10.5826/dpc.1201a34
Introduction: The characteristics and the prognostic value of regression in primary melanomas are controversial.
Objectives: To further characterize “hot” and “cold” tumor’s stromas and to investigate the association between dermoscopy, pathology, and the prognostic implications of regression.
Methods: A 14-year-collection-based retrospective analysis was carried out on 40 patients with confirmed regressive melanomas.
Results: The extent of regression in dermoscopy was associated with the stage of the regression (P = 0.05) and with the MelanA patterns in histology (P = 0.02). Blue-gray and gray-brown color of the peppering (P = 0.01), and  the eccentric, multifocal character of the dermoscopic regression (P = 0.05) were associated with “hot” stromas (CD8+, Granzym B+). Focal histologic regression (regressing melanomas) was associated with a good outcome (P &lt; 0.001), while a complete regression (regressed melanomas) was associated with melanoma-related death (P &lt; 0.001). “Hot” stromas (CD8+ were significantly associated with survival at 10 years (P = 0.044), while “hot” stromas (Granzyme B+) were associated with the locoregional extension (P = 0.016), and the initial distant metastasis (P = 0.016).
Conclusions: Dermoscopic features of regression in primary melanomas were associated with the stage of regression, its extent, and the “hot” or “cold” nature of the tumor stroma, with prognostic implications.
text/xml
2160-9381
1842
en
Luc  Thomas
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
dermoscopy
Significance of Primary Melanoma Regression on Local Infiltrate and Outcome
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-02-02
2021-06-21
2022-02-02
2022-02-09
e2022034
Dermatol Pract Concept
Introduction: The characteristics and the prognostic value of regression in primary melanomas are controversial.
Objectives: To further characterize “hot” and “cold” tumor’s stromas and to investigate the association between dermoscopy, pathology, and the prognostic implications of regression.
Methods: A 14-year-collection-based retrospective analysis was carried out on 40 patients with confirmed regressive melanomas.
Results: The extent of regression in dermoscopy was associated with the stage of the regression (P = 0.05) and with the MelanA patterns in histology (P = 0.02). Blue-gray and gray-brown color of the peppering (P = 0.01), and  the eccentric, multifocal character of the dermoscopic regression (P = 0.05) were associated with “hot” stromas (CD8+, Granzym B+). Focal histologic regression (regressing melanomas) was associated with a good outcome (P &lt; 0.001), while a complete regression (regressed melanomas) was associated with melanoma-related death (P &lt; 0.001). “Hot” stromas (CD8+ were significantly associated with survival at 10 years (P = 0.044), while “hot” stromas (Granzyme B+) were associated with the locoregional extension (P = 0.016), and the initial distant metastasis (P = 0.016).
Conclusions: Dermoscopic features of regression in primary melanomas were associated with the stage of regression, its extent, and the “hot” or “cold” nature of the tumor stroma, with prognostic implications.
Luc  Thomas
2022/02/02
10.5826/dpc.1201a34
e2022034
Dermatology Department, Hôpital Universitaire Lyon Sud, Hospices Civils de Lyon. Pierre-Bénite, France; Lyon 1 University Lyon France; Lyon Cancer Research Center, Centre Léon Bérard Lyon France
2160-9381
dermoscopy
en
e2022034
Tchernev G, Temelkova I. Primary Regressive, But Metastasizing Melanoma!? Open Access Maced J Med Sci. 2019;7(5):893-895. DOI: 10.3889/oamjms.2019.048. PMID: 30962857. PMCID: PMC6447344.
Significance of Primary Melanoma Regression on Local Infiltrate and Outcome
https://dpcj.org/index.php/dpc/article/download/1842/1478
                    Dermatology Practical & Conceptual


    Significance of Primary Melanoma Regression on
              Local Infiltrate and Outcome
       Awatef Kelati1,2, Brigitte Balme3, Brigitte Chouvet3, Alexandra Traverse-Glehen3,
  Juliette Tantot3, Olivier Harou3, Gérard Duru4, Sebastien Debarbieux1, Stephane Dalle1,5,6,
                                         Luc Thomas1,5,6


