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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 621-627

Clinical profile and outcomes of malignant melanoma in patients from an Indian institute: A retrospective analysis


1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiodiagnosis, ABVIMS and Dr. RML Hospital, New Delhi, India
4 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
6 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
7 Department of Radiation Oncology, Paras Hospital, Gurugram, Haryana, India

Date of Submission31-Jan-2021
Date of Decision29-Jul-2021
Date of Acceptance04-Dec-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Sameer Rastogi
Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_25_21

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  Abstract 


Background: The profile of patients with malignant melanoma in Asian countries is distinctly disparate from that of those in Western countries. Malignant melanoma is a rare malignancy with scarce literature from India.
Objectives: We aimed to describe the clinical profiles and outcomes of Indian patients with advanced malignant melanoma.
Materials and Methods: We retrospectively analyzed the data of consecutive patients with malignant melanoma who presented to the bone and soft tissue sarcoma clinic at the All India Institute of Medical Sciences, New Delhi, between January 2016 and March 2019. Our primary endpoint was to evaluate the clinical profile of the patients and the patterns of treatment. The secondary endpoints were response rate, progression-free survival (PFS), and overall survival (OS).
Results: We included 93 patients in the cohort, with a median age of 53 years (range, 25–85). The majority of patients were men (61.3%); almost half had an Eastern Cooperative Oncology Group performance status of 2 or greater. Most (89.2%) patients had metastases at presentation. The most common primary sites were anorectal (24.7%), acral (24.7%), ocular (17.2%), head and neck (15.1%), and thigh (9.7%). The median number of metastatic sites at presentation was 2, with the most common sites of metastases being the lymph nodes (57%), lung (48.3%), liver (35.5%), and bone (25.8%). BRAF V600E mutation was present in three out of four tested patients, while c-KIT mutation was present in two out of seven tested patients. At a median follow-up of 18 months, the median PFS was 2 months (95% confidence interval, 1.2–2.7 months) and median OS was 7 months.
Conclusion: Acral/mucosal melanoma is the most common melanoma among Indians and has poor outcomes. Limited access of patients with melanoma to standard-of-care therapeutic options remains an important issue in a resource-constrained country like India.

Keywords: Chemotherapy, immunotherapy, medical oncology, melanoma


How to cite this article:
Shishak S, Mittal A, Aswar H, Pandey R, Kalra K, Gupta A, Barwad A, Dhamija E, Shamim SA, Aggarwal A, Kaliyath SB, Rastogi S. Clinical profile and outcomes of malignant melanoma in patients from an Indian institute: A retrospective analysis. Cancer Res Stat Treat 2021;4:621-7

How to cite this URL:
Shishak S, Mittal A, Aswar H, Pandey R, Kalra K, Gupta A, Barwad A, Dhamija E, Shamim SA, Aggarwal A, Kaliyath SB, Rastogi S. Clinical profile and outcomes of malignant melanoma in patients from an Indian institute: A retrospective analysis. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 16];4:621-7. Available from: https://www.crstonline.com/text.asp?2021/4/4/621/334195




  Introduction Top


Malignant melanomas comprise a spectrum of melanocytic neoplasms with a grim prognosis but a dynamic treatment landscape. Lesions can be benign, intermediate, or malignant. According to the World Health Organization 2018 classification of melanomas, they can be categorized into nine groups.[1] For over four decades, treatment options for melanoma were few and far between. However, in the past decade, melanoma treatment has undergone a paradigm shift with the introduction of immunotherapy and targeted therapy.

