Synchronizing the Nomenclature Surrounding Synchronous Primary Cutaneous Melanomas: A Systematic Review

J Clin Aesthet Dermatol. 2024;17(8):44–49.

by Justin W. Marson, MD; Rebecca M. Chen, MD; Alisen Huang, MD; Todd Wechter, MD; and
Amor Khachemoune, MD

Drs. Marson, Chen, Huang, Wetcher, and Khachemoune are with the Department of Dermatology at SUNY Downstate Health Sciences University in Brooklyn, New York. Additionally, Dr. Khachemoune is the Department of Dermatology at Veterans Affairs New York Harbor Healthcare System in Brooklyn, New York.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article.

ABSTRACT: Objective. There is little consensus regarding the nomenclature and prognostic implications of synchronous melanomas. Here, we present a case of synchronous cutaneous melanoma and perform a systematic review of similar cases in the literature.

Methods. Pubmed and EMBASE databases were queried for relevant English-language articles published from inception until 2023. Cases of “multiple primary cutaneous melanomas” that occurred within a time frame of three months or less were included. Exclusion criteria included non-cutaneous melanomas and cases without specific time intervals or those occurring beyond a three-month period. Data including patient age, sex, risk factors, cutaneous melanoma (CM) anatomic location, CM clinicohistologic features, and prognosis were extracted from relevant articles.

Results. Nineteen case reports/series documenting 22 patients with multiple primary melanomas (MPM) occurring within a three-month interval. Overall, 66 melanomas were diagnosed, with an average of three (SD±2.1, median: 2) per patient. A majority (63%) of patients had one or more risk factors for skin cancer. Subsequent CM found within three-month interval were thinner than the first found (index) CM, more likely to be melanoma in situ (MMis) and have highest degree of anatomic concordance if the index lesion was first found on the trunk (50%). Two retrospective cohort studies (n=4,703; n=13) of melanomas occurring within three-month interval found similar results.

Limitations. Limitations to our review included inconsistent reporting in the literature and use of terminology and a limited number of case reports and case series found in the literature.

Conclusion. Synchronous primary cutaneous melanomas are a heterogenous collection of terminologies that may limit the ability of dermatologists to accurately diagnose, prognosticate, and treat high-risk patients. Given lack of guidelines, we recommend the use of the term “synchronous” to delineate additional primary cutaneous melanomas found within a three-month interval.

Keywords: Melanoma, synchronous melanoma, multiple primary melanoma, full body skin exam

Introduction

Cutaneous melanoma (CM) is the sixth most common malignancy, with over 200,000 new cases each year, accounting for over 7,000 deaths annually in the United States (US).¹ Up to 5 to 10 percent of patients who develop a primary CM may go on to develop additional CMs, termed multiple primary melanomas.² While patients with MPM tend to have similar risk factors for melanoma (including but not limited to: many dysplastic nevi, family history of dysplastic nevi and/or CM),³ retrospective cohort studies comparing single-primary CM and MPM have found increased rates of five-year recurrence rates (especially of distant metastases) and potential for increased five-year melanoma-specific morality (MSM) among patients with MPM.^4,5

A subset of patients may be diagnosed with their MPM within a short interval following (or during the same visit as) their initial primary CM, termed synchronous primary melanoma (SPM).² Arbitrarily, the current literature designates a successive primary CM as synchronous if it occurred at three months or less after the initial primary (as opposed to metachronous, which occurs more than three months after the initial primary CM).^6,7 Although uncommon, several cohort studies suggest upwards of 20 to 30 percent of MPM may fall in this category.^7–19 However, there is little consensus in the literature regarding this diagnostic entity.² Ambiguity exists regarding definition, with studies using “synchronous,” “concurrent,” and “simultaneous” interchangeably, despite an array of temporal intervals between primary CM diagnoses (from diagnosis during the same visit to up to 6 months after first diagnosis)^7–19 and whether this entity has a materially different morbidity/mortality compared to single-primary CM or MPM. 

The purpose of this review is to reappraise the literature regarding SPM and provide clinical pearls regarding their management through the lens of a clinical case. For clarity throughout this reappraisal, we will refer to MPM by the temporal intervals between diagnosis (as opposed to non-standardized adjectives). 

Case study. A 78-year-old White man with no known personal or family history of skin cancer was referred to our department by his primary care physician for a concerning pigmented lesion on his left upper mid back. The patient reported he was unaware of any lesions or moles and had presented as his primary care physician was concerned about its appearance and recommended it be evaluated by dermatology. On physical examination, the lesion was a 0.8cm by 0.6cm brown macule with irregular borders and few foci of darker pigment, clinically suspicious for malignant melanoma (Figure 1). On closer physical examination of the patient’s back, he was also noted to have a larger 1.2cm by 1.0cm pink patch with overlying fine scale on the right mid back approximately 7.0cm from the pigmented lesion, clinically suspicious for squamous cell carcinoma in situ (cSCCis) (Figure 1). There was no lymphadenopathy. 