1 Dermatology Department, Hôpital Universitaire Lyon Sud, Hospices Civils de Lyon. Pierre-Bénite, France
2 Dermatology Department, Cheikh Khalifa International University Hospital, Mohammed VI University of Health Sciences (UM6SS),
  Casablanca, Morocco
3 Anatomo-Pathology Department, Hôpital Universitaire Lyon Sud, Hospices Civils de Lyon. Pierre-Bénite, France
4 Research director in the Claude Bernard University, Lyon, France
5 Lyon 1 University Lyon France
6 Lyon Cancer Research Center, Centre Léon Bérard Lyon France



Key words: primary melanoma, local infiltrate, outcome, histopathology, dermoscopy
Citation: Kelati A, Balme B, Chouvet B et al. Significance of primary melanoma regression on local infiltrate and outcome.
Dermatol Pract Concept. 2022;12(1):e2022034. DOI: https://doi.org/10.5826/dpc.1201a34
Accepted: September 1, 2021; Published: January 2022
Copyright: ©2022 Kelati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: this work is supported in part by grants from Université Claude Bernard Lyon 1 (to LT and SD), from the Hospices Civils de Lyon
(to LT and SD), from the association Vaincre le mélanome (to LT), from Melarnaud (to SD), from Lyrican (to SD), from the Fondation ARC
(to SD).
Competing interests: None.
Authorship: All authors declare that they have sufficiently participated in the submitted work; all have had access to clinical material
and have revised the manuscript before submission. Study concept and design: AK, BB, SD, and LT; Data acquisition, data analysis and
interpretation, critical revision of the manuscript, and intellectual input: all authors; Drafting of manuscript: AK, BB, OH, SD, and LT;
Statistical analysis: GD.
Corresponding author: Awatef Kelati, MD, Dermatology Department, Cheikh Khalifa International University Hospital, Mohammed VI
University of Health Sciences (UM6SS), Casablanca, Morocco. E-mail: awatkelati@gmail.com



  ABSTRACT             Introduction: The characteristics and the prognostic value of regression in primary melanomas are
                       controversial.
                       Objectives: To further characterize “hot” and “cold” tumor’s stromas and to investigate the associa-
                       tion between dermoscopy, pathology, and the prognostic implications of regression.
                       Methods: A 14-year-collection-based retrospective analysis was carried out on 40 patients with con-
                       firmed regressive melanomas.
                       Results: The extent of regression in dermoscopy was associated with the stage of the regression (P
                       = 0.05) and with the MelanA patterns in histology (P = 0.02). Blue-gray and gray-brown color of
                       the peppering (P = 0.01), and the eccentric, multifocal character of the dermoscopic regression (P =
                       0.05) were associated with “hot” stromas (CD8+, Granzym B+). Focal histologic regression (regressing
                       melanomas) was associated with a good outcome (P < 0.001), while a complete regression (regressed
                       melanomas) was associated with melanoma-related death (P < 0.001). “Hot” stromas (CD8+ were




Original Article | Dermatol Pract Concept. 2022;12(1):e2022034                                                                              1
                     significantly associated with survival at 10 years (P = 0.044), while “hot” stromas (Granzyme B+) were
                     associated with the locoregional extension (P = 0.016), and the initial distant metastasis (P = 0.016).
                     Conclusions: Dermoscopic features of regression in primary melanomas were associated with the
                     stage of regression, its extent, and the “hot” or “cold” nature of the tumor stroma, with prognostic
                     implications.