The age-adjusted incidence rates of melanoma have increased steadily over the past two decades, with the highest incidence seen in Australia and New Zealand (33/100,000 persons per year).[2] A study from India revealed that the age-adjusted incidence rate for melanoma of the skin was the highest in North India for both males and females (1.62 and 1.21/100,000 persons, respectively). The incidence of non-melanoma cancer of the skin for males (6.2/100,000 persons) was the highest in East India and that for females was the highest in Northeast India (3.49/100,000 persons). Northeast India had the maximum incidence of non-melanoma skin cancers for both men (75.6/100,000 persons) and women (43.6/100,000 persons).[3]

Previous studies from Asia have shown a higher incidence of mucosal and acral melanomas compared to the superficially spreading melanomas which are the most common subtype in the West and have the best prognosis.[4],[5],[6],[7],[8],[9] Similar to histological subtypes, the mutational profile of melanoma is heterogeneous and depends on the type of melanoma and sun exposure. According to western literature, 40%–60% of melanomas harbor the BRAF mutations, V600E (70%–80%) and V600K (20%), with c-KIT mutations seen in 15%–40%; BRAF mutations are predominant in melanomas arising from sun-damaged skin, while c-KIT mutations commonly occur in melanomas arising from causes other than sun exposure.[10] However, there is a dearth of literature on the mutational profiling of melanoma from India.[11],[12] A recent study from India reported that 10.8% of patients with metastatic melanoma had BRAF mutations.[13]

With the advent of immunotherapy and targeted therapy against BRAF/MEK, the management of metastatic melanoma has become one of the greatest success stories of oncology; the 5-year survival has jumped from <10%[14] before 2011 with chemotherapy to more than 50% with combination immunotherapy in 2020.[15] However, given the limited access to these costly drugs and the different mutation profile of melanoma in Indian patients, such an extended survival in advanced melanoma remains a distant dream for oncologists in India. Hence, we performed this retrospective study to gain insights into the real-world data on advanced melanoma from a tertiary care center of a low- and middle-income country.


  Materials and Methods Top


General study details

This was a retrospective study of a prospectively maintained database of consecutive patients with advanced, unresectable, metastatic malignant melanoma who presented to the bone and soft tissue medical oncology clinic at the All India Institute of Medical Sciences (AIIMS), New Delhi, India, between January 2016 and March 2019. The patients were followed up till December 2019. The study (IEC-603/02.08.2019, RP-69/2019) was approved by the Institutional Ethics Committee on September 6, 2019 [Supplementary Appendix 1] and was conducted according to the ethical guidelines outlined in the Declaration of Helsinki, Good Clinical Practice guidelines, and the Indian Council of Medical Research guidelines. Registration of the study in a public clinical trial registry was not needed. As this was a retrospective study, informed consent of participants was not needed as per our institutional protocol. No funding was required for the study.

Participants

All consecutive patients aged over 18 years with a histopathologically proven diagnosis of malignant melanoma and with advanced disease (metastatic or unresectable) were included in the study. Patients with missing records were excluded.

Variables

The primary endpoint of the study was to evaluate the clinical profiles of the patients and the patterns of treatment. The secondary endpoints included response rate, progression-free survival (PFS), and overall survival (OS).

Study methodology

Baseline clinical details were recorded in a predesigned pro forma. All patients had baseline staging done by either a contrast-enhanced computed tomography (CT) scan of the local site, head, chest, and abdomen or a whole-body fluorodeoxyglucose positron-emission tomography-CT scan. Informed consent was obtained from each patient before administering chemotherapy or performing any other clinical procedure. c-KIT mutation testing was done using reverse transcriptase–polymerase chain reaction (RT-PCR) method for consenting patients using formalin-fixed paraffin-embedded (FFPE) tissue samples. Testing for BRAF V600E and V600K mutations was subject to affordability and was done by RT-PCR using FFPE tissue samples. For response assessment, we relied on data entered in the files and the responses were grouped as partial response (PR), stable disease (SD), and progressive disease (PD). For patients who received immunotherapy, data entered according to the Response Evaluation Criteria in Solid Tumors for immune-based therapeutics criteria (iRECIST) were captured. At first response assessment, if there was PD with preserved performance status, the patient was deemed to have immune-unconfirmed PD (iUPD) and received additional cycles of nivolumab and was re-assessed after another 6–8 weeks.

Definitions

PFS was calculated as the time from the initiation of first-line treatment (at our institute) to disease progression. OS was calculated from the date of diagnosis to the date of death from any cause or the date of the last follow-up.