After discussion with the patient, without preceding confirmatory biopsy, and based on clinical assessment of a likely thin melanoma (less than 0.8mm Breslow depth), the pigmented lesion was excised with 1.0cm margin through subcutaneous fat down to fascia in accordance with NCCN guidelines.²⁰ Eventual histopathologic examination revealed superficial spreading melanoma with a Breslow depth of 0.25mm without ulceration or mitoses and clear margins (Figure 2). At the same visit, the second lesion presumed to be cSCCis was biopsied and returned superficial spreading melanoma with regression (and no mitoses or ulceration) (Figure 3). This lesion was subsequently treated with wide local excision with a 1.0cm margin.²⁰

Systematic review and reappraisal. Search strategies. A systematic review of available English language literature Pubmed and EMBASE databases was queried for all relevant articles published from inception until 2023 using exploded MeSH terms and keywords pertaining to the following themes: simultaneous primary, synchronous primary, concurrent primary. The Boolean term “AND” was used to find the intersection of these themes with the term “cutaneous melanoma.” 

Selection of studies. One author (JWM) screened articles for relevancy and eligibility with abstract reviewal of studies with ambiguous titles. Two authors (JWM/RMC) independently reviewed eligible available full-text studies utilizing the inclusion criteria of “multiple primary cutaneous melanomas” that occurred within a set (≤3 month) time frame. Studies that did not focus on CM, provide specific time intervals, or focused on subsequent primary CM occurring outside the time frame were excluded from the study. In the event of reviewer discordance, a third reviewer (AH) reviewed the study in question. Data including patient age, sex, risk factors, CM anatomic location, CM clinicohistologic features, and prognosis were extracted from relevant articles. Cases were restaged based on available information in accordance with AJCC8 guidelines.

Results

Study selection. In total, 319 articles were screened (Figure 4) of which 21 were included in the final appraisal. A meta-analysis could not be conducted given material qualitative disparities (e.g., inconsistent reporting or risk factors, histologic findings such as mitoses or ulceration, clinical follow up period and/or outcomes) among published works. 

Patient and tumor characteristics. Case reports. There were 19 case reports/series documenting 22 patients with MPM occurring within a three-month interval with a majority present during a single visit (two exceptions found over 2 weeks and 3 months) (Table 1).^21–39 Patient’s mean age was 63.3 years old (SD±10.8; median 64 years old) and majority (85%) male. At least one clinical risk factor was reported in 14 of 22 patients with the two most common being lighter skin phototype (8/14) and increased number of (atypical) nevi (7/14).^{21,26–28,30,32,34} Three patients had a history of skin cancer, of which two had prior melanomas^27,21,32,37 while two patients had MPM within a nevus spilus.^24,30 Quantity of time to diagnosis of index lesion was only provided for 7 of 22 patients with a mean of 53.8 months (SD±60.8; median 48 months) with two patients reportedly waiting a “few months” for evaluation of the first discovered “index lesion.”

Overall, 66 melanomas were diagnosed with an average of 3 (SD±2.1, median: 2) per patient. Melanomas were most frequently found on the trunk (n=26), followed by upper extremities (UE) (n=17), lower extremities (LE) (n=12) and head/neck (HN) (n=4). Overall anatomical concordance was 50 percent and was greatest on the trunk (25%), followed by UE (9.1%), LE (6.8%), acral (6.8%), and head and neck (2.3%). 

Mean Breslow depth of the index invasive melanomas was 1.79mm (SD±1.45; median 1.45) while Breslow depth of the subsequently discovered invasive melanomas were 1.15mm (SD±0.64; median 0.95mm). Of note, only two of the index lesions were in-situ (both LM) while MMis was the more commonly identified as a subsequent lesion. Using AJCC8 T-staging there were 29 T0, 17 T1, 8 T2, 5 T3 and 3 T4. Three total cases had lymphatic (n=1; stage T4N1) or distant (n=2; T3bN3M1c, T1aNXM1d) metastases. Outcomes were only reported in 11 out of 22 cases, with a mean follow-up time of 19.4 months (SD±14.6; median: 24). Of the 11 patients, seven had no further melanomas detected during follow up; one patient had a dysplastic nevi found within 24 months,³⁰ one had an additional melanoma found within 12 months,²³ and two patients died within 3 to 4 months of evaluation.^28,39 

There were 32 invasive melanomas (n=32) (superficial spreading [SSM], n=18; nodular [NM], n=12; lentigo maligna melanoma [LM], n=1; acral lentiginous melanoma [ALM], n=1; not reported [NR], n=1), 29 melanoma in-situ (MMis) [including subungual melanoma (SuM), n=2; LM, n=7; ALMis, n=1] and two subungual melanomas without provided Breslow depth nor histological subtype. The most common histological subtype among second primaries was MMis (n=19); among invasive melanomas, overall concordance was 43 percent and greatest for SSM (17%), followed by NM (9%), subungual (9%), LMM (4%), and acral (4%). 

