10.5826/dpc.1401a28
Introduction: Pigmentation of lip and/or genitalia is mainly due to the development of benign melanotic macules, with a less occurrence of melanocytic and other non-melanocytic lesions. Mucosal melanoma has worse prognosis compared with cutaneous counterpart, hence identification of atypical features for an early diagnosis is crucial.
Objectives: The aim of this study was to report further data of confocal features characterizing pigmented mucosal lesions of genital area and of the lips and test the diagnostic role of the reflectance confocal microscopy (RCM)lip score.
Methods: Clinical, dermoscopic and RCM images of histologically proven pigmented lesions, involving the genital area (vulva or glans penis) and lip, were retrospectively reviewed. RCM images were evaluated for malignant criteria, and statistical analysis was conducted for categorical variables.
Results: Seventy pigmented lesions were included in the study and divided into two groups based on the body area location: lip (17) and genital area (53). Architectural disarray (P = 0.002), dendritic (P = 0.031) and roundish cells in epidermis (P &lt; 0.0001), interpapillary dendritic cells (P = 0.039) and junctional atypical cells (P = 0.002) were associated to genital melanoma. Melanoma involving the lip was characterized by roundish cells in epidermis, a criterion found in one labial benign lesion, only (P = 0.005). Main limitations of the study are the inclusion of low melanomas and the presence of epidermal dendritic cells in melanosis and melanoma, as a confusing factor in imaging.
Conclusions: Dermatologists should consider confocal microscopy as an adjunctive tool to dermoscopy in the differential diagnosis of pigmented mucosal lesions, especially in presence of clinical and dermoscopic findings suspicious for malignancy.
text/xml
2160-9381
3524
en
Ketty Peris
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
skin neoplasms
Confocal Assessment of Pigmented-Mucosal Lesions: A Monocentric, Retrospective Evaluation of Lip and Genital Area 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2024-01-31
2023-05-10
2024-01-31
2024-03-29
e2024028
Dermatol Pract Concept
Introduction: Pigmentation of lip and/or genitalia is mainly due to the development of benign melanotic macules, with a less occurrence of melanocytic and other non-melanocytic lesions. Mucosal melanoma has worse prognosis compared with cutaneous counterpart, hence identification of atypical features for an early diagnosis is crucial.
Objectives: The aim of this study was to report further data of confocal features characterizing pigmented mucosal lesions of genital area and of the lips and test the diagnostic role of the reflectance confocal microscopy (RCM)lip score.
Methods: Clinical, dermoscopic and RCM images of histologically proven pigmented lesions, involving the genital area (vulva or glans penis) and lip, were retrospectively reviewed. RCM images were evaluated for malignant criteria, and statistical analysis was conducted for categorical variables.
Results: Seventy pigmented lesions were included in the study and divided into two groups based on the body area location: lip (17) and genital area (53). Architectural disarray (P = 0.002), dendritic (P = 0.031) and roundish cells in epidermis (P &lt; 0.0001), interpapillary dendritic cells (P = 0.039) and junctional atypical cells (P = 0.002) were associated to genital melanoma. Melanoma involving the lip was characterized by roundish cells in epidermis, a criterion found in one labial benign lesion, only (P = 0.005). Main limitations of the study are the inclusion of low melanomas and the presence of epidermal dendritic cells in melanosis and melanoma, as a confusing factor in imaging.
Conclusions: Dermatologists should consider confocal microscopy as an adjunctive tool to dermoscopy in the differential diagnosis of pigmented mucosal lesions, especially in presence of clinical and dermoscopic findings suspicious for malignancy.
Ketty Peris
2024/01/31
10.5826/dpc.1401a28
e2024028
UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli – IRCCS; Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
2160-9381
skin neoplasms
en
e2024028
Navarrete-Dechent C, Uribe P, Rabinovitz H, Abarzua-Araya A, Kittler H. Basal Cell Carcinomas Presenting as Flat Pigmented Macules on the Face Mimicking Lentigo Maligna on Dermoscopy: A Case Series. Dermatol Pract Concept. 2023;13(1):e2023038. DOI: 10.5826/dpc.1301a38. PMID: 36892346. PMCID: PMC9946124.
Confocal Assessment of Pigmented-Mucosal Lesions: A Monocentric, Retrospective Evaluation of Lip and Genital Area 
https://dpcj.org/index.php/dpc/article/download/3524/2427
     Confocal Assessment of Pigmented-Mucosal
   Lesions: A Monocentric, Retrospective Evaluation
               of Lip and Genital Area
           Valeria Coco1, Simone Cappilli1,2, Alessandro Di Stefani1,2, Costantino Ricci3,4,
                Francesca Perino1, Lucia Di Nardo1, Caterina Longo5,6, Ketty Peris1,2


