Primary cutaneous melanoma of the scalp: Patterns of clinical, histological and epidemiological characteristics in Brazil.

BACKGROUND/
OBJECTIVES: Scalp melanoma is a subgroup of melanomas on the head and neck, historically associated with worst prognosis. Knowledge of the usual presentation of scalp melanoma can help to understand the reasons for the poor outcomes of treatment. This is the first publication to describe the clinical, histopathological and epidemiological profile of patients with scalp melanoma in a Latin American population.
METHODS: A cross-sectional study was performed of all primary cutaneous melanoma seen by the A.C.Camargo Cancer Center between 2008 and 2018, using an electronic health records to access clinical and pathology data.
RESULTS: When compared to trunk and limbs, increasing age is expected for patients with scalp melanoma (10.865; CI (95%) = [8.303; 13.427]). Regarding risk of invasion, scalp melanomas have a higher chance to be invasive than in situ (OR = 1.783; CI (95%) = [1.196; 2.657]) and present with higher Breslow thickness (OR = 3.005; CI (95%) = [2.507; 3.601]). Scalp site was significantly associated with male sex (OR = 3.750; CI (95%) = [2.533; 5.554]), perineural invasion (OR = 13.739; CI (95%) = [5.919; 31.895]), ulceration (OR = 2.311; CI (95%) = [1.488; 3.588]), and mitosis (OR = 2.366; CI (95%) = [1.701; 3.292]), when compared to trunk and limbs melanoma.
CONCLUSION: In the present study, head and neck melanomas represented 14.9% of all melanomas, a frequency slightly lower than that described in the literature and the mean age of melanoma on the scalp found was lower than that reported in the literature. These results could be explained by the demographic characteristics of Brazil, which has a population with a lower life expectancy compared to the European and North American population. Scalp melanomas occurred in older men, were diagnosed with greater Breslow thickness and were associated with the presence of perineural invasion, mitosis and ulceration.

Introduction

Twenty percent of melanomas are located on the head and neck [1], a higher frequency than expected, considering that this area represents only 9% of the body surface [2]. Melanomas on this location occur in older patients [3] and a higher incidence is expected with the increase in life expectancy of the population. Historically, they are associated with a greater risk of disease progression and death from melanoma than melanomas located elsewhere [4-7].

Melanomas located on the scalp are a subgroup that represent 35% of cases of head and neck melanomas, and are responsible for 5% of all melanomas. Scalp melanomas are characterized by a risk of death approximately 2 times greater than that of tumors located in the extremities, even after adjusting for Breslow thickness, age, sex and presence of ulceration [3,5,8]. Ozao-Choy et al showed that scalp location was an independent risk factor for worse overall survival and specific melanoma survival and concluded that scalp melanoma is a distinct entity and it is responsible for the worst prognosis associated with the head and neck melanoma group [2].

The reasons are uncertain [9], but some hypotheses cited to justify the worse prognosis of melanoma on this location are: hair coverage would result in a later diagnosis, high proportion of melanomas with rapid vertical growth, such as nodular and desmoplastic melanomas [10], higher blood and lymph flow [11,12] and the difficulty of obtaining adequate therapeutic surgical margins [2].

The gene profile signature in primary cutaneous melanoma appears to distinguish patients with low risk of metastatic recurrence from patients with high risk of recurrence. The presence of BRAF V600K mutation is associated with higher age, higher degrees of chronic sun damage and lower disease-free interval [13]. The possibly higher prevalence of V600K in scalp melanoma can be another explanation for its worst prognosis, but there is a lack of studies proving this association [10].

Knowledge of the usual presentation of scalp melanoma can help to understand the reasons for the worse prognosis on this location.

This study aimed to describe the clinical and histopathological profile of patients with melanoma on the scalp and to compare it with other areas of the head and neck, trunk and limbs.

Methods

This is an observational, cross-sectional and retrospective study carried out at A.C.Camargo Cancer Center, São Paulo, Brazil, a tertiary clinical reference center. The study was determined to be exempt from needing informed consent and it was approved by the A.C.Camargo Cancer Center institutional Research Ethics Committee (2379/17). The study was conducted according to the Helsinki ethical principles

In the retrospective review of the electronic medical records from A.C.Camargo Cancer Center, São Paulo, Brazil, from January 2008 to December 2018, we identified all patients who had a histopathological diagnosis of melanoma.

