Acral Melanocytic Neoplasms: A Comprehensive Review of Acral Nevus and Acral Melanoma in Asian Perspective
Jivko A. Kamarashev
Round 1
Reviewer 1 Report
Well written, comprehensive, up to date review of an important field. Well illustrated and with appropriate citations.
Author Response
Thank you very much for your comments and review.
Reviewer 2 Report
The authors have submitted a review of acral nevus and acral melanoma. The review is well written, comprehensive, interesting, and clinically relevant. It could benefit from more emphasis on expert analysis and explanation of stated opinions, as detailed below. Beautiful Figures!
For consistency, please include a section on management of acral nevi.
Title: Rather than simply naming the diseases and disease category, suggest adding something about what the article is covering, pending Editorial input.
E.g.,
Acral Melanocytic Neoplasms: A comparison of Acral Nevus and Acral Melanoma
Acral Melanocytic Neoplasms: A comprehensive review [or Update] of Acral Nevus and Acral Melanoma
Acral Melanocytic Nevus and Acral Melanoma: Clinical, Histologic, and Molecular Features
Following current WHO convention, please stratify “sun-exposed skin” as being low-CSD (cumulative sun damage) and/or high-CSD whenever possible throughout the manuscript.
1.1 Epidemiology. Reference #2 does not seem to add anything as written. Suggest combining this result with prior studies or explaining how this study advances knowledge ,e.g., larger number of cases, better study design, etc.
1.1 Epidemiology “Interestingly . . . “ Please state why this finding is interesting or unexpected.
1.1 Epidemiology: Rather than listing sentences summarizing studies, suggest concluding this section with summary statement(s), either overall or per country, and acknowledgement of limitations in study design relative to the true population, e.g., retrospective study design, underreporting, lack of histologic confirmation.
Etiology and Genetics, Staging and treatment. “We also found . . . “ “We showed . . . “ “We reported . . . “ Please specify throughout the manuscript which authors, since they are not identical to those of the cited papers. E.g., “One of us ([author(s) initials]) found. . . “ or “Yun and coworkers . . . “
Etiology and Genetics. “Copy number variations (CNVs) are 43 more common in acral melanoma than cutaneous melanoma.” Suggest insert “non-acral” before “cutaneous”
Clinical features. Please define “small” with a size or size range. E.g., less than 6 mm
Dermoscopic features. Please define micro-Hutchinson’s sign, e.g., is this simply synonymous with dermoscopy, even if a clinical Hutchinson’s sign is present?
Histopathological features. Please describe any clinical (i.e., anything other than site), histologic and/or molecular features that distinguish ALM from SSM and nodular melanoma on acral skin.
Histopathologic features. In this Reviewer’s experience, compound acral nevi are not at all uncommon, perhaps equally likely to be biopsied compared to junctional acral nevi. The only cited reference is a case report. Please include/cite any studies focused on prevalence or acknowledge limitations.
Epidemiology. “The fingernails of the right hand are more susceptible . . “ implies a genetic predisposition, but since trauma or other external factors might be related, it may be preferable to combine this statement with the prior sentence, and then comment as to suspected reasons for the site predilections (R > L, fingernails > toenails, 1st digit > other digits) in a separate sentence.
Etiology and genetics. “CNVs in acral melanoma include CCND1 . . . “ Since CNV is not gene-specific, suggest revising to “Identified CNVs in acral melanoma have implicated several genes, including CCND1 . . . “ or comparable.
Clinical features: “Acral melanoma begins as a large . . “ Since most acral melanoma arises de novo, they must be small before they become large. Suggest replacing “begins” with “at the time of biopsy are typically” “are usually only detectable” “are usually only clinically distinguished from nevi” or comparable
Since micro-Hutchinson’s sign was reported in both nevi and melanoma, please comment on relative sensitivity and specificity of this finding in acral nevus vs acral melanoma.
Do the authors regard nodular melanoma to be a subset of melanoma mutually exclusive from ALM or SSM versus a histologic classification of tumors that may evolve from ALM or SSM? The manuscript currently reads as the former, but this would not be consistent with current WHO classification.
Histopathologic features. “Immunohistochemical staining for HMB45 and Melan-A highlights prominent dendritic processes of melanocytes . . “ Please define “prominent” and comment on whether prominent dendrites (confirm junctional melanocytes only, not dermal melanocytes) may vary by skin type, degree of lesional pigmentation, or may be seen in acral nevi.
Suggest commenting on the use of PRAME and P16 immunohistochemical staining for distinguishing acral melanoma from acral nevus.
Author Response
The authors have submitted a review of acral nevus and acral melanoma. The review is well written, comprehensive, interesting, and clinically relevant. It could benefit from more emphasis on expert analysis and explanation of stated opinions, as detailed below. Beautiful Figures!