1 UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli – IRCCS,
  Rome, Italy
2 Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
3 Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy
4 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi University Hospital, University of Bologna,
  Bologna, Italy
5 Centro Oncologico ad Alta Tecnologia Diagnostica, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
6 Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy



Key words: diagnostic imaging, clinical dermatology, reflectance confocal microscopy, malignant melanoma, skin neoplasms
Citation: Coco V, Cappilli S, Di Stefani A, et al. Confocal Assessment of Pigmented-Mucosal Lesions: A Monocentric, Retrospective
Evaluation of Lip and Genital Area. Dermatol Pract Concept. 2024;14(1):e2024028. DOI: https://doi.org/10.5826/dpc.1401a28
Accepted: July 26, 2023; Published: January 2024
Copyright: ©2024 Coco 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: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Simone Cappilli, MD, PhD candidate, UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche,
Fondazione Policlinico Universitario A. Gemelli - IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy Tel: +39 06-30154227 - Fax: +39
06-30154919 Email: simo.cappilli@gmail.com




  ABSTRACT             Introduction: Pigmentation of lip and/or genitalia is mainly due to the development of benign
                       ­melanotic macules, with a less occurrence of melanocytic and other non-melanocytic lesions. Mucosal
                        melanoma has worse prognosis compared with cutaneous counterpart, hence identification of atypical
                        features for an early diagnosis is crucial.
                       Objectives: The aim of this study was to report further data of confocal features characterizing
                       ­pigmented mucosal lesions of genital area and of the lips and test the diagnostic role of the reflectance
                        confocal microscopy (RCM)lip score.
                       Methods: Clinical, dermoscopic and RCM images of histologically proven pigmented lesions, involv-
                       ing the genital area (vulva or glans penis) and lip, were retrospectively reviewed. RCM images were
                       evaluated for malignant criteria, and statistical analysis was conducted for categorical variables.




Original Article | Dermatol Pract Concept. 2024;14(1):e2024028                                                                           1
                     Results: Seventy pigmented lesions were included in the study and divided into two groups based on
                     the body area location: lip (17) and genital area (53). Architectural disarray (P = 0.002), dendritic
                     (P = 0.031) and roundish cells in epidermis (P < 0.0001), interpapillary dendritic cells (P = 0.039) and
                     junctional atypical cells (P = 0.002) were associated to genital melanoma. Melanoma involving the lip
                     was characterized by roundish cells in epidermis, a criterion found in one labial benign lesion, only
                     (P = 0.005). Main limitations of the study are the inclusion of low melanomas and the presence of
                     epidermal dendritic cells in melanosis and melanoma, as a confusing factor in imaging.
                     Conclusions: Dermatologists should consider confocal microscopy as an adjunctive tool to dermos-
                     copy in the differential diagnosis of pigmented mucosal lesions, especially in presence of clinical and
                     dermoscopic findings suspicious for malignancy.