Patients originated from public and private outpatient clinics in the skin cancer nucleus of A.C.Camargo Cancer Center, including non-referred and referred patients with a suspected or biopsy proven skin cancer.

The anatomical sites of primary cutaneous melanomas were classified into the following subgroups: scalp melanoma (SM), other areas in the head and neck region melanoma except scalp (HNM), trunk / limbs melanoma (TLM). For all patients, the following data were collected: sex, age at diagnosis, histopathological subtype of melanoma, presence of ulceration, mitosis, perineural invasion and association with nevus.

Descriptive analysis was performed to assess the clinical and histopathological characteristics of melanomas diagnosed in the studied period. Summary measures of position and dispersion, such as mean and standard deviation (SD), median and minimum and maximum, were considered for quantitative variables and absolute and relative frequencies (%) were used for qualitative variables.

To assess a possible association between two qualitative variables, the chi-square test was applied to the data. In order to compare the distribution of data for quantitative variables in relation to the three groups, the Kruskal-Wallis non-parametric test was used followed by multiple comparison (with Bonferroni correction) when the null hypothesis is rejected.

In order to identify if topography is an independent factor that explains the clinical and histopathological characteristics of melanoma, simple linear and logistic regression models were fitted to the data depending on the outcome variable. To assess if topography affects the Breslow thickness, a generalized linear model with Gamma distribution and log link function was fitted to the dataset. For the logistic regression the measure of association of interest is given by the odds ratio (OR) with a 95% confidence interval (CI (95%)). For all hypothesis tests, the level of significance was set at 5%. Thus, results from which p-values were less than 0.05 were considered statistically significant. IBM SPSS version 24 software was used in all data analyzes.

Results

From January 2008 to January 2018, 3026 patients were diagnosed with melanoma at the institution. Of these, 453 (14.9%) were located on the head and neck region, including 154 (5.1%) located on the scalp. The clinical and histopathological characteristics of the melanomas diagnosed in the studied period and the results are described in Table 1.

Table 1

Clinical and histopathological characteristics of melanoma in relation to the scalp, head and neck and trunk/limbs.

Variable		SM (n = 154)	HNM (n = 299)	TLM (n = 2567)	Value p*	Multiple comparison
						Group	Value p* adjusted
Sex—n (%)	Female	33 (21.5)	115 (38.5)	1298 (50.6)	<0.0001*
	Male	121 (78.6)	184 (61.5)	1269 (49.4)
Age (years)—mean (SD)		62.48 (15.87)	59.31(18.08)	51.62 (15.46)	< 0.0001*	TLM vs SM	< 0.0001**
						TLM vs HNM	< 0.0001**
						SM vs HNM	0.141**
Breslow thickness—n (%)	In situ	32 (21.2)	144 (48.2)	830 (3.,4)	<0.0001*
	Invasive	119 (78.8)	155 (51.8)	1731 (67.6)
Invasive Breslow thickness (mm)	Mean (SD)	4.36 (5.89)	1.24 (1.35)	1.45 (2.29)	<0.0001*	TLM vs SM	< 0.0001**
	Median (min—max)	1.98 (0.22–40)	0.75 (0.1–8)	0.7 (0.1–26)		TLM vs HNM	0,999(m**
						SM vs HNM	< 0.0001**
Histopathological n (%)	Superficial spreading	78 (52.7)	167 (65)	1979 (86.2)	< 0.001*
	Lentiginous	16 (10.8)	65 (25.3)	102 (4.4)
	Nodular	22 (14.9)	9 (3.5)	131 (5.7)
	Desmoplastic	12 (8.1)	1 (0.4)	2 (0.1)
	Spitzoid	2 (1.4)	7 (2.7)	33 (1.4)
	Others	18 (12.2)	8 (3.1)	49 (2.1)
Ulceration—n (%)	Present	27 (18.5)	16 (5.5)	222 (8.9)	< 0.001*
Neurotropism -n (%)	Present	10 (6.8)	3 (1.1)	13 (0.5)	< 0.001*
Mitosis n (%)	Present	77(51))	69 (23.8)	762 (30.5)	< 0.001*	TLM vs SM	< 0.0001**
						TLM vs HNM	0.034**
						SM vs HNM	< 0.0001**
Nevus—n (%)	Present	18 (12.5)	51 (18.4)	540 (22.4)	< 0.001*

*Teste de Kruskal-Wallis.