Cohort studies. While several studies of multiple primary melanomas (variably) included a subset discussion of synchronous primaries,^8–11 only two studies focused solely on synchronous primary melanomas (defined by the authors as diagnosis within three months of the first primary cutaneous melanoma).^6,7 In their retrospective cohort of 4,703 patients with a primary cutaneous melanoma, 3.1 percent of patients with multiple primary melanomas presented synchronously; however, among multiple primary melanomas, synchronous diagnosis accounted for 27 percent of patients [consistent with sub-cohort analysis from other studies (~25–30%).^7–11 The authors also found a 78.9 percent and 64.8 percent concordance in melanoma histologic subtype and location, respectively, between lesions.⁷ While individuals with synchronous melanomas were more likely to be older (56.1 years, p<0.001), have blue/green eyes and phototype I/II skin, and more likely to develop future melanomas (25.7% versus 8.6%, p<0.001), they did not significantly differ from patients with single primary melanomas in terms of lesion ulceration or regression or overall survival, recurrence-free survival, distant-metastasis-free survival, or melanoma-specific survival over a median follow-up time of 2.9 years.⁷

A small cohort study of 13 individuals also found that among patients with multiple melanomas found ≤3 months apart they were older (median age 75), over 50 percent male, with risk factors including skin phototype I (n=9/13), significant sun-exposure (n=6/13), personal (n=3/12) and/or family history of melanoma (n=2/13).⁶ Here, a majority of the subsequent (i.e., synchronous) melanomas had an equal if not smaller Breslow depth than (n=10/13) and had a histologic subtype concordant with (n=9/13) the index lesion.⁶

Discussion

The terminology surrounding synchronous primary melanomas continues to present both semantic and clinical challenges. Studies have historically used “synchronous”, “concurrent” and occasionally “simultaneous” interchangeably to refer to multiple primary melanomas that are diagnosed from as temporally close together as a single visit to up to six months apart.² It is unclear if this temporal distinction carries difference in outcomes when stratified by time between diagnoses of the discrete primaries. Using a three-month window, there was no difference in survival comparing synchronous to single melanoma over a 2.9 year follow-up period.⁷ While this may be due to shortened follow-up frequency or increased scrutiny during full-body skin exams (FBSE), this finding may be limited by their arbitrary definition (i.e., 3 months) of “synchronous.” A multivariate analysis of 31,896 multiple-primary melanomas taken from the SEER-18 database found that having two primary melanomas diagnosed within a two-month window was a significant independent risk factor for overall survival (HR 2.212, 95% confidence interval 2.087–2.346) and melanoma-specific survival (HR 1.98, 95% CI 1.776–2.207) after adjusting for age, male sex, and year of diagnosis.⁴⁰ 

An additional limitation in the literature is the inconsistency of reported findings. Studies have significant heterogeneity in reporting time to initial diagnosis, follow-up period and patient outcomes, additional histopathological findings (e.g., presence of ulceration, mitoses, regression), and even reported histological subtype. While some of these discrepancies may be due to changes in staging and treatment guidelines over time, the variability in reporting further limits the ability to perform meta-analysis. Further studies are needed to better define the critical temporal interval between diagnoses at which point increased tumor burden⁴¹ may affect patient outcomes and relevant clinicopathological risk factors that may further assist in determining optimal follow-up frequency/interval and treatment plans.

While studies suggest a majority of synchronous primary lesions will have concordant presentation both anatomically and clinicopathologically, this may not be true for 20 to 30 percent of synchronous primaries.^6,7 

Despite anatomic concordance (Table 2), our patient’s second primary (amelanotic) melanoma was clinically discordant presentation and appeared more similar to cutaneous squamous cell carcinoma (in situ). To our knowledge, this is type of discordance has not been reported in the literature. As was the case with our patient, approximately 30 percent of patients who will have an additional primary melanoma may present with their second melanoma during their initial visit. These data further reinforce the importance of full-body skin examinations for high-risk patients. Even after finding one suspicious pigmented lesion, dermatologists should continue to perform a thorough examination and maintain a high degree of clinical suspicion. 

A final consideration should be given to timing of treatment. In our case, given classic clinical appearance macroscopically and on dermoscopy of the initial melanoma, we opted to proceed with wide local excision with 1cm margins without initial confirmatory biopsy. This approach of empiric treatment, especially on areas such as the back that are not cosmetically sensitive, may provide increased utility for patients who may be lost to follow up or may not be able to follow up for an extended period of time (e.g., more rural locations, patients with physical or socioeconomic barriers to care).

Conclusion 

Synchronous primary cutaneous melanomas are currently heterogenous collection of terminologies and temporal intervals that may limit dermatologists’ ability to accurately diagnose, prognosticate, and treat high-risk patients. Given the current lack of guidelines, we endorse the use of the term “synchronous” to delineate additional primary cutaneous melanomas found within a three-month interval. Adoption of this terminology may clarify findings and future reports in the literature, aid in further research to determine if/when a critical time interval exists that may alter patient outcomes, and facilitate development of subsequent guidelines for treatment and follow-up. Pending additional research, current clinical practice pearls include maintaining a high degree of clinical suspicion during FBSE, even after a discrete lesion is identified and empirically treating clinically classic and amenable suspicious lesions. 

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