Introduction                                                     A. Gemelli-IRCCS, Rome, within 24 months (March
                                                                 2016-February 2018) were retrospectively reviewed. Demo-
Pigmentation of lip and/or genitalia is mainly due to the        graphic characteristics (patient age, gender, body site) were
development of benign melanotic macules (also called mel-        recorded, and clinical, dermoscopic and RCM images were
anoses or mucosal pigmented macules), with a less occur-         acquired with digital imaging system (Dermaview DUAL,
rence of melanocytic lesions (naevi and melanoma) and            Tre T Medical snc, Cicciano, Italy; VivaScope® 1500, Cal-
other non-melanocytic lesions (non-melanoma skin cancers,        iber Inc). RCM mosaics (VivaBlock®, horizontal sections
inflammatory conditions, infective diseases, or foreign-body     of 8x8 mm) were taken at the level of epidermis, epithelial-
pigmentations) [1,2]. Mucosal melanoma has worse progno-         chorion junction (ECJ), and upper chorion, with VivaS-
sis compared with cutaneous melanoma and lacks effective         tack® (frames taken at incremental depths from epidermis
treatment options, hence identification of atypical features     to superficial chorion) acquired in areas of special interest.
for an early diagnosis is crucial. Dermoscopy has improved       Two investigators (V.C., F.P.) jointly reviewed RCM images
diagnostic accuracy of pigmented mucosal lesions (PMLs),         blinded for histopathological diagnosis, evaluating RCM fea-
indicating multiple colors and structureless areas as strong     tures based on previously described criteria [1,8,9]. In case
indicators for malignancy [3,4], supported more recently, by     of disagreement, a third experienced dermatologist (A.D.S.)
reflectance confocal microscopy (RCM) in the identification      was consulted to reach a consensus. Additionally, the RCM
of features more associated to mucosal melanoma, like atyp-      lip score proposed by Uribe et al was considered in the eval-
ical pattern of the epithelium, pagetoid cells and disarranged   uation of pigmented lip lesions [9]. The patients have given
papillae [2,5-9]. Recently, Uribe et al proposed a RCM lip       written informed consent for their case details. All data were
score that can assist in the differential diagnosis of mela-     de-identified before use.
notic macules and melanoma of the lip. Given the rarity of
mucosal melanoma only 23 cases including genital and lip         Statistical Analysis
area, have been investigated using RCM, and incisional bi-       Statistical analysis was performed using specific software
opsy or surgical excision is still recommended for equivocal     (SAS Analytics software) and a descriptive evaluation for
lesions [4].                                                     categorical variables, expressed as the absolute number of
                                                                 cases and percentage values, was conducted. Dowling-Degos
Objectives                                                       disease was not included in the analysis due to the presence
                                                                 of peculiar and distinct RCM features. Fisher exact test was
The aim of this study was to report further data of confocal     used for the comparison of different confocal parameters
features characterizing PMLs of genital area and of the lips,    between malignant and benign lesions and their association
and test the diagnostic role of the RCM lip score.               with histological diagnosis. P value less than 0.05 was con-
                                                                 sidered as statistically significant.

Methods
Clinical and Imaging Data
                                                                 Results
A consecutive series of histologically proven PMLs, involv-      Seventy PMLs in 68 patients (52 [76.5%] females; mean
ing the genital area (vulva or glans penis) and lip, collected   age 76.5 [13-78] years) were included in the study and di-
at Dermatology Unit, Fondazione Policlinico Universitario        vided into two groups based on the body area location: lip