Introduction                                                      Methods
Histopathological features of regression, encountered in          The present study was approved by the Hospices Civils de
10%-35% of primary cutaneous melanomas [1,2], classi-             Lyon ethics committee, project N°20-15 (2019). It is a collec-
cally appear on dermoscopy as white (or blue-white) scar-         tion-based retrospective study of a consecutive series of patients
like areas (WSA) [3,4], variably admixed with blue-gray           having cutaneous melanomas with both confirmed dermoscopic
granularity (BGG) or “peppering”. Both WSA and BGG                and histopathological changes of regression, over a period of 14
are unspecific features of regression, and are often regu-        years (2006-2019), for whom a complete set of clinical dermo-
larly distributed on more than 50% of the surface benign          scopic photographs was available. All patients gave their written
lesions, while they are smaller and irregularly distributed in    informed consent for the use of their clinical records, clinical
melanomas [3–6]. Recently, reticulated regression has been        and dermoscopic images, pathological specimen at the time of
described in in situ or slow-growing invasive melanomas as        the primary excision of the tumor, and subsequent inclusion
a new dermoscopic feature of regression, and appears as a         in the Centre de Ressources Biologiques (Institutional biobank)
coarse blue-gray net, with thick gray-blue lines with large       of the Hospices Civils de Lyon for research purposes.
pink-colored holes [2,7]. Although classic histopatholog-             This study has not been registered in a public trial regis-
ical features of primary melanoma regression have been            try because it does not prospectively assigns human subjects
described over the past decades, their clinical implications      to intervention or comparison groups to evaluate the cause
and prognostic value remain unclear and controversial             and effect relationship between a medical intervention and a
[2,8–16].                                                         health outcome. This study does not fall into the scope of the
    New interest in the evaluation of the nature of the host      French Jardé law, of 16th November 2016 because it uses a
response, and the subsequent regression features in malignant     preexisting cohort of patients and preexisting clinical records.
tumors, especially melanomas, came after the development of           The exclusion criteria were the absence or the poor qual-
immunotherapy. Tumor stromas have been sub-classified into        ity of the dermoscopic images and the non-confirmation of
“hotly” and “coldly” infiltrated by immune cells [17], with       the presence of histopathological features of regression upon
the pathogenic hypothesis that “hot” tumors may respond           reevaluation of the original histopathological slides. Clinical
better to immunotherapy, which stimulates the already pres-       history, clinical and dermoscopic images, histopatholog-
ent immune cells, whereas “cold” tumors should (or could)         ical reports, standard immunochemistry data (MelanA),
be initially stimulated by specific neo-adjuvant agents before    and, when applicable, genotyping of BRAF mutations were
the initiation of immunotherapy.                                  directly collected from patient electronic records.
                                                                      Dermoscopic images were analyzed by 3 independent expe-

Objectives                                                        rienced dermoscopists. Regression-associated features were
                                                                  recorded as well (WSA and BGG), and were specifically evalu-
The primary aim of the present study was to further char-         ated for their presence, their disposition (central, eccentric, uni-
acterize “hot” and “cold” stromas in regressive melanomas         focal, multifocal), and their surface extension (on less than 25%,
based on dermoscopic and histopathologic criteria, and to         between 25% and 50%, or on more than 50% of the lesion). The
preoperatively analyze dermoscopic features at different          presence or absence of reticular regression was also recorded.
stages of regression. The secondary aim was to investigate            Histopathological and MelanA slides were evaluated
the association between dermoscopy, pathology, and the            independently by 4 dermatopathologists with no knowl-
prognostic implications of regression, with the ultimate goal     edge of the original histopathology report; the regression
of helping in the pre-therapeutic definition of “hot” tumors,     was sub-classified into 3 stages as reported in the literature
which may benefit from postoperative adjuvant immunother-         [2]. Stage 1, or “inflammatory phase”, is characterized by
apy, and “cold” tumors, which could be included in potential      a still recognizable tumor, with dense lymphocytic infil-
neo-adjuvant clinical trials in priority before the excision of   trates admixed with nests of malignant melanocytes. Stage
the primary tumor.                                                2 or “regressing phase” is characterized by still recognizable



