Review Reports

Round 1

Reviewer 1 Report

The reviewer wishes to thank the editors and the authors for the opportunity to review such a well written and comprehensive manuscript.  This review seeks to identify and comment on various tools available (and their deficiencies) in regards to the diagnosis of and possible prediction of biologic behavior in melanoma and most importantly looks to the future of melanoma staging.  

While I agree that the current melanoma staging system must be improved,  this article only briefly mentions histologic criteria for melanoma and indeed supporting immunohistochemistry.  Given the name of journal (Dermatopathology) to which this manuscript was submitted, a more substantial discussion involving newer IHC studies (including PRAME, perhaps p16 etc) to match the very nicely written clinical counterpart (5. clinical diagnostic tools- line 211) would be of help.  Additionally, mentioning available molecular studies that can be done at the time of diagnosis to further support diagnoses of benign vs. malignant may be enlightening.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

This is a concise review of various publications on the causes and implications of early melanoma diagnosis as well as a sophisticated discussion on under- and overdiagnosis as well as „epidemic“ melanoma. Important ideas have been intensely discussed in the cited paper of Weyers (The ‘epidemic’ of melanoma between under- and overdiagnosis. J Cut Pathol 39: 9-16, 2012) and a variety of comments and editorials, i.e. Glusac EJ (The melanoma ‘epidemic’, a dermatopathologist's perspective. J Cut Pathol 38: 264-7, 2011), Weyers W (Screening for malignant melanoma, a critical assessment in historical perspective. Dermatol Pract Concept 8: 89-103, 2018), Kutzner H et al. (Overdiagnosis of melanoma – causes, consequences and solutions. JDDG 18: 1236-43, 2020), Caitlin R et al. (Do we need to rethink the diagnoses melanoma in situ and severely dysplastic naevus? Br J Dermatol 186: 1030-2, 2022), David C et al. (The effect of screening on melanoma incidence and biopsy rates. Br J Dermatol 187: 515-22, 2022), Katy JL et al. (Melanoma overdiagnosis: why it matters and what can be done about it, Br J Dermatol 187: 459-60, 2022).

Actually, the discussion has to be seen in perspective. Interestingly, the estimated rate of cancer overdiagnosis in Australia in 2012 for women ranged from 22-73% in breast, renal and thyroid carcinoma in contrast to invasive melanoma with 15%, only in situ melanoma was higher with 54% overdiagnosis, and for men it ranged from 33-42% in thyroid, prostate and renal carcinoma in contrast to invasive melanoma with 22%, only in situ melanoma was higher with 58% overdiagnosis (Glasziou et al.: Med J Australia 212: 163-8, 2020).

On the whole, this article is well written, the use of English is native. I felt, however, greater use of citation would be of benefit (see above).

The authors argue there is a dilemma when the incidence of melanoma has increased up to 6-fold in the last 40 years, but the mortality rate has not. Based on this bias, the authors assume, there are early melanomas, that are indolent whereas other (early) melanomas are (already) aggressive melanomas. The drawback in this concept is as follows:

- The authors do not define “early melanoma”.

- The authors should clarify the incidence of “early aggressive melanoma” versus “indolent early melanoma” to qualify the information on epidemic overdiagnosis of melanoma.

- The authors should state, at least discuss what will happen if the so-called indolent early melanoma is not removed?

During the last 4 decades the spectrum in describing and subtyping the histologic variety in atypical moles has broadened. Diagnostic considerations include Spitz nevus / low-risk (atypical) Spitz tumor (with mild to moderate atypia), severely atypical Spitz tumor (of uncertain malignant potential) and low-risk pediatric melanoma, Spitz melanoma and spitzoid melanoma versus conventional melanoma. In addition, diagnosis such as dysplastic nevus became common as well as nevus with mild atypia, low-risk lesion (i.e. moderate atypical nevus, Spitz nevus, melanocytoma) versus high-risk lesion (i.e. severely atypical nevus, atypical Spitz tumor, precursor of melanoma) versus malignant melanoma or melanocytic tumors with known genetic abnormalities. Some pathologists hierarchically classify melanocytic lesions from mild atypia (class I) and moderately dysplastic nevi (class II) to melanoma in situ, synonymous with severe atypia (class III), to early-stage invasive melanoma (class IV) and late-stage, invasive melanoma (class V). In this context, evaluating the reproducibility of the histopathological diagnosis of melanoma and related melanocytic lesions, Piepkorn et al. (JAAD Int 9: 7-10, 2022) showed in their study the histopathological diagnoses for moderate and severe dysplasia are not reproducible, whereas the diagnoses nevus with mild dysplasia and high-grade invasive melanoma are the most reproducible. In the authors’ view it is important to know the limitations of histopathology in order to avoid overdiagnosis. What is crucial, however, many of these borderline lesions are often presented in lessons, but very rare in daily practice. As a result, in spite of different terminologies used by dermatopathologists most patients are managed adequately. It turns out that while dermatopathologists cannot often agree about how to best sign-out a case, they generally agree about how to manage a lesion. Awareness of these concepts is very helpful when reporting everyday dermatopathology cases especially atypical melanocytic nevi, because the dermatopathologists want to make sure that not only the lesions but also the patients are managed appropriately. In this context, it remains to be discussed whether we should soon consider cost-intensive NGS as a standard diagnostic adjunct in the evaluation of melanocytic lesions.