2                                                                    Original Article | Dermatol Pract Concept. 2024;14(1):e2024028
(17 pigmented lip lesions, PLLs) and genital area (53 pig-       inter-papillary dendritic cells (100% and 75% respectively)
mented genital lesions, PGLs).                                   (Figure 2). In dysplastic nevi, RCM revealed a regular hon-
                                                                 eycomb pattern in more than half-cases (66%) with sparse
Pigmented Genital Lesions                                        dendritic and roundish cells in 33% of cases. DEJ pattern
Fifty-three PGLs (38/53, 74% in women) were evaluated: 29        was heterogeneous showing the simultaneous presence of
melanoses, 18 melanocytic nevi, 3 seborrheic keratoses (SK),     draped and meshwork pattern, or nonspecific pattern. Me-
2 mucosal melanomas, 1 Dowling–Degos disease. Architec-          lanocytic nests were seen in the superficial chorion (100%).
tural disarray (P = 0.002), presence of dendritic (P = 0.031)       RCM of pSK showed epidermal bulbous projections
and roundish pagetoid cells in the epidermis (P < 0.0001),       and keratin-filled invaginations with plump bright cells and
interpapillary dendritic cells (P = 0.039) and atypical cells    bright horn cysts. Ring pattern edged-papillae character-
at the DEJ (P = 0.002) were associated to genital melanoma       ized ECJ.
(Table 1).                                                          Dowling Degos disease exhibited a honeycomb pattern
    Melanosis occurred on labia minora (15/22, 68%)              in epidermis, junctional ring pattern or elongated and thick
and labia majora (7/22, 32%) in women while involved             cord-like structures, corresponding to irregular, filiform epi-
glans penis (3/7, 43%), foreskin of the glans (2/7, 29%)         dermal elongation downward into the upper dermis. Keratin
or skin (2/7, 29%) in men. Three melanoses had a multi-          cysts were also seen.
focal distribution, and 2 melanoses were associated to li-
chen sclerosus. With RCM, melanoses displayed a regular          Pigmented Labial Lesions
honeycomb pattern with sparse dendritic cells in 21% of          Seventeen pigmented labial lesions (PLLs) (14/17, 82% in
cases. Ringed pattern and draped pattern with homoge-            women) were included in the study: 8 melanoses, 3 basal
neous distribution of papillae represented the main fea-         cell carcinomas (BCCs), 2 actinic keratoses (AKs), 1 naevus,
tures at epidermal-chorion junction (ECJ) (76% and 55%),         1 atypical nevus, 1 mucosal melanoma, 1 pSK. Although a
along with dendritic cells around papillae (41%), mainly         single melanoma involved the lip, this malignant lesion was
exhibiting a fusiform shape (79%). Junctional atypical           characterized by the presence of roundish cells in epidermis,
cells were seen in 14% lesions (14%) (Figure 1). Melanosis       a criterion found in one labial benign lesion, only (melano-
was associated to lichen sclerosus in two patients, reveal-      sis) (P = 0.005) (Table 2).
ing in imaging non-specific pattern at epidermal-chorion            Melanoses mainly occurred on the lower lip and showed
junction and an inflammatory infiltrate with a prominent         disarranged honeycomb pattern (7/8, 88%) with dendritic
vascularization.                                                 cells in half cases (4/8, 50%); DEJ was mainly character-
    Mucosal melanoma was localized on labia minora in a          ized by a draped pattern (5/8, 63%) and ringed pattern (4/8,
21-year-old girl and on the glans penis in a 36-year-old man     50%) with papillae homogeneously distributed (6/8, 75%);
(Figures 1 and 2). RCM images showed honeycomb pattern           dendritic cells had a prevalent peri-papillary distribution
with epidermal disarray and a widespread infiltration of         (6/8, 75%) (Figure 3); plump bright cells were seen in 5/8
pagetoid roundish and dendritic cells (>10 cells/mm2). At the    cases (63%) in papillary dermis.
ECJ a meshwork and ringed pattern co-existed, with atypi-           Melanoma was localized on the lower lip and RCM re-
cal peri- and inter-papillary dendritic cells (>10 cells/mm2).   vealed a broadened honeycomb pattern with dendritic and
Junctional atypical cells (5-10 cells/mm2 and >10 cells/mm2)     roundish cells (<5 cells/mm2) in epidermis. DEJ was char-
were detected in both cases along with melanocytic nests in      acterized by non-edged draped pattern, peri-papillary and
the chorion.                                                     inter-papillary dendritic cells (5-10 cell per mm2), showing
    Melanocytic lesions included 6/18 (33%) compound             stellate or fusiform shape (Figure 3).
nevi, 5/18 (28%) intradermal nevi, 4/18 (22%) AGN and               Compound naevus was found on the upper lip and
3/18 (17%) dysplastic nevi. Compound nevi were charac-           showed on RCM a regular honeycomb pattern in epidermis,
terized by regular honeycomb pattern and a prevalent ring        non-edged ringed pattern at DEJ and dermal melanocytic
pattern (66%) at ECJ. Melanocytic nests in superficial cho-      nests. Atypical nevus was located on the lower lip and nu-
rion were observed in all lesions. Intradermal nevi showed       merous cyto-architectural atypia were seen on RCM: dis-
a regular honeycomb pattern in the epidermis with a pre-         arranged honeycomb pattern with dendritic cells (>10 per
dominance of nonedged, ringed or meshwork pattern at             mm2) in epidermis, nonspecific pattern at DEJ, numerous
ECJ (75%), and melanocytic nests in superficial chorion.         peri- and inter-papillary dendritic cells (>10 per mm2). Me-
AGN mostly revealed honeycomb pattern with epidermal             lanocytic nests and plump bright cells were observed in pap-
disarray and a sparse or widespread pagetoid infiltration        illary dermis.
in superficial layers (75%). Meshwork pattern represented           BCCs were clearly detected by the presence of bright tu-
the prevalent criterion (75%) at ECJ, along with peri- and       mor islands and peri-tumoral vessels in papillary dermis.