** Multiple comparison with Bonferroni correction.

SM, scalp melanoma; HNM, head and neck melanoma; TLM, trunk/limb melanoma; standard deviation (SD); min, minimum; max, maximum

Scalp melanomas occurred in significantly older patients (mean = 62 years, SD = 16 years) compared to trunk and limb melanoma (mean = 52 years, SD 15 = years), but at a similar age to patients with melanoma on other head and neck areas (mean = 59 years, SD 18 years).

Through the association test, we observed that topography is associated with sex (p <0.0001). Males represent 78,6% of patients with melanoma on the scalp, 49,6% of patients with melanoma on the trunk and limbs, 61,5% of patients with melanoma in the other head and neck areas.

A greater proportion of invasive melanomas was observed on the scalp (78.8%) in comparison to trunk and limbs (67.6%) and other head and neck areas (51.8%). When in situ melanomas were excluded, invasive melanomas on the scalp were significantly thicker than melanomas in the other groups (SM mean = 4.36mm, SD = 5.89mm; TLM mean = 1.45mm, SD = 2.29mm; HNM mean = 1.24mm, SD = 1.35mm). The desmoplastic and nodular histopathological subtypes, the presence of ulceration and perineural invasion were significantly associated with scalp location (p <0.001).

According to estimates from the fitted linear regression model (Table 2), patients with SM are on average 10.8 years older than patients with TLM (10.865; CI (95%) = [8.303; 13.427). Patients with HNM are on average 7.6 years older than TLM patients (7.692; CI (95%) = [5.805; 9.579).

Table 2

Estimates of the parameters from simple linear, logistic and generalized regression models.

Linear regression model
Outcome	Topography	Coefficient	95% CI		Value p
			Lower	Upper
Age	TLM	Ref
	SM	10.865	8.303	13.427	<0.0001
	HNM	7.692	5.805	9.579	<0.0001
Intercept		51.616	51.006	52.225	<0.0001
Simple Logistic Regression Model
Outcome	Topography	OR	95% CI		p
			Lower	Upper
Gender–Male	TLM	Ref			<0.0001
	SM	3.750	2.533	5.554	<0.0001
	HNM	1.637	1.280	2.092	<0.0001
Ulceration–Yes	TLM	Ref			<0.0001
	SM	2.311	1.488	3.588	<0.0001
	HNM	0.595	0.353	1.003	0.051
Nevus–Yes	TLM	Ref			0.009
	SM	0.495	0.299	0.818	0.006
	HNM	0.781	0.568	1.075	0.129
Perineural invasion–Yes	TLM	Ref			<0.0001
	SM	13.739	5.919	31.895	<0.0001
	HNM	2.002	0.567	7.070	0.281
Invasive Melanoma (Breslow > 0mm)–Yes	TLM	Ref			<0.0001
	SM	1.783	1.196	2.657	0.004
	HNM	0.516	0.405	0.657	<0.0001
Mitosis–Yes	TLM	Ref			<0.0001
	SM	2.33	1.701	3.292	<0.0001
	HNM	0.710	0.535	0.943	0.018
Generalized linear model—Gamma distribution
Outcome	Topography	OR	95% CI		p
			Lower	Upper
Breslow thickness	TLM	Ref
	SM	3.005	2.507	3.601	<0.0001
	HNM	0.859	0.732	1.008	0.062
Intercept		1,453	1,387	1,521	<0.0001

SM, scalp melanoma; HNM, head and neck melanoma; TLM, trunk/limb melanoma; standard deviation (SD); OR, odds ratio.

From the simple logistic regression, scalp site was significantly associated with male sex (OR = 3.750; CI (95%) = [2.533; 5.554]), as well as others areas in the head and neck region (OR = 1.637; CI (95%) = [1.280; 2.092]), compared to trunk / limbs.