2                                                                      Original Article | Dermatol Pract Concept. 2022;12(1):e2022034
melanoma cells, with tumor reduction or disappearance in          Statistical Analysis
the overlying epidermis, while in the papillary dermis the        Analyses were performed using the Statistical Package for
malignant tissue is replaced by lymphocytes and fibrosis. An      the Social Studies software version 20. Quantitative variables
increased vascularity is also observed because of angiogenesis,   were expressed as mean (± standard deviation, SD) and qual-
and heavily pigmented macrophages can be observed. Stage          itative variables as count (percentage). Progression-free sur-
3 or “regressed melanoma” is characterized by the complete        vival was defined as the number of months from the diagnosis
disappearance of the tumor that is replaced by a dense fibrotic   to the identification of locally recurrent or metastatic disease
tissue with vessels and melanophages in varying numbers,          in the lymph nodes or distant organs. Death was considered
with few or no lymphocytes underneath a thinned epidermis.        as melanoma-related in patients for whom the melanoma had
The extent of regression was also examined, and classified as     progressed. A univariate analysis was performed to investigate
focal if it involved a portion of the dermal component of the     the association between histological regression characteristics,
tumor, partial if it involved the entire dermal component, and    inflammatory infiltrate status, and prognosis, using a chi-
complete if it involved the entire tumor [2].                     squared 2 test. A P value ⩽0.05 was considered as significant.
    Additional immunophenotypic studies (CD8, Langerin,
Granzyme B, and PDL-1) and an Orcein stain were performed         Results
on formalin-fixed paraffin-embedded original pathological
specimens. The proportion (%) of cells positive for CD8,          Among the 98 patients from the collection database, only
Granzyme B, Langerin, and PDL-1 was evaluated in the area         40 were included (30 were excluded because of incomplete
of the regression and in the tumor stroma, and categorized        dermoscopy record, 28 were excluded because of the absence
as covering < 5%, ⩾5 and <10%, ⩾10and <25%, ⩾25and <              of clear-cut histopathological features of regression). The
50%, ⩾50 and >75%, or >75% of the whole inflammatory              mean (SD) age of included patients was 63.6 (15.7) years,
infiltrate. After discussion between the authors and a review     and 82.5% of them presented with melanomas in the local
of all the slides, tumors were considered as “hot” if their       stage (I and II of the AJCC 2018 Melanoma staging; Table 1).
stroma was CD8+ on more than 25%, Granzyme B+ on more                Within the regression area of the tumor, WSA were
than 10% of the inflammatory infiltrate, PDL-1 on more +          observed in 55% of lesions, blue-WSA in 45%, BGG in 97.5%
than 5%, or Langerin+ on more than 5%. Otherwise, they            (Figures 1-3). Reticular regression was observed in 75% of
were considered as “cold”.                                        cases, and was associated with the polychromatic character
    Following our clinical practice, BRAF mutation was            of the lesion (P = 0.047) and the stage 2 of the regression in
tested only for primary tumors thicker than 1.00 mm.              histology (P = 0.049).



                     Table 1. Descriptive Analysis of Patients Included in the Present Study
                    Total population n = 40                                                  N (%)
 Mean age, years (SD)                                                                      63.6 (15,7)
 Sex, male                                                                                   24 (60)
 Lymph node metastasis                                                                       6 (15)
 Metastatic melanoma                                                                         6 (15)
 Dermoscopic regression variables
 Blue-white areas
  Blue-white                                                                                 18 (45)
    White                                                                                    22 (55)
 Blue –white areas characteristics
 Central                                                                                      2 (5)
    Eccentric                                                                               37 (92,5)
 Coverage of the lesion
   Less than 25%                                                                             14 (35)
   25-50%                                                                                    10 (25)
     More than 50%                                                                           16 (40)
 Peppering                                                                                  39 (97,5)

 Focal                                                                                      37 (92,5)
  Total                                                                                       2 (5)

                                                                                                               Table 1 continues
Original Article | Dermatol Pract Concept. 2022;12(1):e2022034                                                                  3
            Table 1. Descriptive Analysis of Patients Included in the Present Study (continued)
                  Total population n = 40                                         N (%)
Color of the lesion
    Brown-gray                                                                  13 (32.5)
    Grey-blue                                                                    14 (35)
      Grey-blue and brown-gray                                                   12 (30)
Reticular regression in less palpable area                                       30 (75)
    Grey-blue lines                                                              20 (50)
     Brown-gray lines                                                            10 (25)


Vascularization
    Polymorphic vessels                                                         25 (62.5)
     Linear irregular                                                             2 (5)
Histopathology and immunochemistry
Melanoma histological subtype
 SSM                                                                            25 (62.5)
 Regressive unclassifiable                                                       7 (17.5)
 LM                                                                               6 (15)
 ALM                                                                               2 (5)
Stage of the regression
  1                                                                              3 (7.5)
  2                                                                              24 (60)
  3                                                                             13 (32.5)
Extent of regression
  Complete                                                                       1 (2.5)
  Focal                                                                         27 (67.5)
  Partial                                                                        12 (30)
MelanA
 Normal (stage 1 of regression)                                                  1 (2.5)
 Reduced in the dermis, reduced in the epidermis                                 26 (65)
 Absent in the dermis, reduced in the epidermis                                 13 (32.5)
Orcein in the regression area
 Repressed, condensed, horizontal                                               35 (87.5)
 Repressed, not condensed, horizontal                                            5 (12.5)
Immunochemistry (Hot stromas)
CD8+                                                                            37 (92.5)
Granzyme B+                                                                      22 (55)
Langerin +                                                                      21 (52.5)
PDL1+                                                                            14 (35)
Mutation BRAF V600 E                                                             5 (12.5)
Melanoma staging AJCC 2018
I and II (local)                                                                33 (82.5)
III (loco-regional)                                                               2 (5)
IV (Metastatic)                                                                 5 (12.5)
Evolution after 2 years of treatment
Death                                                                             2 (5)
Stable without clinical or radiologic evolution                                   6 (15)
Complete remission after more than 2 years                                       30 (75)