Original Article | Dermatol Pract Concept. 2024;14(1):e2024028                                                                3
                  Table 1. Comparison between benign and malignant pigmented genital lesions.
                                Benign                                                                   Benign
                             pigmented Malignant                                                      pigmented Malignant
                               lesions1 lesions2                                                        lesions1 lesions2
                                (n=50)          (n=2)       P Value                                      (n=50)          (n=2)       P Value
Sex                                                                          Draped Pattern          19/50 (38.0)      1/2(50.0)      0.732
    F n (%)                  38/50 (76.0)     1/2 (50.0)     0.405           Meshwork Pattern         5/50 (10.0)      1/2(50.0)      0.083
    M n (%)                  12/50 (24.0)     1/2 (50.0)                     Clod Pattern              3/50 (6.0)      0/2 (0.0)      0.721
Age (years)                   44.3(17.6)     28.6 (10.3)     0.219          Nonspecific Pattern       4/50 (8.0)      1/2(50.0)      0.048
[Mean(±SD)]                                                                Distribution of papillae
Localization                                                                 Homogeneously           36/50 (72.0)      1/2(50.0)      0.501
    Women                                                                    Nonhomogeneously 14/50 (28.0)            1/2 (50.0)
     Labia majora                14/50            0/2         >.99         Papillae
     Labia minora                24/50            1/2         >.99           Edged papillae          33/50 (66.0)      1/2(50.0)      0.578
    Men                                                                      Nonedged papillae       15/50 (30.0)      1/2(50.0)
     Glans                       7/50          1/ (50.0)      >.99           Mixed                     2/50 (4.0)      0/2 (0.0)
     Foreskin                    2/50             0/1         >.99         Presence of               20/50 (40.0) 2/2(100.0)          0.092
     Penis                       2/50             0/1         >.99         peripapillary
     Pubis                       2/50             0/1         >.99         dendritic cells
Architectural Pattern                                                        Density of cells
    Honeycomb n (%)          49/50 (98.0) 2/2 (100.0)        0.959            <5 cells/mm2            7/20 (35.0)      0/2 (0.0)      0.204
                                                                                              2
    Cobblestone n (%)         1/50 (2.0)       0/2 (0.0)                      5-10 cells/mm           6/20 (30.0)      0/2 (0.0)
Epidermal Disarray                                           0.002            >10 cells/mm2           7/20 (35.0)     2/2 (100.0)
    No n (%)                 43/50 (86.0)      0/2 (0.0)                   Presence of               15/50 (30.0) 2/2 (100.0)         0.039
                                                                           interpapillary
    Yes n (%)                 7/50 (14.0)    2/2(100.0)
                                                                           dendritic cells
Broadened HP                                                 0.166
                                                                             Density of cells
    No n (%)                 43/50 (86.0)     1/2 (50.0)
                                                                              <5 cells/mm2            6/15 (40.0)      0/2 (0.0)      0.365
    Yes n (%)                 7/50 (14.0)     1/2 (50.0)
                                                                              5-10 cells/mm2          2/15 (13.3)      0/2 (0.0)
Presence of dendritic 14/50 (28.0) 2/2 (100.0)               0.031
                                                                              >10 cells/mm2           7/15 (46.7)      2/2 (100)
cells in the epidermis
n (%)                                                                      Morphology of             22/50 (44.0) 2/2 (100.0)
                                                                           dendritic cells§
    Density of cells
                                                                           [tot. obs. (%)]
     <5 cells/mm2 n (%) 5/14 (35.7)            0/2 (0.0)     0.230
                                                                             fusiform                17/22 (77.3) 2/2 (100.0)         0.449
                     2
 5-10 cells/mm               4/14 (28.6)      0/2 (0.0)
                                                                             stellate                 7/22 (31.8)     1/2 (50.0)      0.602
  n (%)
                                                                             triangular               7/22 (31.8)     1/2 (50.0)      0.602
 >10 cells/mm2               5/14 (35.7)    2/2 (100.0)
  n (%)                                                                    Presence of atypical       7/50 (14.0)     2/2 (100.0)     0.002
                                                                           cells at DEJ
Distribution of cell         12/50 (24.0)     2/50 (4.0)
[tot. obs. (%)]                                                              Density of cells
    Localized n (%)           4/12(33.3)       0/0(0.0)      0.014            <5 cells/mm2             2/7 (28.6)      0/5(0,0)       0.669
                                                                                              2
    Sparse n (%)              7/12(58.3)       0/0(0.0)                       5-10 cells/mm            3/7 (42.99      ½(50.0)
                                                                                              2
    Widespread n (%)           1/12(8.3)     2/28(100.0)                      >10 cells/mm             2/7 (28.6)      ½(50.0)
Roundish cells in             4/50 (8.0)     2/2 (100.0) <0.0001           Papillary dermis
epidermis                                                                  Papillary nests           18/50 (36.0)      2/2(100)       0.068
DEJ                                                                        Tumor Islands               0/50 (0.0)     0/50 (0.0)
DEJ architecture§                                                          Vessels visible            5/50 (10.0)      0/2 (0.0)      0.638
    Ringed Pattern           32/50 (64.0) 2/2 (100.0)        0.294         Plump bright cells        14/50 (28.0)      0/2 (0.0)      0.381
1
    Benign pigmented lesions: melanosis, atypical melanocytic lesion, naevus, pigmented seborrheic keratosis, atypical nevus of genital type
2
    Malignant lesions: melanoma