SM have a higher chance to present ulceration in relation to TLM (OR = 2.311; CI (95%) = [1.488; 3.588]),]), while there were no difference in the occurrence of ulcerations on HNM in relation to TLM (OR = 0.595; CI (95%) = [0.353; 1.003]). SM have lower chance of being associated with nevi (OR = 0.495; CI (95%) = [0.299; 0.818]), while there were no difference in the association with nevi between HNM and TLM (OR = 0.782; CI (95%) = [0.568; 1.075]),

The SM have higher chance to present with mitosis (OR = 2.366; CI (95%) = [1.701; 3.292]) and perineural invasion (OR = 13.739; CI (95%) = [5.919; 31.895]), while HNM have a lower chance to present with mitosis (OR = 0.710; CI (95%) = [0.535; 0.943]) and no difference in the presence of perineural invasion (OR = 2.002; CI (95%) = [0.567; 7.070]), when compared to TLM.

Regarding Breslow thickness, SM have higher chance to be invasive (OR = 1.783; CI (95%) = [1.196; 2.657]) and, when invasive, to present with increased Breslow thickness (OR = 3.005; CI (95%) = [2.507; 3.601]). However, HNM have a higher chance to be in situ (OR = 0.516; CI (95%) = [0.405; 0.657]) and, when invasive, to present with lower Breslow thickness (OR = 0.858; CI (95%) = [0.732; 1.008]).

Discussion

We describe one of the largest series of cases of scalp melanoma and its clinical and pathological characteristics, compared with melanomas located in other regions of the head and neck and melanomas on the trunk / limbs. In the present study, head and neck melanomas represented 14.9% of all melanomas, a frequency slightly lower than that described in the literature: 26.7% in a French regional study [2], 18% of invasive melanomas in the USA according to Surveillance, Epidemiology and End Results program [3], 15–24% of all melanomas in other European populations [1,14,15]. These results could be explained by the demographic characteristics of Brazil, which has a population with a lower life expectancy compared to the European and North American population [16].

The mean age of melanoma on the scalp found in our study was lower than that described in the literature (62 vs. 65 years, respectively) [17], a fact also justified by the lower life expectancy in the Brazilian population [16]. Patients with scalp melanoma were almost 11 years older than patients with melanomas located on the trunk and limbs (62 vs. 51 years), but only 3 years older than patients with melanomas located on the other head and neck areas (62 vs. 59 years). These results are in agreement with other population studies, in which head and neck melanomas are more frequent in the elderly than in young people. Scalp melanomas occurred predominantly in males, six times more commonly in men than in women, which is consistent with other reports in the literature [10,18].

Scalp melanomas were more frequently invasive and associated with greater mean Breslow thickness than melanomas elsewhere in the head and neck and in the trunk and limbs (78.6% and 4.36mm; 51.8% and 1.24mm; 67.6% and 1.45mm, respectively), a finding reported in other studies [5]. Late diagnosis due to the fact that the tumor is hidden under the hair has been a justification often described for this greater Breslow thickness. Interestingly, androgenetic alopecia is highly prevalent in patients with scalp melanoma and Benati et al found thicker melanomas in bald patients compared to patients with hair, a fact that weakens the above justification [17].

Rapidly growing tumors appear to have a greater influence on tumor thickness than delayed diagnosis [19]. Nodular and desmoplastic melanomas are subtypes associated with rapid growth and some previous reports have shown that they occur more frequently on the scalp. Both are often amelanotic, more common in older age groups and diagnosed with greater Breslow thickness [5,10]. Nodular melanoma grows 0.49 mm/month of thickness and it accounts for nearly 50% of all melanomas thicker than 2 mm [20]. In our study, 14.9% of melanomas on the scalp were nodular, a proportion significantly higher than that observed in other areas. Desmoplastic melanoma is an uncommon type of melanoma, representing less than 5% of all melanomas, and it has a different clinical behavior, which includes a higher recurrence rate, and less propensity to metastasize to the regional lymph nodes [21]. Additionally, desmoplastic melanoma has a high frequency of NF1 mutations, distinct from conventional melanoma [22]. In our study, 8.1% were desmoplastic melanoma, a proportion significantly higher than that observed in other head and neck areas and trunk and limb sites.

Compared with head/neck and trunk/limb melanomas, scalp melanomas were associated with greater Breslow thickness, mitosis, ulceration and perineural invasion, histological features associated with more aggressive tumors and a worse prognosis.