SSM=Superficial spreading melanoma
LM: Lentigo maligna
ALM=Acral lentiginous melanoma
AJCC =American Joint Committee on Cancer




4                                                         Original Article | Dermatol Pract Concept. 2022;12(1):e2022034
                 Figure 1. Clinical and dermoscopic images of a regressing melanoma. Multicomponent pattern with
                 multiple peripheral eccentric white scar-like areas (blue arrow) covering less than 50% of the lesion, with
                 reticular regression (black circle). Focal peppering (brown arrow).




                 Figure 2. Clinical and dermoscopic images of a regressed melanoma. White–blue scar-like areas (blue
                 arrow), and extensive peppering (brown arrow) covering more than 75% of the lesion, with reticular
                 regression (black circles).



    Peppering was associated with thin melanomas (< 1mm, P              with stage 1 and 2 of regression (P = 0.035), irregular thick
= 0.012) and positive BRAF mutations (P = 0.028). WSA were              reticular lines (P = 0.049) and blue white veil (P = 0.014)
associated with follicular migration in histology (P = 0.014).          were associated with stage 2 of regression. Annular granular
The extent of regression in dermoscopy was associated with              pattern was associated with stage 2 and 3 of regression (P =
the stage of regression (P = 0.05) and to MelanA patterns               0.009). Skin fissures exaggeration in dermoscopy (P < 0.001),
in histology (P = 0.023). Chaotic lesions were associated               the presence of eccentric globules (P = 0.027), blue-white area



Original Article | Dermatol Pract Concept. 2022;12(1):e2022034                                                                       5
                                                                       veil (P = 0.038), and perifollicular circles (P = 0.045) were
                                                                       associated with focal regression in histology. The loss of nor-
                                                                       mal elastic fiber architecture in Orcein stain was associated
                                                                       with the WSA with peppering (P = 0.001; Table 2).
                                                                          On the other hand, red milky areas (P = 0.033), irregular
                                                                       thick reticular lines (P = 0.044), polygones (P = 0.044), and
                                                                       blue-gray and gray-brown color of the peppering gran-
                                                                       ules (P = 0.011) were associated with “hot” Granzyme B+
                                                                       tumors, while “hot” CD8 + stromas were associated with
                                                                       skin fissures exaggeration (P = 0.043) and with the eccentric
                                                                       and multifocal character of regression in dermoscopy (P =
                                                                       0.05). “Cold” PDL1+ stromas were associated with inversed
                                                                       network in dermoscopy (P = 0.05) and eccentric globules (P
                                                                       = 0.044), while “cold” Langerin+ stromas were associated
Figure 3. Hot stroma in a regressive melanoma. Stage 2 of histologic
regression with the corresponding melanA pattern as reduced in the     with the multicomponent pattern (P = 0.032), peripheral
dermis and reduced in the epidermis, and CD8+ immunochemistry on       structureless area (P = 0.026), and the rhomboidal pattern
more than 50% of the inflammatory infiltrate (magnification x10).      (P = 0.049) (Table 2).