Response: First, we are very grateful to receive your generous and sincere comments and review. Your insightful advice is greatly helpful in improving the manuscript’s quality. We thank you for the suggestions.
For consistency, please include a section on management of acral nevi.
Response: Thank you for your proper advice. We added a section on management of acral nevi.
Title: Rather than simply naming the diseases and disease category, suggest adding something about what the article is covering, pending Editorial input. E.g., Acral Melanocytic Neoplasms: A comparison of Acral Nevus and Acral Melanoma
Acral Melanocytic Neoplasms: A comprehensive review [or Update] of Acral Nevus and Acral Melanoma Acral Melanocytic Nevus and Acral Melanoma: Clinical, Histologic, and Molecular Features
Response: According to your comment, we changed the title to “Acral Melanocytic Neoplasms: A comprehensive review of Acral Nevus and Acral Melanoma in Asian perspective”.
Following current WHO convention, please stratify “sun-exposed skin” as being low-CSD (cumulative sun damage) and/or high-CSD whenever possible throughout the manuscript.
Response: Thank you for your attentive comment. We changed some “sun-exposed skin” to more accurate term “low-CSD”.
1.1 Epidemiology. Reference #2 does not seem to add anything as written. Suggest combining this result with prior studies or explaining how this study advances knowledge ,e.g., larger number of cases, better study design, etc.
Response: We address the reason why we referred reference #2 in manuscript. Reference #2 analyzed more larger number of cases (1052 vs 462) and include other races like Asian and Hispanic.
1.1.Epidemiology “Interestingly . . . “ Please state why this finding is interesting or unexpected.
Response: We added the interesting points as “ Interestingly, the total number of melanocytic nevus and distribution at the anatomic sites are different according to racial populations”
1.1Epidemiology: Rather than listing sentences summarizing studies, suggest concluding this section with summary statement(s), either overall or per country, and acknowledgement of limitations in study design relative to the true population, e.g., retrospective study design, underreporting, lack of histologic confirmation.
Response: We stated summary statement in the end of paragraph and described limitations of those studies, as follows “In summary, acral melanocytic nevi are more common in colored people than in whites, even though overall prevalence of melanocytic nevi is lower in Asian than in American. The limitation of this data is they analyzed only patients who visited dermatologic clinic, therefore the possibility of selection bias may exist”
Etiology and Genetics, Staging and treatment. “We also found . . . “ “We showed . . . “ “We reported . . . “ Please specify throughout the manuscript which authors, since they are not identical to those of the cited papers. E.g., “One of us ([author(s) initials]) found. . . “ or “Yun and coworkers . . . “
Response: We have corrected as you recommended. We changed “we” as “one of us ([SJY]) and coworkers”.
Etiology and Genetics. “Copy number variations (CNVs) are 43 more common in acral melanoma than cutaneous melanoma.” Suggest insert “non-acral” before “cutaneous”
Response: We have corrected that expression as your comments.
Clinical features. Please define “small” with a size or size range. E.g., less than 6 mm
Response: We added definition of “small” you mentioned.
Dermoscopic features. Please define micro-Hutchinson’s sign, e.g., is this simply synonymous with dermoscopy, even if a clinical Hutchinson’s sign is present?
Response: We added definition of micro-Hutchinson’s sign. (Ronger S, Touzet S, Ligeron C, Balme B, Viallard AM, Barrut D, Colin C, Thomas L. Dermoscopic examination of nail pigmentation. Arch Dermatol. 2002 Oct;138(10):1327-33. doi: 10.1001/archderm.138.10.1327. PMID: 12374538.)
Histopathological features. Please describe any clinical (i.e., anything other than site), histologic and/or molecular features that distinguish ALM from SSM and nodular melanoma on acral skin.
Response: The histopathological features of nodular melanoma and superficial spreading melanoma on acral sites are similar to those of examples at other body site. We added this in the text.
Histopathologic features. In this Reviewer’s experience, compound acral nevi are not at all uncommon, perhaps equally likely to be biopsied compared to junctional acral nevi. The only cited reference is a case report. Please include/cite any studies focused on prevalence or acknowledge limitations.
Response: We cited other references that analyzed nail matrix nevi. According to one report, among 22 specimens, only three specimens were compound nevus. (Tosti A, Baran R, Piraccini BM, Cameli N, Fanti PA. Nail matrix nevi: a clinical and histopathologic study of twenty-two patients. J Am Acad Dermatol. 1996 May;34(5 Pt 1):765-71. doi: 10.1016/s0190-9622(96)90010-9. PMID: 8632071.) In the other reference, Haneke also mentioned that nail matrix nevus is usually a junctional and only rarely a compound nevus. (Haneke E: Histopathology of the Nail: Onychopathology. Boca Raton, CRC Press, Taylor & Francis Group, 2017.)