Statistics

All data were entered into Microsoft Excel and analyzed using the Statistical Package for the Social Sciences software (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Descriptive statistics such as mean and median were used to summarize the qualitative variables. PFS and OS were estimated using the Kaplan–Meier method.[16] The Kaplan–Meier curve is the graphic representation of this function that shows the probability of an event (progression or death) at a respective time interval. Sample size calculation was not performed as this was a retrospective study, and all patients fitting the eligibility criteria within the time frame were included. Median follow-up was calculated using the reverse Kaplan–Meier method which takes the last follow-up in surviving patients as the primary endpoint while events (death) were censored.


  Results Top


A total of 101 patients with metastatic malignant melanoma visited our clinic during the study period and were screened for the study [Figure 1]. Of these, 93 patients were included in the study and 8 were excluded due to missing records, histology other than melanoma, and non-metastatic/resectable disease.
Figure 1: Patient recruitment flowchart in the observational study of clinical features and outcomes of patients with malignant melanoma (RT=radiotherapy)

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Patient characteristics are shown in [Table 1].
Table 1: Baseline characteristics of patients with malignant melanoma

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Out of 7 patients tested for c-KIT mutation, 2 (28.6%) were positive and the remaining 5 (71.4%) were negative. Presence of the BRAF V600E mutation was tested in 4 patients of which 3 (75%) tested positive.

Treatment

Dacarbazine was our preferred initial treatment for patients who could not afford immunotherapy or targeted therapy, as it was available in-house free of cost. The typical regimen used was 1000 mg/m2 administered once every 3 weeks, with adjustments made for toxicity. Nab-paclitaxel was offered as first-line treatment to patients based on their affordability and was preferred over dacarbazine. A dose of 150 mg/m2 on days 1, 8, and 15 every 4 weekly was administered. Since ipilimumab was not available in India during the period of present study, none of the patients in our study received combination immunotherapy. Nivolumab was the immunotherapeutic agent used in first-line treatment at a dose of 3 mg/kg once every 2 weeks. No patient received targeted therapy with BRAF and MEK inhibitors, as mutation testing results were available in only four patients and none of them could afford the combination. Details of first-line treatment are presented in [Table 2].
Table 2: First-line treatment delivered and the response to treatment

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Response to treatment

Of the 50 patients who received first-line treatment (chemotherapy/immunotherapy), only 37 were evaluable for response [Table 2]. The overall disease control rate (PR + SD) was 22.7%.

The median number of nivolumab cycles was 5 (range, 2–15). At first assessment for nivolumab, the performance status (PS) deteriorated for seven patients, and immunotherapy was discontinued. Seven patients had iUPD and subsequently had PD, one patient had SD, and response assessment was not available for one patient.

Of the 17 patients who progressed on first-line chemotherapy, 5 (29.4%) received second-line treatment which consisted of nab-paclitaxel (n = 2), paclitaxel (n = 1), dacarbazine (n = 1), and imatinib (n = 1). Response assessment for second-line treatment was available for only one patient who showed PD.

At a median follow-up of 18 months for the entire cohort, the median PFS was 2 months (95% confidence interval, 1.2–2.7 months) [Figure 2]. The median OS was 7 months [Figure 3].
Figure 2: Kaplan–Meier analysis of progression-free survival of patients with malignant melanoma

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Figure 3: Kaplan–Meier analysis of overall survival of patients with malignant melanoma

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  Discussion Top


Even with recent advances in immunotherapy and targeted therapy, metastatic melanoma remains an incurable malignancy, more so in India where the epidemiology is different, disease burden is usually higher, and access to drugs is limited. We found that the median age of presentation in our study was 53 years which is a decade younger than that reported in the West.[17] This observation is consistent with previous Indian studies where the majority of patients presented in the fifth to sixth decades as opposed to the sixth to seventh decades of life in Western studies.[18],[19] Published literature from other Asian countries supports this observation. Younger age at diagnosis in India is seen in other cancers as well, particularly breast cancer, where the median age is 47 years as opposed to 64 years in the Western population.[20],[21] In a retrospective study by Austin et al., age more than 65 years was associated with lower disease-free survival in localized melanoma.[22] More data are required to ascertain the impact of younger age on prognosis in advanced melanoma.