Limitations

This study has some limitations, it is a retrospective observational analysis, so important data such as the presence of alopecia, some clinical characteristics and the pattern of sun exposure have not been evaluated. Knowledge of the pattern of sun exposure and the molecular profile of melanoma on the scalp will likely contribute to understanding the unique behavior of this subgroup of melanomas.

Strengths

This is the first publication to describe scalp melanomas in a Latin American population. We believe that our study will contribute to the literature and that additional studies, which include the molecular profile of melanoma on the scalp, will be necessary to understand the unique behavior of this subgroup of melanomas.

Conclusion

Melanoma on the scalp has distinct clinical and histopathological characteristics compared to melanoma from other head and neck areas and melanoma on the trunk / limbs. Scalp melanomas are more frequently invasive and diagnosed with greater Breslow thickness, presence of ulceration, mitosis and perineural invasion. These characteristics may justify the more aggressive behavior of the tumor at that location. As it is associated with higher rates of mortality and recurrence, careful examination of the scalp should be part of the routine dermatological examination.

(XLSX)

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3 Aug 2020

PONE-D-20-18647

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

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Reviewer #1: The authors have submitted a single institution retrospective case series of scalp melanoma. The study is interesting and clinically relevant. Although the findings are not particularly novel or unexpected, they strengthen existing knowledge and are novel in terms of apparently being the first reported series from Brazil and Latin America overall. Important variables not reported include molecular features (e.g., BRAF V600E mutation status) and outcome/survival.

Although melanoma involving the scalp is well established, the high proportion of desmoplastic melanoma (DM) (compared to non-scalp, both NNM and TLM) might seem to mitigate adverse prognostic factors (DM perhaps with same or higher rate of local recurrence but lower rate of distant metastasis and death compared to nodular melanoma). DM is also genetically distinct from other forms of melanoma and can be subdivided into pure and mixed types. Can the authors comment on these aspects?

Please comment, if possible, regarding the significance, if any, of specific regions within the scalp. E.g., were photographs available? Was there a correlation with covered versus bald/alopecic scalp sites (e.g., Ref #19) The authors appear to acknowledge in Limitations that they did not evaluate this.

Abstract, 1st sentence: As worded, this sentence is not true (e.g. PMID 24281175 from 10 years prior). Please re-word to state that this is the 1st series from Latin America to focus on the unique clinical/histologic/epidemiological aspects of scalp melanoma.

Reviewer #2: These authors performed a retrospective analysis of all cutaneous melanomas diagnosed at a South American referral center between 2008-2018. They identify statistically-significant demographic and histopathologic differences comparing scalp melanomas to melanomas involving other anatomic locations. Specifically, they find that scalp melanoma patients are generally older and that the tumors are more likely to demonstrate adverse prognostic indicators. Their findings are generally consistent with findings reported in other studies, but this study adds additional information to the literature as it represents a geographic region and study population that has is historically underrepresented in the melanoma literature. I thank the authors for this work.

In your methods, please specify if your analysis included melanoma in situ (I believe it did). If so, I suggest you include data on MIS in Table 1 -- perhaps, show the distribution of all melanomas, MIS, and invasive disease. Page 9, lines 142-148 describe data on the variation in distribution of invasive melanomas -- I'd like see those numbers displayed in your table.

When you reference Breslow depth I recommend that you round to the nearest one tenth -- i.e., 3.43 should be 3.4. This aligns with current AJCC staging criteria.

I defer to the editors, but I believe Tables 2 and 3 could either be simplified or presented as supplemental material. Is talbe 2 necessary? Your point is, for example, that scalp melanomas have higher ORs for depth, perineural invasion, male sex, etc following regression modeling. Clinicians and pathologists will read this manuscript, and I suggest the analysis be explained in simplified terms (with more detail available).

Page 11, line 161 you state, "Increased Breslow thickness was identified as an important independent factor to explain the occurrence on the scalp.." I believe this statement is backwards. At the very least it is more biologically plausible that scalp location is a risk factor for higher Breslow depth. Further in your discussion you make similar statement regarding other variables (ulceration, mitoses, perineural invasion). It does not make sense that poor prognostic indicators "explain" scalp location but, rather, scalp location "explains" the presentation with poor prognostic indicators.

Do you have outcomes data based on anatomic location? I will not be surprised if the answer is 'no' -- outcomes data more more difficult to collect -- but if you have them, please report them (in this manuscript or another).