                                                  Table 2. Univariate Analysis
                                                        Variables                                                             P value
 Immunodepression                                            Stage 3 of regression                                          0,000
 Elevated lesion (plaque ou nodular)                         Hot stroma Granzyme B+                                         0,038
 Lesion color (polychromatic or achromic)                    BRAF mutation                                                  0,035
                                                             Regression extent                                              0,041
                                                             Reticular regression in an area les palpable than the          0,014
                                                             other areas
 Loco-regional metastasis                                    Dermoscopic regression (Blue-white areas (scar like))          0,041
                                                             Focal regression in histology                                  0,004
                                                             Hot stroma Granzym B +                                         0,016
 Peppering                                                   Focal regression (focal peppering)                             0,000
                                                             Low risk of recurrence after complete remission after          0.029
                                                             surgery
 Extent of regression in dermoscopy                          MelanA expression                                              0,023
                                                             Regression stages in histology                                 0,05
 Eccentric character of regression in dermoscopy             Stage 2 and 3                                                  0,012
                                                             Hot stroma CD8 +                                               0,05
 Granules color                                              Hot stroma Granzym B +                                         0,011
 Reticular type of regression                                Regression stage 2                                             0,049
 Annular granular pattern                                    Stage 2 and 3 of regression                                    0,009
                                                             Good outcome with complete remission, and no                   0.001
                                                             evolution after treatment
 Irregular thick reticular lines                             Stage 2 of regression                                          0,049
                                                             Hot stroma Granzyme B +                                        0,044
 Skin fissures exaggeration                                  Focal regression in histology                                  0,000
                                                             Hot stroma CD8 +                                               0,043
                                                             Good outcome with complete remission, and no                   0.002
                                                             evolution after treatment
                                                             Good response to immunotherapy                                 0.003

                                                                                                                       Table 2 continues



6                                                                            Original Article | Dermatol Pract Concept. 2022;12(1):e2022034
                                         Table 2. Univariate Analysis (continued)
                                                          Variables                                                         P value
 Blue-white area (veil)                                       MelanA pattern: reduced in the dermis, reduced or          0,010
                                                              normal in the epidermis
                                                              Stage 2 of regression                                      0,014
                                                              Focal regression in histology                              0,038
 Pseudopods                                                   Good outcome with Complete remission, and no               0.033
                                                              evolution after treatment
 Peripheral focal irregular network                           Good outcome with a complete remission, and no             0.05
                                                              evolution after treatment
 Polygones                                                    Hot stroma Granzym B+                                      0,044
 Melanoma stage (AJCC 2018)
                                                              The extent of regression                                   0.01
                                                              Hot stroma CD8+                                            0.038
 Regression stage                                             Stage 2    local extension                                 0.030
                                                              Stage 3    melanoma specific death (at 2 years, 5          p=0.048/
                                                                         years of initial treatment)                     p=0.020
 Immunotherapy response                                       Hot stroma CD8 +                                           0.032

 Progression free survival                                    Regression extent                                          0.005
                                                              Hot stroma CD8+                                            0.044
 Melanoma specific death                                      Regression extent                                          0.000



    Focal regression was associated with good outcome (P <              infiltrate had interesting prognostic implications, as CD8+
0.001) and the immunotherapy response (P < 0.001), while                stromas were significantly associated with a good response to
complete and partial regression of histology were associated            immunotherapy, and to the disease free survival at 10 years,
with melanoma-related death (P < 0.001), regression stage 3             which confirms a study that has previously reported an asso-
of histology was associated with melanoma-related death at              ciation between CD8 T-cell infiltration and better prognosis
both 2 years (P = 0.048) and 5 years (P = 0.020) since initial          [14]. Also, “hot” Granzyme B+ stromas were associated with
treatment. “Hot” CD8+ stromas were associated with a good               locoregional extension and the initial distant metastasis, while
response to immunotherapy (P = 0.032), and with the survival            no prognostic implication of Langerin or PDL-1 expression
at 10 years (P = 0.044). Also, “hot” Granzyme B stromas   +             around the tumor and in the regression were found in the
were associated with locoregionnal extension (P = 0.016), and           present study. The prognostic value of PDL-1 is controversial,
initial distant metastasis (p=0.016) (Table 2).                         as some authors have failed to observe a correlation between
    The local extension (in transit metastasis) of these regressive     PDL-1 expression in sentinel lymph node metastases and the
melanomas was associated with the stage 2 of regression (P =            outcome (which is consistent with our results), while others
0.030), while locoregional extension and initially distant metas-       have reported PDL-1 as an independent negative prognostic
tasis were associated with WSA in dermoscopy (P = 0.041) and            marker in conventional melanoma, and, in contrast, others
with focal regression in histology (P = 0.008; Table 2).                have reported PDL-1 expression in mucosal melanomas as
                                                                        correlated with longer recurrence-free survival [18].
                                                                           A preoperatively comparison of various dermoscopic
Conclusions
                                                                        features of regressive melanoma at different stages of regres-
In the present study we were able to further characterize “hot”         sion was made, and the association between dermoscopy,
and “cold” stromas in the context of melanoma regression                pathology, and the prognostic implications of regression was
based on dermoscopic criterias and the inflammatory infil-              investigated. Peppering was found as significantly associated
trate status. Indeed, we found an association of many and spe-          with thin melanomas in histology, this refines knowledge
cific dermoscopic features with “hot” Granzyme B and “hot”
                                                      +
                                                                        about peppering that has been described as an expression
CD8+ stromas, or “cold” PDL1+ and “cold” Langerin+ stro-                of melanophages in the dermis [2], and has been signifi-
mas. This further characterization of the previous sub-clas-            cantly associated with BRAF mutation [2], confirming that
sification of “hot” and “cold” stromas in melanomas [17]                regression may be a hallmark of BRAFV600 melanomas. In
based on the immunopathology nature of the inflammatory                 addition, in primary melanomas, mutated BRAF has been