Our study had a male preponderance, and the majority of patients presented with metastatic disease at diagnosis. This male preponderance was consistent with other studies.[18],[23],[24] Our cohort was enriched with patients having poor prognostic factors such as male sex, poor PS, metastatic disease at diagnosis, and mucosal/acral primary sites. The effect of sex on the prognosis of melanoma has been established, with female patients having better outcomes.[25] Poor PS is an important deterrent to aggressive therapy, as 40% of our patients received only best supportive care. A pooled analysis of the Eastern Cooperative Oncology Group (ECOG) trials has established that an ECOG PS of 1 or greater was an independent predictor of death.[26] The majority of the patients had 2 or more metastatic sites (median = 2), and this could explain the poor PS of our patients at presentation. Among patients who received systemic therapy, 12 had a PS of 2 or greater, and all 33 patients who received best supportive care had a PS of 2 or greater.

The pattern of metastasis in our study was similar to that previously reported in the literature. The most common site of metastasis was the lymph nodes, followed by lungs and liver. In a large series of patients with metastatic melanoma by Lian et al., lymph nodes were reported as the most common sites of metastasis;[27] this is related to spread via the subdermal lymphatics to the regional, followed by non-regional nodes.[28] Although uveal melanoma has a special predilection for spread to the liver,[29] cutaneous melanoma usually first spreads to the lung, a trend which was also seen in our study.

In our patient cohort, 23 (24.7%) patients had acral, 23 (24.7%) had anorectal, 16 (17.2%) had ocular, and 14 (15.1%) had head-and-neck melanomas; of the patients with head-and-neck melanomas, 1 had cutaneous and 13 had mucosal melanomas. A retrospective study of 182 patients from India reported a high rate of cutaneous melanomas (93.4%) compared to non-cutaneous (6.6%) melanomas.[30] Of all cutaneous melanomas, the majority occurred in the lower extremity.

In a large retrospective analysis, the median OS for mucosal melanoma was 9.4 months and that for acral melanoma was 11 months, highlighting the poor prognosis of this subset of patients.[31] Callender et al. studied the prognosis of melanoma according to the primary site and found that head-and-neck primary melanomas fared significantly worse compared to those of the face and extremities.[32] Although the nasal cavity and sinuses have been reported to be the most common sites of mucosal melanomas in previous studies,[33] anorectum is a frequent site in the gastrointestinal tract and was the most common site of mucosal melanoma in our cohort. Bajpai et al., in a recently published study from a tertiary cancer center in India, reported extremities (36.6%) and anorectum (31.4%) as the most common primary sites, with a higher incidence of mucosal (55.2%) melanomas as compared to cutaneous (44.8%) melanomas.[13]

Of 50 patients who received first-line therapy in our cohort, 34 (68%) received chemotherapy, with dacarbazine being the most common agent in 26 patients (52%), followed by nab-paclitaxel in 6 patients (12%). Dacarbazine-based chemotherapy was the standard of care for treating melanoma before the advent of immunotherapy. Various single-institution experiences and phase II studies reported response rates between 10% and 20% with dacarbazine-based combination approaches and a median OS of 6–7 months; long-term survivals were rare (around 5%), and combination therapy did not improve survival.[34],[35],[36] A randomized phase III trial showed an improved disease control rate (39% vs. 27%), PFS (4.8 vs. 2.5 months), and OS (12.6 vs. 10.5 months) with nab-paclitaxel versus dacarbazine in the first-line treatment of melanoma.[37] However, the lack of in-house availability of nab-paclitaxel and high cost restricted its use in our setting. The median OS of 7 months in our study is short compared to that reported in another study from India in patients with metastatic melanoma, where the median OS was 3.9 months for patients treated with best supportive care and 12 months for those who received systemic therapy.[13]

