Table 5 Proposed immunohistopathological and molecular diagnostic criteria for classification of deep penetrating tumors based on the results of the current study and previous studies.^{6,7,8,9,11,13,14,15,19,20,21,23}.

Classification (WHO)

Low-grade intermediate (melanocytoma)

High-grade intermediate (melanocytoma)

Malignant (melanoma)

Dermal mitoses⁹

0-2 per mm²

Often > 2 per mm²

 < 2 per mm² does not exclude DPM

Often > 2 per mm²

 < 2 per mm² does not exclude MDPT

Cytonuclear atypia

Mild to moderate

Mild to moderate

Might be severe in some cases

Often severe

Mild to moderate atypia does not exclude MDPT

Severe inflammation

Can be present

Can be present

Usually present

Ki-67

< 5%

Mostly < 10%

< 5% does not exclude DPM

Mostly ≥ 10%

< 5% does not exclude MDPT

p16 expression¹⁸

Present

Present or partially lost

Expression does not exclude DPM

Absent or partially lost

Expression does not exclude MDPT

PRAME expression^13,19,20

Absent

Usually absent

Usually positive

β-catenin staining^8,14

Usually positive nuclear expression

Usually positive nuclear expression

Positive or negative nuclear expression

WNT pathway mutations^7,14,15,21

CTNNB1 (most frequent) or APC

CTNNB1 (most frequent) and/or APC

CTNNB1 and/or APC (more frequent than in DPN/DPM)

MAPK pathway mutations^6,7,14,15

BRAF (most frequent) or MAP2K1

BRAF (most frequent) or MAP2K1

BRAF (most frequent), MAP2K1, or NRAS (less frequent)

TERT-p mutation

Absent

Usually absent

Usually present

Additional mutations^6,7,14,15,22

Absent

IDH1^R132C, KIT, TP53

ARID1A, CDKN2A, GRIN2A,

IDH1 ^R132C, KIT, MECOM, NF1, PIK3CA, RBB4, TET2, TP53

CNVs^4,11,23

0-1 CNVs

1-2 CNVs

≥ 3 CNVs

< 3 CNVs does not exclude MDPT

Molecular aberrations^4,6,11,23

Absent

Heterozygous loss of 9p21 (CDKN2A)

−9p21; homo- or heterozygous loss (CDKN2A), +1q, +6p (RREB1), +11q13 (CCND1) −5q22.2 (APC), −6q (MYB), −9q