Epidemiology. “The fingernails of the right hand are more susceptible . . “ implies a genetic predisposition, but since trauma or other external factors might be related, it may be preferable to combine this statement with the prior sentence, and then comment as to suspected reasons for the site predilections (R > L, fingernails > toenails, 1stdigit > other digits) in a separate sentence.
Response: According to your advice, we combined those two sentences and described suspected reason after that. We speculate that trauma or external factors might be related to this location preference.
Etiology and genetics. “CNVs in acral melanoma include CCND1 . . . “ Since CNV is not gene- specific, suggest revising to “Identified CNVs in acral melanoma have implicated several genes, including CCND1 . . . “ or comparable.
Response: We have corrected those expressions as your comments.
Clinical features: “Acral melanoma begins as a large . . “ Since most acral melanoma arises de novo, they must be small before they become large. Suggest replacing “begins” with “at the time of biopsy are typically” “are usually only detectable” “are usually only clinically distinguished from nevi” or comparable
Response: Thank you very much for your critical comments. You are right. Acral melanomas start as small lesion. So, we changed the you had mentioned sentence to “Acral melanomas begins as an asymmetrical, black-to-brown macule or small irregular patch. At the time of biopsy, the lesion is typically large in size after a long radial growth phase (RGP), and elevated nodules and ulceration associated with the vertical growth phase (VGP) may occur.”
Since micro-Hutchinson’s sign was reported in both nevi and melanoma, please comment on relative sensitivity and specificity of this finding in acral nevus vs acral melanoma.
Response: We added reference including those data (sensitivity 0.42, specificity 0.96) (Ohn J, Jo G, Cho Y, Sheu SL, Cho KH, Mun JH. Assessment of a Predictive Scoring Model for Dermoscopy of Subungual Melanoma In Situ. JAMA Dermatol. 2018 Aug 1;154(8):890-896. doi:10.1001/jamadermatol.2018.1372. PMID: 29926108; PMCID: PMC6143019.)
Do the authors regard nodular melanoma to be a subset of melanoma mutually exclusive from ALM or SSM versus a histologic classification of tumors that may evolve from ALM or SSM? The manuscript currently reads as the former, but this would not be consistent with current WHO classification.
Response: Thank you very much for your comment. As you mentioned, in WHO classification, nodular melanomas represent accelerated evolutional trajectories of melanoma subtypes, rather than a subtype with a distinct genomic profile. We added the sentence of “Nodular melanoma on acral site represents VGP of acral melanoma without an RGP.” Actually, we think that nodular melanoma is an unique melanoma with various pathway concept rather than evolving form of ALM or SSM, because genetic profiles of nodular melanomas are distinct from those of ALM or SSM. With this regard, further studies and consensus are needed, wo we did not include details in the revised manuscript.
Histopathologic features. “Immunohistochemical staining for HMB45 and Melan-A highlights prominent dendritic processes of melanocytes . . “ Please define “prominent” and comment on whether prominent dendrites (confirm junctional melanocytes only, not dermal melanocytes) may vary by skin type, degree of lesional pigmentation, or may be seen in acral nevi. Suggest commenting on the use of PRAME and P16 immunohistochemical staining for distinguishing acral melanoma from acral nevus.
Response: I would like to thank you for your valuable and helpful comment. We described in detail as “Immunohistochemical staining for HMB45 and Melan-A highlights prominent dendritic processes of melanocytes melanoma cells in the epidermis of acral lentiginous melanoma,” We also added the comments and reference evaluating role of PRAME and p16 IHC in diagnosis of acral melanocytic neoplasm. (McBride JD, McAfee JL, Piliang M, Bergfeld WF, Fernandez AP, Ronen S, Billings SD, Ko. JS. Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms. J Cutan Pathol. 2022 Mar;49(3):220-230. doi: 10.1111/cup.14130. Epub 2021 Sep20. PMID: 34476825.)
Author Response File: 
Author Response.docx
Round 2
Reviewer 2 Report
Thank you for responding to the comments and improving the manuscript.
Epidemiology: "colored" is an older historical term and may be perceived negatively by some readers. Suggest replacing with "darker completed" or comparable.
Epidemiology: It can be confusing to know exactly who are "Asians" and "Americans." Suggest replacing with ". . . in Asia than in the United States . . . " to avoid confusion with Canada, Central America, South America.
Author Response
Epidemiology: "colored" is an older historical term and may be perceived negatively by some readers. Suggest replacing with "darker completed" or comparable.
Response: Thank you very much for your sincere comments and review. We revised the “colored” as “darker completed”.
Epidemiology: It can be confusing to know exactly who are "Asians" and "Americans." Suggest replacing with ". . . in Asia than in the United States . . . " to avoid confusion with Canada, Central America, South America.
Response: We revised the “Americans” as “United States”. We thank you for the suggestions.
Author Response File: Author Response.docx