The advent of monoclonal antibodies against programmed cell death protein 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 has brought a new ray of hope to patients with advanced melanoma, with evidence of potential cure in 50% of patients with metastatic melanoma with combination immunotherapy.[38],[39] Since toxicities of combination immunotherapy are significant (59% grade 3/4 adverse events and 39% discontinuation rates), single-agent pembrolizumab and nivolumab are excellent first-line options and have shown survival benefit in the treatment-naïve and ipilimumab-refractory settings.[40],[41],[42],[43]

The response rates reported to single-agent immunotherapy vary between 40% and 50% with a PFS of around 6 months; however, the response is often durable with sustained benefits seen in the OS (44% 5-year OS in the nivolumab arm of the CheckMate 067 trial).[44] However, an important caveat to all these trials is that they excluded patients with ocular and mucosal melanomas, and the exact distribution of the anatomic sites was not presented. In our cohort, only 16 patients were able to afford front-line immunotherapy, and all were treated with single-agent nivolumab. None of these patients showed a response (after ruling out pseudoprogression), one had SD, and 14 had PD. These dismal outcomes to immunotherapy are surprising and open a Pandora's box of new questions. Overrepresentation of acral and mucosal melanoma, a subset which has not been tested in immunotherapy trials, could be a plausible explanation for this finding but is likely not the only reason.

c-KIT mutation testing was done in seven patients (two received imatinib as second-line therapy), and BRAF mutation testing was done in only four patients. Although three patients had a BRAF mutation, none of them could afford targeted therapy, highlighting the bench to bedside lacuna in rare cancers in developing countries.[45] BRAF testing is recommended in all patients with melanoma, but the lack of availability and cost is a significant hindrance to its universal applicability. Dabrafenib and trametinib were first approved by the Food and Drug Administration in 2013, based on pivotal phase III trials,[46],[47],[48] and launched in the Indian market in 2020, after a gap of nearly 7 years with an exorbitant monthly cost of around ₹4 lakhs.[49]

Rare cancer research often takes a backseat in a country like India where limited resources are preferentially utilized toward improving the outcomes for more common cancers; however, it is important to realize that some of these rare malignancies are actually not so rare, and there is a substantial scope of improvement if the right kind of resources are directed toward them.[43]

Our study was limited by its retrospective nature, variability in the first- and second-line treatments, lack of response assessment to first-line therapy in one-third of the patients, and unavailability of information regarding biomarkers such as PD-L1 and LDH. Moreover, we acknowledge the inherent problems in assessing the response to therapy in a retrospective study. Future research should be focused on improving the survival outcomes by developing better therapeutics for patients with melanoma. In addition, it also necessary that the new drugs are made accessible and affordable to patients in resource-constrained settings.


  Conclusion Top


Acral/mucosal melanoma is the most common melanoma among Indians and has poor outcomes. Limited access of patients with melanoma to standard-of-care therapeutic options remains an important issue in a resource-constrained country like India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: Study Protocol


  Retrospective analysis to study pattern of occurrence of Melanoma and its outcome in Indian patients at medical oncology clinic Top



  Review of Literature Top


Malignant melanoma is a rare malignancy with a poor prognosis. The therapeutic landscape of melanoma has seen substantial progress in the last few years and there is plenty of data from western countries, but data from India remain scarce. Even with recent advances in immunotherapy and targeted therapy, metastatic melanoma remains an incurable malignancy, more so in our setting where epidemiology is different, disease burden is usually higher, and access to drugs is limited.

