrafenib, have shown improved response rates for patients with previously untreated BRAF V600E/K mutated unresectable metastatic melanoma. These therapies have been approved by US Food and Drug Administration (FDA) for first line treatment of the disease.^58,59 Chapman et al. compared Vemurafenib versus Dacarbazine and noted an improved OS of 13.6 months versus 9.7 months (OS: HR 0.37, 95 % CI, 0.26–0.55) and improved PFS of 5.3 months versus 1.6 months (PFS: HR 0.26, 95 % CI, 0.20–0.33).⁵⁸ Hauschild et al. compared Dabrafenib to Dacarbazine and noted an improved OS of 20 versus 15.6 months (OS: HR 0.61, 95 % CI, 0.25–1.48)) and an improved PFS of 5.1 versus 2.7 months (PFS: HR 0.30, 95 % CI, 0.18–0.51).⁵⁹ In addition, the FDA supports the following combination therapies for metastatic or unresectable disease as first line therapies: BRAF kinase inhibitors with MEK inhibitors; dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib.^60–64

NRAS

NRAS is an oncogene that is part of the Ras family of oncogenes that encode small GTP-binding proteins that respond to RTK activation and facilitate downstream activation of Raf (Fig. 1).⁵³ Mucosal melanomas harbor NRAS mutations at a lower frequency when compared to cutaneous melanomas (8% vs 28 %) (Fig. 2A/2B). NRAS is currently not a therapeutic target in melanoma but there is some evidence that NRAS mutational status may predict response to other therapies. A retrospective analysis of 208 patients with unresectable/advanced melanoma found that patients with NRAS mutations were more than twice as likely to respond to high-dose interleukin-2 than patients who were wild type for NRAS (47 % versus 19 %, p = 0.04).⁶⁵ The focus has shifted to targeting the signal transduction pathway that drive Ras-mediated transformation, with the most attention directed to targeting the MAPK pathway using MEK inhibitors.⁶⁶ Ascierto et al. studied patients with NRAS mutated melanoma who were treated with binimetinib, a small-molecule MEK1/2 inhibitor, and noted six (20 %) of 30 patients had a partial response.⁶⁷ A subsequent study by Dummer et al. compared binimetinib and dacarbazine resulting in a 2.8 months median PFS, compared to 1.5 months median PFS in the dacarbazine single treatment group (HR: 0.62, 95 % CI, 0.47–0.80).⁶⁸ Several studies are actively testing other MEK targeting therapies.^69–71

Immune checkpoint inhibition.

Immune check point (ICI) inhibition is a rapidly evolving field in the treatment of cancer. Immunotherapies are effective independently of mutational status in melanoma (ex: BRAF or NRAS).⁷² The treatment and prognosis of metastatic/unresectable melanoma has changed drastically since the approval of ICIs, mainly those directed to programmed cell death-1 (PD-1) and protein 4 associated with cytotoxic T-lymphocytes (CTLA-4).⁷³ Considering how uncommon ARMM is, additional studies are needed to clarify treatment effect as most studies do not report outcomes specifically by disease site. One retrospective analysis of 47 patients with ARMM did not show a significant difference in OS or disease-free survival when comparing patients who received ICI therapy to those who did not (median, 52 and 20 months, respectively; 5-year rate, 41% vs. 35 %, respectively; p = 0.25).⁷⁴ Though the lack of significant difference is likely due to the relatively small sample size, the need to further elucidate the benefit of ICI for ARMM is warranted.

Anti-CTLA-4/anti-PD-1/ therapies

Initial studies with Ipilimumab, an IgG₁ monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4) to potentiate an antitumor T-cell response, were completed in 2010 and 2011. Ipilimumab improved median OS in patients with previously treated metastatic melanoma when compared to patients who received glycoprotein 100 (gp100) peptide vaccine alone (10 months vs 6.4 months respectively, HR for death: 0.68; p<0.001).⁷⁵ Robert et al. studied ipilimumab plus dacarbazine versus dacarbazine plus placebo in untreated metastatic melanoma, and noted an improved OS (11 months versus 9.1 months respectively, p<0.001) and higher survival rates (3 years: 21% vs. 12 %, HR for death: 0.72; p<0.001).⁷⁶ Ipilimumab was approved by the FDA in 2011.

