NTRK2-fused Spitz neoplasms are rare. In one case report of an
NTRK2-fused Spitz nevus, the morphologic features were those of a pigmented spindle cell nevus with essentially large junctional nests of spindled pigmented melanocytes with an abundant eosinophilic cytoplasm, no nuclear atypia and associated hyperplastic epidermis and Kamino bodies
[58][28].
2.5. MET-Fused Spitz Tumors
MET is a proto-oncogene found on chromosome 7q that synthesizes a receptor tyrosine kinase that activates MAPK, PI3K-AKT, PLCγ1, β-catenin, and STAT pathways to promote cell proliferation and motility
[62][31]. The number of cases of MET-fused Spitz neoplasms in the literature is limited; however, all the cases reported thus far harbored a breakpoint in intron 14 of the
MET gene, which contains the regulatory domain of the Met protein and is located upstream of the kinase domain, which is preserved in the fusion protein
[63][32].
2.6. RET-Fused Spitz Tumors
RET is a proto-oncogene that resides on chromosome 10q and encodes a receptor tyrosine kinase that can activate MAPK, PI3K-AKT, and PLCγ1 signaling pathways, thereby regulating cell growth and differentiation
[64,65][33][34].
RET fusions with several partner genes have been reported in a minor subset of Spitz melanocytic neoplasms
[13,14][19][35]. Spitz neoplasms with RET fusions are not currently associated with specific morphological features. The reported cases are often well-circumscribed, symmetric, plaque-like compound proliferations containing large expansile discohesive nests of small to intermediate-sized, monotonous, epithelioid melanocytes with mild to moderate cytologic atypia
[13,14][19][35].
2.7. BRAF-Fused Spitz Tumors
Spitz neoplasms with serine/threonine kinase fusions or mutations are a subtype of tumors characterized by worrisome histologic features, higher grade cytologic atypia and a greater likelihood of being classified as atypical Spitz tumor (AST) or malignant Spitz tumor (MST)
[4,9,15,16,17,18,63,66,67][14][25][32][36][37][38][39][40][41].
BRAF is a proto-oncogene located on chromosome 7q that encodes Braf protein, a member of the Raf family of serine/threonine protein kinases, which signals through the MAK kinase pathway to regulate cell proliferation and cell growth
[68,69][42][43].
Clinically, Spitz neoplasms with
BRAF fusions most commonly present in young females as pink papules on the extremities
[16][37]. Morphologically, these lesions can be compound or intradermal with variable plaque-like, wedge-shaped, or nodular configurations and are mostly composed of large epithelioid melanocytes with an abundant amphophilic cytoplasm, vesicular pleomorphic nuclei and prominent nucleoli
[4,9,15,16,17,18][14][25][36][37][38][39]. Cytologic atypia is frequently moderate to severe, and high mitotic activity is usually evident
[4,9,15,16,17,18][14][25][36][37][38][39].
2.8. MAP3K8-Mutated Spitz Tumors
The mitogen-activated protein kinase kinase kinase 8 (
MAP3K8) gene is located on chromosome 10p. It encodes a serine/threonine and tyrosine kinase that is primarily expressed by the immune system and is activated by TNF-alpha, IL1R, and toll-like receptors to promote signaling through activation of the RAF-MEK1/2-ERK1/2 pathway
[71,72,73][44][45][46].
Clinically,
MAP3K8-fused Spitz neoplasms usually present as pigmented exophytic lesions on the lower extremities of patients of all ages, with a slight female predilection
[20,22][47][48]. Morphologically, most of these lesions are nodular or dome-shaped, asymmetric with overlying epidermal hyperplasia, and show a compound melanocytic proliferation with a predominantly nested junctional component
[7,9,19,20,21,22,23][17][25][47][48][49][50][51]. Melanocytes are invariably epithelioid with large, uniform nuclei, prominent nucleoli and an abundant eosinophilic cytoplasm
[7,20,23][17][47][51].
2.9. MAP2K1 Mutated Spitz Tumors
Mitogen-activated protein kinase kinase 1 (
MAP2K1) is a proto-oncogene that resides on chromosome 15q. It encodes MEK1, a serine-threonine kinase downstream of RAF in the RAS-RAF-MEK-ERK pathway, which in turn activates the MAPK pathway in cell proliferation and differentiation
[21,76][50][52]. Although rare,
MAP2K1 mutations, particularly in-frame deletions in exons 2 and 3, have been reported in Spitz neoplasms
[24][53]. These deletions frequently lead to the inactivation of the autoinhibitory domain of the MEK1 protein resulting in unopposed activation of the kinase domain
[24][53].