Difference in disease biology, different age structures of the Indian population, racial disparities, and genetic heterogeneity are all plausible explanations, but none has been conclusively proven. In a retrospective study by Austin et al., age >65 years was associated with inferior disease-free survival in localized melanoma with a trend toward more ulcerated lesions.[1]

More data are required to ascertain the impact of younger age on prognosis in advanced melanoma. Poor performance status is a poor prognosticator. A pooled analysis of ECOG trials established ECOG PS ≥1 as an independent predictor of death.[2]

Frequent metastases are observed in melanoma patients. In a large series of metastatic melanoma by Lian et al., lymph nodes were reported as the most common site of metastasis.[3]

In a recent large SEER database analysis, the prevalence of acral melanomas was 2 per million person-years and majority of them were seen in Africans.[4] Acral melanoma was associated with a lower stage adjusted survival than other subtypes, and this was further decreased in black versus non-Africans, highlighting the racial differences in prognosis.

In another large retrospective analysis,[5] median overall survival for mucosal melanoma was 9.4 months and acral melanoma was 11 months, highlighting the poor prognosis of this subset of patients.

Callender et al.[6] studied the prognosis of melanoma according to the primary site and found that head-and-neck primary melanomas fared significantly poorly compared to face and extremity.

The advent of immunotherapy in melanomas offers some hope for improved outcomes in this disease. Taylor et al.[7] recently reported data of 1331 patients treated from 2004 to 2015, of which 16.93% of patients received immunotherapy. Patients who received immunotherapy had a significantly better 2-year OS (42.47% vs. 49.21%, P < 0.001).

In our setting, the challenges faced by our patients with regard to immunotherapy include the exorbitant cost as well as lack of reimbursement/government funding.

Through this study, we aim to understand the clinical profiles of melanoma patients and the various factors affecting treatment outcomes.


  Study Protocol Top


Aims and objectives

To study the clinical profiles and treatment outcomes of malignant melanoma patients treated under medical oncology clinic at IRCH, All India Institute of Medical Sciences (AIIMS).


  Primary objective Top


To analyze the clinical profiles and treatment outcomes of melanoma patients treated over a period of 3 years (January 2016-March 2019).


  Secondary objective Top


To identify patterns of relapse and factors affecting treatment outcome.


  Materials and Methods Top


  • Study design: Retrospective, single-center study
  • Place of the study: Department of Medical Oncology, Dr. B. R. A I. R. C. H, AIIMS, New Delhi
  • Study duration: From January 2016 to March 2019.


Inclusion criteria

  1. Histopathologically confirmed cases of melanoma
  2. Received treatment at IRCH, AIIMS.


Exclusion criteria

  1. Medical records not available.


Methodology

Case records of all histopathologically proven cases of melanoma treated under medical oncology clinic, IRCH, AIIMS, between January 2016 and March 2019 were screened.

Information regarding the baseline demographic parameters, radiological characteristics, treatment modality, response to treatment, relapse pattern, etc., were filled in as per the case pro forma chart.


  References Top


  1. Austin PF, Cruse CW, Lyman G, Schroer K, Glass F, Reintgen DS. Age as a prognostic factor in the malignant melanoma population. Ann Surg Oncol 1994;1:487-94.
  2. Manola J, Atkins M, Ibrahim J, Kirkwood J. Prognostic factors in metastatic melanoma: A pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 2000;18:3782-93.
  3. Lian B, Cui CL, Zhou L, Song X, Zhang XS, Wu D, et al. The natural history and patterns of metastases from mucosal melanoma: An analysis of 706 prospectively-followed patients. Ann Oncol 2017;28:868-73.
  4. Huang K, Fan J, Misra S. Acral lentiginous melanoma: Incidence and survival in the united states, 2006-2015, an analysis of the SEER registry. J Surg Res 2020;251:329-39.
  5. Kuk D, Shoushtari AN, Barker CA, Panageas KS, Munhoz RR, Momtaz P, et al. Prognosis of mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma from the time of first metastasis. Oncologist 2016;21:848-54.
  6. Callender GG, Egger ME, Burton AL, Scoggins CR, Ross MI, Stromberg AJ, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg 2011;202:659-64.
  7. Taylor JP, Stem M, Yu D, Chen SY, Fang SH, Gearhart SL, et al. Treatment strategies and survival trends for anorectal melanoma: Is it time for a change? World J Surg 2019;43:1809-19.




 
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