4                                                                               Original Article | Dermatol Pract Concept. 2024;14(1):e2024028
Figure 1. (A-D) Melanosis of a 45-year-old woman and (E-H) invasive melanoma (Breslow tumor thickness, 0,2 mm) of a 30-year-old
woman: (A) Multiple pigmented macules in the labia minora, exhibiting with dermoscopy (B) parallel lines, clods and brown color, and (C)
with RCM focal dendritic cells in epidermis (yellow circle); (D) Histopathology features of increased basal keratinocyte pigmentation mostly
restricted to tips of rete ridges, mild increase in the number of melanocytes (no cytologic atypia and/or nests) at dermo-epidermal junction,
melanin pigment incontinence and melanophages in the upper chorion/lamina propria (H&E stain, original magnification × 200); (E) Asym-
metric pigmented macule of the skin adjacent to the clitoris (F) showing structureless pattern, circles, and multiple colors with dermoscopy;
(G) Confocal revealing junctional non-specific pattern with numerous atypical cells (yellow circle) and melanocytic nests (red arrows); (H)
histopathology section exhibiting a radial proliferation of atypical melanocytes at epidermal basal layer and upper lamina propria with focal
pagetoid spread (H&E stain, original magnification × 150).




Figure 2. (A-D) In situ melanoma of a 40-years-old man and (E-H) atypical melanocytic nevus of genital type of a 15-year-old woman:
(A) brown irregular macule on the glans penis (B) exhibiting reticular lines and circles with dermoscopy; (C) Confocal unveils inter- and
peri-papillary atypia with sheets of atypical cells at the epithelial-chorion junction (yellow arrow); (D) Histopathology showing a radial pro-
liferation of contiguous, mildly atypical melanocytes at the basal layer of epidermis, with focal pagetoid spread in the supra-basal layer (H&E
stain, original magnification × 200); (E) Dark pigmented irregular macule on labia majora displaying (F) globules and clods, reticular lines
and brown color on dermoscopy; (G) confocal image of pagetoid spreading with dendritic and roundish cells in epidermis (yellow circles),
with (H) histology showing irregularly shaped and sized nests, large and roundish, with bizarre balloon or cannonball appearance (H&E
stain, original magnification × 200).