Clinically,
MAP2K1-mutated Spitz neoplasms are mostly present on the lower extremities of young females as small, pigmented, flat, or mildly elevated lesions
[21,24,25,26][50][53][54][55]. No distinctive histomorphological features have been established for these lesions given the small number of cases. However, recurring histologic characteristics among the cases described include a wedge-shaped compound or intradermal melanocytic proliferation composed of large epithelioid cells with vesicular nuclei and moderate to severe nuclear pleomorphism arranged in nests and showing a plexiform growth pattern, poor maturation and a tendency to converge around the adnexal structures and neurovascular bundles
[21,24,25,26][50][53][54][55].
3. Blue Nevi
Blue nevi are associated with activating mutations in the Gαq pathway, namely point mutations in GNAQ or
GNA11 and less commonly hotspot mutations in
CYSLTR2 or fusions of protein kinase C (
PKC) isoforms
[77,78,79,80][56][57][58][59].
GNAQ and
GNA11 are oncogenes located on chromosomes 9q and 19p, respectively, and encode G protein subunits alpha q and alpha 11 consecutively, which are guanine-binding proteins (G proteins) that are activated upon ligand binding to G-protein-associated receptors and function in downstream signaling
[81][60].
GNAQ and
GNA11 hotspot mutations alter intrinsic GTPase activity, leading to constitutive pathway activation
[81,82,83][60][61][62].
Clinically, blue nevi typically present as grayish blue-black macules, papules, or nodules on the head, buttock, or lower extremities and are more frequent in young adult females. The blue color is caused by the Tyndall effect, where light preferentially scatters shorter wavelengths by the melanin in the dermis
[84,85,86][63][64][65]. Histologically, multiple variants are present; however, in all cases, these tumors are almost always intradermal and are characterized by bipolar spindle dendritic pigmented melanocytes and melanophages, often growing in between sclerotic collagen bundles
[27][66]. The cellular variant is usually biphasic and contains distinct cellular areas of plump, spindled to oval melanocytes with clear or finely pigmented melanocytes arranged in fascicles and nests
[27,28][66][67].
4. Deep Penetrating Melanocytoma (DPM)
Deep penetrating melanocytomas (DPMs) are of the low cumulative sun damage (CSD) pathways that, in addition to activating mutations in
BRAF or
MAP2K1, harbor mutations that result in constitutive activation of the Wnt/β-catenin pathway, most often point mutations in catenin beta 1 (
CTNNB1) gene on chromosome 3p, a component of the cadherin-based adherens junction, which prevent its degradation, but alternatively biallelic inactivation of adenomatous polyposis coli (
APC) gene on chromosome 5q, a major component of the
CTNNB1 degradation complex
[87,88,89][68][69][70].
CTNNB1 imbalance is implicated in tumor growth, progression, and survival advantage
[90][71].
Clinically, DPNs present in young to middle-aged patients as pigmented papules or nodules, usually on the face, neck, or shoulder
[30,31,32][72][73][74]. Histologically, these lesions can arise in a pre-existing compound nevus. They are characterized by a wedge-shaped silhouette, an inconspicuous junctional component, and a cellular dermal component that can extend to the reticular dermis or even subcutis
[30,31,32,33][72][73][74][75]. Melanocytes are commonly arranged in fascicles or nests and typically show heavy pigmentation and a plump epithelioid to spindle cell morphology with a lack of maturation
[30,31,32,33][72][73][74][75]. Mild cytologic atypia, nuclear pleomorphism, and occasional dermal mitotic figures are not uncommon
[30,31,32,33][72][73][74][75].
5. Pigmented Epithelioid Melanocytoma (PEM)
Pigmented epithelioid melanocytomas (PEM) are intermediate-grade melanocytic tumors of the low-CSD pathway that can harbor either biallelic inactivation of the protein kinase cAMP-dependent type I regulatory subunit alpha (
PRKAR1A) gene on chromosome 17q, a major component of protein kinase A (PKA), which mediates cAMP-dependent signaling and regulates PKA activation, or fusions in the protein kinase C alpha (
PRKCA) gene, a member of the protein kinase C (PKC) family of serine/threonine kinases, which is involved in a number of essential cellular processes including proliferation, differentiation, survival, and migration
[34,35,36,37,38,39,92,93,94][76][77][78][79][80][81][82][83][84].
Clinically, PEM is classically present as pigmented, blue to blue-black, dome-shaped, papular or nodular lesions, mostly on the extremities, head and neck, and trunk of young adults, children, and infants
[38,39,40][80][81][85]. Histologically, these lesions typically show a nodular or wedge-shaped proliferation of heavily pigmented large multinucleated and small epithelioid, spindled, and dendritic melanocytes and melanophages with the majority having overlying epidermal hyperplasia
[34,36,38,39,40][76][78][80][81][85]. The junctional component is usually inconspicuous, and the dermal component characteristically consists of melanocytes with large vesicular nuclei and prominent nucleoli arranged in single cells and small nests that show a lack of maturation
[34,36,38,39,40][76][78][80][81][85].