What if environmental factors or behavior are responsible for the so-called explosion of the indolent, i.e. initially not potentially metastatic melanoma? Then we should all be pleased about early diagnosis, before the worst case occurs. To be fair, discordances in the histological diagnosis mainly refer to rare melanoma entities, special localization, skin type and age of the patient, for the most part, however, to the experience of the investigator. Conversely, the vast majority of melanomas are histologically undisputed, not only among experts.

Recently, Tejera-Vaquerizo et al. (Actas Dermosifiliogr 111: 629–8, 2020) investigated the estimated effect of COVID-19 lockdown on skin on skin tumor size and survival and simulated the course of squamous cell carcinoma and malignant melanoma with a diagnosis delayed by one to three months and postulated in particular an increase in ultra-thick tumors due to the pandemic. The same working group calculated a possible stage increase in 45% of the melanomas after a delay of three months (Tejera-Vaquerizo et al.: J Eur Acad Dermatol Venereol 34: e351–3, 2020).

The recent study of Welzel et al. (JDDG 20: 1027-9, 2022) on the impact of the COVID-19 pandemic on the care of patients with malignant melanoma showed that with the corona-related decline in the number of melanoma cases, caused by the fact that patients with suspicious pigment lesions consulted a doctor too late due to the contact restrictions and fear of infection, the tumor thickness and stage had increased. As a result, the earlier a malignant melanoma is detected, the better the chances of recovery, since skin cancer knows no lockdown or tolerates late diagnosis.

Finally, the authors’ statement is not validated that there is limited understanding (page 3, line 141 ff), that has caused over-treatment of early-stage, innocuous melanomas and under-treatment of early-stage, biologically aggressive melanomas. In this context, it is speculative to claim, “perhaps indolent melanomas are ubiquitous and remain undiagnosed until they present more aggressively” (page 3, line 125 ff), or “some tumors spontaneously regress” (page 3, line 129) or “which lesions will progress and which lesion will not” (page 3, line 130).

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report

 

Dear Academic Publisher, thank you for giving me the opportunity to review this interesting manuscript by Kaviyon Sadrolashrafi et al. This is a review of the current knowledge acquired on the incidence (epidemiology), diagnosis and prognosis of cutaneous melanoma (CM), with attention both to the classic clinical, histological, immunohistochemical and even molecular features, such as gene expression profiles (GEP ), NGS, etc. In their attempt I believe that the authors have clearly defined their point of view regarding the fact that, while on the one hand the incidence of malignant melanoma (MM) has "really" increased, on the other it reflects a kind of diagnostic "epidemic" due not only to new tools able to assist dermatologist and dermatopathologist, but also to a disarray also objectively it is present among histologically malignant lesions with benign behavior, and, vice versa, apparently harmless lesions that lead the patient to exitus. In defending this concept, the authors cite an extensive literature on the subject. I believe that this manuscript does not add anything new / original to what is already known, but I consider it suitable for Dermatopathology as it offers an overview of the state of the art. For this reason I opt for a minor revision, but I have some suggestions for the authors:

Please, correct some typos in the manuscript and, furthermore, some error of English. Cite, study and briefly discuss some very recent papers that can, in my opinion, enhance the paper:
Cazzato G, Arezzo F, Colagrande A, Cimmino A, Lettini T, Sablone S, Resta L, Ingravallo G. "Animal-Type Melanoma/Pigmented Epithelioid Melanocytoma": History and Features of a Controversial Entity. Dermatopathology (Basel). 2021 Jul 5;8(3):271-276. doi: 10.3390/dermatopathology8030033. PMID: 34287308; PMCID: PMC8293039.
Cazzato G, Lospalluti L, Colagrande A, Cimmino A, Romita P, Foti C, Demarco A, Arezzo F, Loizzi V, Cormio G, Sablone S, Resta L, Rossi R, Ingravallo G. Dedifferentiated Melanoma: A Diagnostic Histological Pitfall-Review of the Literature with Case Presentation. Dermatopathology (Basel). 2021 Oct 15;8(4):494-501. doi: 10.3390/dermatopathology8040051. PMID: 34698090; PMCID: PMC8544555.
Saginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. Epidemiology of Melanoma. Med Sci (Basel). 2021 Oct 20;9(4):63. doi: 10.3390/medsci9040063. PMID: 34698235; PMCID: PMC8544364.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors' corrective additions to the manuscript have clarified the addressed questions and resulted in a significant update in the clinical discussion on the causes and effects of early melanoma diagnosis.