Original Article | Dermatol Pract Concept. 2024;14(1):e2024028                                                                               5
                  Table 2. Comparison between benign and malignant pigmented labial lesions.
                                 Benign                                                                 Benign
                              pigmented Malignant                                                    pigmented Malignant
                                lesions1 lesions2                                                      lesions1 lesions2
                                 (n=16)         (n=1)      P Value                                      (n=16)         (n=1)      P Value
Sex                                                                          Nonhomogeneously 6/16 (37.5)            0/1 (0.0)
                                                                                   §
     F                       13/16 (81.3) 1/1 (100.0)       0.633         Papillae                   15/16 (93.7) 1/1 (100.0)
     M                         3/16(18.7)       - (0.0)                   [tot. Obs(%)]
Mean Age (years)              50.0 (19.0)         42                         Edged papillae          4/15 (26.7)     0/1 (0.0)     0.587
Localization                                                               Nonedged                 7/15 (46.6) 1/1 (100.0)
                                                                            papillae
     Upper lip                5/16 (31.3)     0/1 (0.0)     0.801
                                                                             Nonvisible papillae     4/15 (26.7)     0/1 (0.0)
     Lower lip               11/16 (68.7) 1/1 (100.0)
                                                                          Presence of                9/16 (56.2) 1/1 (100.0)       0.388
Epidermis
                                                                          Peripapillary
Architectural pattern                                                     dendritic cells
     Honeycomb               15/16 (93.7) 1/1 (100.0)       0.797         Presence of                5/16 (31.2) 1/1 (100.0)       0.163
     Cobblestone               1/16 (6.3)     0/1 (0.0)                   Interpapillary
Epidermal Disarray            6/16 (37.5)     0/1 (0.0)     0.446         dendritic cells
Broadened HP                  8/16 (50.0) 1/1 (100.0)       0.331         Morphology of              9/16 (56.2) 1/1 (100.0)
                                                                          dendritic cells§
Presence of Dendritic         6/16 (37.5) 1/1 (100.0)       0.218
                                                                          [tot. Obs (%)]
cells in the epidermis
                                                                             fusiform                     8/9       1/1 (100.0)    0.998
Roundish cells in              1/16 (6.3)    1/1 (100.0)    0.005
epidermis                                                                    stellate                     3/9       1/1(100.0)
DEJ                                                                          triangular                   3/9        0/1(0.0)
DEJ architecture             15/16 (93.7) 1/1 (100.0)                     Presence of atypical        2/16(12.5)     0/1 (0.0)     0.707
[tot. Obs(%)]                                                             cells at DEJ
     Ringed Pattern            6/15(40.0)     0/1 (0.0)     0.309         Papillary dermis
     Draped Pattern           4/15 (26.7)    1/1(100.0)                   Papillary nests            2/16 (12.5)     0/1 (0.0)     0.707
 Nonspecific Pattern         5/15 (33.3)     0/1 (0.0)                   Tumor Islands              3/16 (18.7)     0/1 (0.0)     0.633
Distribution of papillae                                                  Vessels visible            6/16 (37.5)     0/1 (0.0)     0.446
     Homogeneously            10/16(62.5) 1/1 (100.0)       0.446         Plump bright cells         10/16 (62.5)    0/1 (0.0)     0.218

1
    Benign pigmented lesions: melanosis, naevi, atypical melanocytic naevus, pigmented seborrheic keratosis
2
    Malignant lesions: melanoma



      AKs disclosed disarranged honeycomb pattern and den-               junctional atypia was statistically associated to a diagnosis
dritic cells in epidermis; nonspecific pattern was observed at           of mucosal melanoma, supporting results of a recent review
DEJ with peri- and inter-papillary dendritic cells.                      that identified pagetoid large cells, high density of basal den-
      Images of SK revealed a regular honeycomb pattern with             dritic cells and loss of chorion normal architecture as the
bulbous projections and invaginations in epidermis, plump                major features of mucosal melanoma [10].
bright cells at DEJ and in the upper dermis.                                 In our series, dendritic cells in epidermis were detected
                                                                         in mucosal melanoma and in considerable proportion of

Conclusions                                                              melanoses (6/29, 21%), potentially representing a confound-
                                                                         ing factor and a major problem for differential diagnosis.
Diagnosis of PMLs may be challenging with clinical/dermo-                Lamier et al defined “irregular dendritic type”, a subtype of
scopic examination alone [4,5]. Melanosis is the most fre-               melanoses showing RCM overlapping features with mucosal
quent cause of mucosal pigmentation, although a skin cancer,             melanoma: epidermal atypical cells, junctional atypia and
an inflammatory condition, foreign-body pigmentation and                 focal loss of regular architecture. In presence of epidermal
pigmented cicatricial scar may rarely occur in clinical setting          atypia, the density of dendritic cells may represent an im-
[1,2]. In this study 70 PMLs were assessed based on a large              portant clue, since ≥10 cells/mm2 are more suggestive of mu-
series of RCM criteria. Epidermal disarray, pagetoid cells,              cosal melanoma [8,10]. Roundish cells at DEJ, seen in 4/29