Original Article | Dermatol Pract Concept. 2022;12(1):e2022034                                                                        7
described as an adverse prognostic factor [20]. In the present       was therefore not possible to draw conclusions about the
study, even though BRAF mutation status was not found in             prognostic value of BRAF mutation in regressive melanomas.
many patient records because most had thin melanomas, it             However, even though this aspect would have been interest-
was significantly associated to rapidly growing melanomas,           ing to determine, and for future studies, it was not among
which were polychromatic, chaotic, or with a multicom-               our main objectives. Also, the small number of patients was
ponent pattern in dermoscopy, or with signs of horizontal            due to the retrospective collection of the records and to the
growth and local extension. As a result, BRAF mutation may           dermoscopic images themselves that were often not found
be a prognostic factor in regressive melanomas. Also, the            or of poor quality, leading to the exclusion of some patient.
dermoscopic extent of regression (WSA with peppering) was            Additionally, some patients were excluded after review by
significantly associated with regression stages in histology         experienced pathologists because regression was not objec-
and enabled us to evaluate the aggressiveness of the tumor,          tively observed.
since the results presented herein demonstrated an association          The present study provides a better characterization
between advanced stages of regressive melanomas and the              of regression in primary melanomas, and a better compre-
extent of regression, and between stage III melanoma and             hension of the “hot” or “cold” character of the stroma.
melanoma-related death. In addition, the presence of der-            An important outcome of the study is that regressing
moscopic signs associated with hot stromas CD8+ or Gran-             melanoma (early stages of regression) is associated with
zyme B + ( rRed milky areas, irregular thick reticular lines,        favorable outcome whereas regressed melanoma (complete
polygones, the peppering granules’ color, and the eccentric,         regression stage 3) is associated with a worse outcome.
multifocal character of regression), supports the idea that          Further studies with a prospective design could help in
further dermoscopic investigations of the regression in pri-         confirming and investigating these results, especially the
mary melanomas would be of great help in the pre-excision            importance of dermoscopy in predicting the immunophe-
therapeutic evaluation and predictable therapeutic response.         notypic host response, with the       ultimate goal to help in
    Reticular regression in a clinically less palpable area,         the pre-therapeutic definition of “hot” tumors that may
which has been recently reported [7,19], was frequent in             benefit of postoperative adjuvant immunotherapy, and
patients who had stage 2 of regression in thin melanomas.            “cold” tumors in which inclusion in potential neo-adjuvant
This type of regression may be correlated with the remain-           clinical trials could be proposed in priority before excision
ing junctional component and the heterogeneous dermal                of the primary tumor.
regression in stage 2 before the complete disappearance of
the dermal tumor.                                                    Acknowledgments
    Remarkably, MelanA red immunostaining could be a good            We are grateful to Hélène Boyer and Philip Robinson (Direc-
tool to confirm, characterize, and probably classify the histo-      tion de la Recherche Clinique et de l’Innovation, Hospices
logic regression, especially when histologic regression is not       Civils de Lyon) for their help to improve the manuscript.
so obvious. Despite contradictions in the literature, patients          We would like also to thank Garance Tondeur from the
with thin melanomas who show partial regression cannot be            research unity of the department of Dermatopathology for
included in the “low-risk” group if the extent of regression is      her help in obtaining consent from patients and in performing
more than 50% [16,21,22]. Completely regressive lesions repre-       the immunochemistry analysis.
sent a factor of delay in diagnosis, and of development of locore-
gional and distant metastasis, as it has been reported in some
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Original Article | Dermatol Pract Concept. 2022;12(1):e2022034                                                                                   9