Your references require significant editing. Cursory review reveals multiple incomplete references (9, 12, 13).

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9 Sep 2020

PONE-D-20-18647

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

Dear Editor Paula Soares and reviewers,

We would like to thank you for the opportunity to submit our manuscript to the Plos One as well as for considering our paper as interesting for your readership. Referent to our manuscript (PONE-D-20-18647), the questions pointed by the reviewers are answered as follows:

# Editor

Comment: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Answer: Thank you for the instructions, we changed the text as necessary.

Comment: 2. Thank you for including your ethics statement: 'The project was approved by the institutional Research Ethics Committee (2379/17).'

(a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

(b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

Answer: Thank you for the instructions, we included the full name of the ethics committee review board.

Comment: 3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; and c) the source of the medical records analyzed in this work (e.g. hospital, institution or medical center name). If patients provided informed written consent to have data from their medical records used in research, please include this information.

Answer: Thank you for the instructions, we add this information in the manuscript

# Reviewers

Reviewer #1:

Comment: “The authors have submitted a single institution retrospective case series of scalp melanoma. The study is interesting and clinically relevant. Although the findings are not particularly novel or unexpected, they strengthen existing knowledge and are novel in terms of apparently being the first reported series from Brazil and Latin America overall. Important variables not reported include molecular features (e.g., BRAF V600E mutation status) and outcome/survival.”

Answer: Thank you very much for your considerations. As it is a retrospective research, unfortunately these data were not available.

Comment: “Although melanoma involving the scalp is well established, the high proportion of desmoplastic melanoma (DM) (compared to non-scalp, both NNM and TLM) might seem to mitigate adverse prognostic factors (DM perhaps with same or higher rate of local recurrence but lower rate of distant metastasis and death compared to nodular melanoma). DM is also genetically distinct from other forms of melanoma and can be subdivided into pure and mixed types. Can the authors comment on these aspects?”

Answer: Thank you for the instructions, we comment with more details, between lines 197 and 207, the specific behavior of nodular and desmoplastic melanomas.

Comment: “Please comment, if possible, regarding the significance, if any, of specific regions within the scalp. E.g., were photographs available? Was there a correlation with covered versus bald/alopecic scalp sites (e.g., Ref #19) The authors appear to acknowledge in Limitations that they did not evaluate this.”

Answer: As it is a retrospective study, the specific location within the scalp was not described in the vast majority of medical records evaluated. And photographs were also unavailable in almost all cases.

Comment: “Abstract, 1st sentence: As worded, this sentence is not true (e.g. PMID 24281175 from 10 years prior). Please re-word to state that this is the 1st series from Latin America to focus on the unique clinical/histologic/epidemiological aspects of scalp melanoma.”

Answer: The article PMID 24281175, published 2010, affirmed that the poor prognosis for scalp melanoma is due to late diagnosis, as the scalp region is often covered by hair. Meanwhile, in a more recent article published in 2018, PMID: 28543136, on multivariate analysis, scalp location was an independent predictor of worse melanoma-specific and overall survival. And the authors concluded that the pathophysiology of this poor prognosis remains to be determined and is not due to the late diagnosis. However, we re-word the 1st sentence as suggested.

Reviewer #2:

Comment:” These authors performed a retrospective analysis of all cutaneous melanomas diagnosed at a South American referral center between 2008-2018. They identify statistically-significant demographic and histopathologic differences comparing scalp melanomas to melanomas involving other anatomic locations. Specifically, they find that scalp melanoma patients are generally older and that the tumors are more likely to demonstrate adverse prognostic indicators. Their findings are generally consistent with findings reported in other studies, but this study adds additional information to the literature as it represents a geographic region and study population that has is historically underrepresented in the melanoma literature. I thank the authors for this work.

Answer: All the authors would really like to thank your comment.

Comment: “In your methods, please specify if your analysis included melanoma in situ (I believe it did). If so, I suggest you include data on MIS in Table 1 -- perhaps, show the distribution of all melanomas, MIS, and invasive disease. Page 9, lines 142-148 describe data on the variation in distribution of invasive melanomas -- I'd like see those numbers displayed in your table.”