6                                                                             Original Article | Dermatol Pract Concept. 2024;14(1):e2024028
Figure 3. (A-D) Melanosis of a 16-year-old man and invasive melanoma (Breslow tumor thickness, 0,2 mm) of a 42-year-old woman: (A)
pigmented macule on the lower lip (B) with structureless pattern, parallel lines and brown color on dermoscopy; (C) Confocal images of the
junction displaying draped pattern edged-papillae with papillary small bright cells (red arrows), (D) histologic section showing increased
basal keratinocyte pigmentation and a mild increase of non-atypical melanocytes at the dermo-epidermal junction (H&E stain, original mag-
nification × 200); (E) Brownish macule on the lower lip with (F) dermoscopic features of brown structureless areas (G) confocal findings of
non-edged papillae, atypical cells at the junction (yellow circle); (H) Histopathology section exhibiting a proliferation of atypical melanocytes
at epidermal basal layer and upper lamina propria with focal pagetoid spread (H&E stain, original magnification × 200).




melanoses (14%), are generally also detected in lentiginous                   Results from PLLs revealed roundish cells in epidermis as
pattern of in situ mucosal melanoma, originating from an                  the unique criterion significantly associated with melanoma
atypical melanocytic hyperplasia ie the so-called “intraepi-              (P = 0.005). Calculating the RCM lip score of Uribe et al, it
dermal atypical melanocytic proliferation of uncertain sig-               was ≥ 4 in atypical/malignant lesions and lower in benign le-
nificance (IAMPUS)” [11]. Following a continuous model,                   sion, providing further evidence of its utility, as already sug-
in its early phase, melanoma may show minimal cytological                 gested by Gomez-Martin et al, evaluating 51 PLLs, of which
atypia without clear architectural disarrangement, mimick-                5 mucosal melanomas [1]. In our series 2/8 melanoses (25%)
ing a melanosis. Thus, RCM can be useful in the monitoring                were considered false positives obtaining a LIP score ≥ 4, due
of atypical PMLs over time detecting minimal worrisome                    to disarray and dendritic cells in epidermis and junctional
changing.                                                                 atypical cells. Such discrepance could be related to the pres-
    AGN represent a subset of benign nevi occurring in                    ence of epidermal inflammation, as confirmed by histopa-
young adults that show worrisome clinical features such as                thology revealing numerous Langerhans cells in suprabasal
dark pigmentation, irregular borders and large size, and sus-             layers [1,9].
picious dermoscopic findings, like mixed pattern and mul-                     Diagnosis of benign (SK, AK) and malignant (BCC) ke-
tiple colors [4,12]. Herein, AGN were found in young girls                ratinocyte skin lesions was simplified by the recognition of
(14-18-years-old) exhibiting clinical features of dark brown              common confocal criteria [15-17].
color, fast growth and large size (>1cm in diameter). RCM                     Main limitation of the study is the inclusion of only 3
was not useful for their correct recognition due to relevant              cases of mucosal melanoma, of which 1 melanoma of the
cyto-architectural irregularities, leading therefore to surgical          lip, probably related to rarity of this entity in clinical setting.
excision. It is noteworthy that diagnosis of AGN is also chal-            Additionally, the detection in RCM of dendritic bright cells
lenging with histopathology, because of the presence of ar-               in the epithelium of melanosis and melanoma, may represent
chitectural disorder, nested pattern and pagetoid spreading,              a confusing factor for diagnosis, although density, shape and
with various degree of cellular atypia [12].                              location of this cells may add important clues.
    Pigmentary changes following inflammatory conditions,                     Dermatologists should consider confocal microscopy
like occurring with lichen sclerosus, may be a cause of con-              as an adjunctive technique to dermoscopy, for the differen-
cern often requiring histopathological examination [13,14].               tial diagnosis of PMLs showing clinical and dermoscopic
Confocal displayed classical features of melanosis in our two             findings suspicious for malignancy, and for long-term sur-
cases, leading to a conservative approach.                                veillance of atypical melanocytic lesions. Anyhow, PMLs




Original Article | Dermatol Pract Concept. 2024;14(1):e2024028                                                                                 7
showing overlapping features with melanoma should un-                      9. Uribe P, Collgros H, Scolyer RA, Menzies SW, Guitera P. In
dergo to incisional biopsy or surgical excision for not to miss               vivo reflectance confocal microscopy for the diagnosis of mel-
                                                                              anoma and melanotic macules of the lip. JAMA Dermatol.
an early diagnosis of malignancy.
                                                                              2017;153(9):882-891. DOI: 10.1001/jamadermatol.2017.0504.
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