Anti-PD-1 inhibitors prevent binding of PD1 and its ligands PD-L1 and PD-L2 decreasing the immune response. In 2014, The FDA-approved pembrolizumab and nivolumab as the first anti-PD-1 directed monoclonal antibodies for metastatic/unresectable cutaneous melanoma. Shoushtari et al. have noted that PD-1 blockade in patients with a subtype of cutaneous melanoma and mucosal melanomas were comparable to published rates in cutaneous melanomas.⁷⁷ Robert et al. studied advanced melanoma and showed significantly higher OS rates for pembrolizumab when compared to ipilimumab monotherapy. Pembrolizumab had a superior 48-month OS rate (42 % pembrolizumab versus 34 % ipilimumab) and prolonged PFS (47 % for pembrolizumab every 2 weeks, 46 % for pembrolizumab every 3 weeks, and 27 % for ipilimumab (HR for disease progression: 0.58; p<0.001 for both pembrolizumab regimens versus ipilimumab; 95 % CI, 0.46 to 0.72 and 0.47 to 0.72, respectively).⁷⁸ Luke et al. recently published a study examining pembrolizumab as adjuvant therapy in completely resected Stage IIb/IIc melanoma leading to a significant reduction in disease recurrence/risk for up to a year (HR: 0.65, 95 % CI, 0.46–0.92).⁷⁹ Additional reports further demonstrate the beneficial response of pembrolizumab for patients with advanced melanomas.^80–82 Of note, a retrospective study comparing pembrolizumab and nivolumab in advanced melanomas showed no significant difference between OS rates.⁸³

As previously mentioned, nivolumab was approved by the FDA within a few months of approval of pembrolizumab. The initial study by Robert et al. compared nivolumab to dacarbazine in untreated metastatic BRAF wild-type melanoma patients resulting in median one year OS 73 % and 42 % respectively (HR for death: 0.42, 99 % CI, 0.25 to 0.73). The median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (HR for death or progression of disease: 0.43, 95 % CI, 0.34 to 0.56).⁸⁴ 3-year OS rates were later reported as 51 % (95 % CI, 44.1–57.9) and 22 % (95 % CI, 16.1–27.6), respectively.⁸⁵ Fig. 3 illustrates images of a patient with anal melanoma prior to and after nivolumab treatment, with a near complete response. Wolchok et al. examined nivolumab plus ipilimumab, nivolumab monotherapy, or ipilimumab monotherapy in unresectable advanced melanoma and noted superior OS rates for the combination therapy (median OS [months] was 72, 37, and 20 months in the combination, nivolumab, and ipilimumab groups, respectively).^86,87 A study comparing nivolumab to combination nivoluman/ipilimumab noted higher lymphoid infiltrates in responders to both therapies, and a more diverse T-cell infiltrate in responders to nivolumab suggesting a potential mechanism of immune sensitivity to these treatments.⁸⁸ The field of melanoma ICI has been effectively using combination therapies to enhance the immune response and warrants further studies.

Fig. 3.

Pre and post nivolumab treatment for anal melanoma.

Triplet therapy

Considering the success of combination targeted therapies along with ICI, combining both strategies holds promise. Gutzmer et al. evaluated the addition of atezolizumab, an anti-PD-L1 monoclonal antibody, to the combination BRAF/MEK inhibitor vemurafenib and cobimetinib in patients with BRAFV600 mutant metastatic melanoma. PFS was improved in the PD-L1 + BRAF/MEK inhibitor group versus control (15 vs 11 months; HR: 0.78, 95 % CI, 0.63–0.97).⁸⁹ Another triplet therapy that has been studied is the addition of spartalizumab, an anti-PD1 monoclonal antibody, to dabrafenib and trametinib in patients with BRAFV600E/K mutant advanced melanomas. The combination therapy resulted in high objective response rates (78 % [n = 28]) and complete response rates (44 % [n = 16]).⁹⁰

Conclusions

Anorectal mucosal melanoma is a highly malignant disease that is difficult to study due to its rarity, and difficult to treat effectively. It is a molecularly distinct entity from cutaneous melanoma though there are some similarities in mutations and targeted therapies. Recent research has focused on immunotherapy, though there are reports of development of resistance to therapies. Further research is needed to discover molecular biomarkers and driver mutations to improve clinical outcomes in this rare disease.

Abbreviations:

AJCC

American joint commission on cancer

APR

abdominoperineal resection

ARMM

anorectal mucosal melanoma

CI

confidence interval

FDA

food and drug administration

HR

hazard ratio

ICI

immune check point inhibition

NCCN

national comprehensive cancer network

OR

odds ratio

OS

overall survival

PFS

progression-free survival