Answer:: Yes, we included melanoma in situ in our analysis. However, for the calculation of the average thickness of Breslow, only invasive melanomas were included. We make this clearer in the table and in the text, as you suggested

Comment: “When you reference Breslow depth I recommend that you round to the nearest one tenth -- i.e., 3.43 should be 3.4. This aligns with current AJCC staging criteria.

Answer: We update the Breslow thickness as you suggested.

Comment: “I defer to the editors, but I believe Tables 2 and 3 could either be simplified or presented as supplemental material. Is talbe 2 necessary? Your point is, for example, that scalp melanomas have higher ORs for depth, perineural invasion, male sex, etc following regression modeling. Clinicians and pathologists will read this manuscript, and I suggest the analysis be explained in simplified terms (with more detail available).

Answer: We appreciate and agree with this suggestion. As we had to invert the order of the variables requested in the comment below, we had to adapt the statistical model and we have simplified it to just one table.

Comment: “Page 11, line 161 you state, "Increased Breslow thickness was identified as an important independent factor to explain the occurrence on the scalp.." I believe this statement is backwards. At the very least it is more biologically plausible that scalp location is a risk factor for higher Breslow depth. Further in your discussion you make similar statement regarding other variables (ulceration, mitoses, perineural invasion). It does not make sense that poor prognostic indicators "explain" scalp location but, rather, scalp location "explains" the presentation with poor prognostic indicators.

Answer: We also appreciate and agree with this suggestion However, in order to reverse all the statements, the statistical analysis needed to be modified. Through this new analysis, the results and conclusions were maintained without significant changes.

Comment: “Do you have outcomes data based on anatomic location? I will not be surprised if the answer is 'no' -- outcomes data more more difficult to collect -- but if you have them, please report them (in this manuscript or another).”

Answer: Unfortunately we don’t have these data.

Comment: “Your references require significant editing. Cursory review reveals multiple incomplete references (9, 12, 13).

Answer: We update the references.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

29 Sep 2020

PONE-D-20-18647R1

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

PLOS ONE

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==============================

Thank you for the revisions done in the Ms. However some minor points remain to be revised.

Please addresses the few points raised by Reviewer 1.

Thank you

==============================

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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Reviewer #1: Thank you for responding to nearly all of the Reviewer comments with this improved, revised manuscript.

Line 197: *It would still be useful to address, at least generally, whether the desmoplastic melanomas (DM) in this series were pure vs mixed type. PMID 23267722

Line 197: *The authors have not provided convincing data to support their assertion that DM is a rapidly growing subset of melanoma. Mitotic rate may be reasonably used as a surrogate marker for tumor growth, and although scalp melanoma overall may grow relatively rapidly, especially nodular melanoma, DM had a lower mitotic rate in PMID 25142970. Suggest removing or else providing support for this assertion.

Reviewer #2: (No Response)

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30 Sep 2020

PONE-D-20-18647

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

Dear Editor Paula Soares and reviewers,

We would like to thank you for the opportunity to submit our manuscript to the Plos One as well as for considering our paper as interesting for your readership. Referent to our manuscript (PONE-D-20-18647), the minor questions pointed by the Reviewer #1 are answered as follows:

# Reviewer #1:

Comment: “It would still be useful to address, at least generally, whether the desmoplastic melanomas (DM) in this series were pure vs mixed type. PMID 23267722

Answer: Thank you very much for your suggestions, these considerations has improved our manuscript.

All the scalp desmoplastic melanomas were pure type. We specified this in line 139 and 140.

Comment: “Line 197: *The authors have not provided convincing data to support their assertion that DM is a rapidly growing subset of melanoma. Mitotic rate may be reasonably used as a surrogate marker for tumor growth, and although scalp melanoma overall may grow relatively rapidly, especially nodular melanoma, DM had a lower mitotic rate in PMID 25142970. Suggest removing or else providing support for this assertion.

Answer: Thank you for the instructions, we detailed in line 198 – 201 that nodular melanoma is associated with rapidly growing, while desmoplastic melanoma is associated with higher rate of local recurrence.

5 Oct 2020

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

PONE-D-20-18647R2

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Paula Soares

Academic Editor

PLOS ONE

15 Oct 2020

PONE-D-20-18647R2

Primary cutaneous melanoma of the scalp: patterns of clinical, histological and epidemiological characteristics in Brazil

Dear Dr. Porto:

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