The Morpho-Molecular Landscape of Spitz Neoplasms

Abstract

Spitz neoplasms are a heterogeneous group of melanocytic proliferations with a great variability in the histological characteristics and in the biological behavior. Thanks to recent discoveries, the morpho-molecular landscape of Spitz lineage is becoming clearer, with the identification of subtypes with recurrent features thus providing the basis for a more solid and precise tumor classification. Indeed, specific mutually exclusive driver molecular events, namely HRAS or MAP2K1 mutations, copy number gains of 11p, and fusions involving ALK, ROS, NTRK1, NTRK2, NTRK3, MET, RET, MAP3K8, and BRAF genes, correlate with distinctive histological features. The accumulation of further molecular aberrations, instead, promotes the increasing malignant transformation of Spitz neoplasms. Thus, the detection of a driver genetic alteration can be achieved using the appropriate diagnostic tests chosen according to the histological characteristics of the lesion. This allows the recognition of subtypes with aggressive behavior requiring further molecular investigations. This review provides an update on the morpho-molecular correlations in Spitz neoplasms.

Keywords: ALK; HRAS; MAP2K1; MAP3K8; MET; NTRK1; NTRK2; NTRK3; RET; ROS1; Spitz nevus; atypical Spitz tumor; malignant Spitz tumor.

Figure 1

Photomicrographs of a prototypical Spitz nevus showing a symmetric, slightly raised, compound, and maturating melanocytic proliferation with epidermal hyperplasia, flat base, and scattered Kamino bodies, composed of large clefting nests of spindle and epithelioid melanocytes with abundant eosinophilic cytoplasm, moderately pleomorphic vesicular nuclei, and prominent nucleoli (A–D) H&E staining; original magnification 10×, 100×, 100×, and 400×, respectively).

Figure 2

Photomicrographs of a Spitz nevus harboring HRAS mutation showing a symmetric, exophytic and dermal melanocytic proliferation with flat base, composed of fascicles of large spindle melanocytes with amphophilic cytoplasm, moderately pleomorphic vesicular nuclei, and distinct nucleoli, intermingled with thick collagen bundles (A–C) H&E staining; original magnification 10×, 100×, and 200×, respectively). Mass Array graphic output showing the HRAS p.Q61R c.182A > G mutation detected by mass spectrometry-based analysis (D).

Figure 3

Photomicrographs of a Spitz nevus harboring ALK fusion showing a large, exophytic and dermal melanocytic proliferation with infiltrative base, composed of nonpigmented, large, epithelioid and spindle melanocytes with amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli, arranged in plexiform intersecting fascicles (A–C) H&E staining; original magnification 10×, 100×, and 200×, respectively). ALK (clone D5F3) immunohistochemistry showing a diffuse cytoplasmic staining ((D) original magnification 12.5×).

Figure 4

Photomicrographs of an atypical Spitz tumor harboring NTRK1 fusion showing a slightly raised, compound, and symmetric melanocytic proliferation with filigree-like rete ridges, flat-base silhouette, and lobulated nests of epithelioid and spindle melanocytes with moderate nuclear pleomorphism (A–C) H&E staining; original magnification 12.5×, 100×, and 200×, respectively). Pan-TRK (clone EPR17341) immunohistochemistry showing a diffuse cytoplasmic staining ((D) original magnification 12.5×).