Spitz Melanocytic Tumors: A Fascinating 75-Year Journey

Abstract

Over the last 75 years, our understanding of Spitz lesions has undergone substantial evolution. Initially considered a specific type of melanoma, the perception has shifted towards recognizing Spitz lesions as a spectrum comprising Spitz nevi, Spitz melanocytomas, and Spitz melanomas. Spitz lesions are known for posing a significant diagnostic challenge regarding the distinction between benign neoplasms displaying atypical traits and melanomas. A comprehensive understanding of their molecular basis and genomic aberrations has significantly improved precision in classifying and diagnosing these challenging lesions. The primary aim of this review is to encapsulate the current understanding of the molecular pathogenesis and distinct clinicopathologic characteristics defining this intriguing set of tumors.

Keywords: atypical spitz tumor; melanocytic; melanoma; nevus; spitz; spitzoid.

Figure 1

Spitz nevus with 11p gain. (A,B): Low and medium-power view depicting a dome-shaped lesion with deep growth into the dermis (hematoxylin and eosin stain [H&E], original magnification 20×, 50×). (C): There is mild fibrosis among tumor cells (H&E, original magnification 100×). (D). The cells are mostly epithelioid, with eosinophilic cytoplasm, round, or ovoid nuclei with minimal pleomorphism, and are grown as single units or in nests (H&E, original magnification 200×). Single Nucleotide Analysis (SNP) array analysis detected 11p chromosomal gain.

Figure 2

Spitz nevus with TMP3::ALK fusion. (A): Low-power view showing a relatively large, poorly demarcated melanocytic proliferation extending into the deep dermis and superficial subcutis (H&E, original magnification 20×). (B,C): The lesion is characterized by a confluence of irregular, highly cellular nests or nodules of large epithelioid and spindle-shaped cells. Focal effacement of the overlying epidermis is also observed (H&E, original magnifications 50× and 100×, respectively). (D): Mild to moderate nuclear pleomorphism is appreciated (H&E, original magnification 200×). SNP array analysis did not reveal any unbalanced genomic aberrations.

Figure 3

Spitz melanocytoma (Atypical Spitz Tumor) with TMP3::ALK fusion. (A): Low-power magnification showing a highly cellular spindle and epithelioid melanocytic proliferation (hematoxylin and eosin stain [H&E], original magnification 20×). (B,C): Confluent irregular nests and nodules of epithelioid and spindle-shaped cells are appreciated (H&E, original magnifications 50× and 100×, respectively). (D): The tumor cells exhibit voluminous eosinophilic to basophilic cytoplasm with nucleomegaly and moderate cytologic atypia. (H&E, original magnification 200×). SNP array analysis detected low level loss of 2p and gain of 2q, low level gain of chromosome 4, low level loss of chromosome 9, low level gains in segments 15q11.2-q21.3 and 15q23-qter, low level loss of 17q, and low level gain of chromosome 22. The tumor was negative for TERT promoter mutations. The findings indicate genetic instability, and despite being severely atypical, the overall morphologic and cytogenetic data are not diagnostic of Spitz melanoma.

Figure 4

Spitz melanocytoma (Atypical Spitz Tumor) with AKAP9::BRAF fusion. (A,B): Low-power magnification showing a dome-shaped, intradermal cellular melanocytic proliferation (hematoxylin and eosin stain [H&E], original magnification 20× and 50×, respectively). (C,D): The neoplasm consists of spindle and epithelioid cells growing in nests and short fascicles. The tumor cells have eosinophilic cytoplasm and show moderate nuclear pleomorphism (H&E, original magnification 100× and 200×, respectively). The tumor showed no unbalanced genomic genomic aberrations by single nucleotide polymorphism (SNP) array. Testing by FISH was negative for homozygous deletion of CDKN2A (p16, 9p21). The findings are atypical but not diagnostic of melanoma.

Figure 5

Melanoma with AGK::BRAF fusion. (A): Low-power magnification showing a cellular neoplasm with deep invasive growth into the dermis (hematoxylin and eosin stain [H&E], original magnification 10×). (B,C): The tumor is hypercellular growing in sheets (H&E, original magnification 50× and 100×, respectively). (D): Tumor cells have eosinophilic to basophilic cytoplasm and hyperchromatic nuclei with increased nuclear-to-cytoplasm ratio and moderate nuclear pleomorphism (H&E, original magnification 200×).

Figure 6

Melanoma with CMAS::BRAF fusion. (A): Low-power magnification showing an asymmetrical, cellular neoplasm with infiltrative/invasive growth into the dermis (hematoxylin and eosin stain [H&E], original magnification 20×). (B–D): The tumor grows predominantly in nests and shows mostly epithelioid cytomorphology, with eosinophilic cytoplasm and hyperchromatic nuclei with atypia. Melanin pigment is also evident (H&E, original magnifications 40×, 100× and 200×, respectively).

Figure 7

Spitz nevus with TMP3::ROS1 fusion. (A): Low-power magnification shows a dome-shaped, compound melanocytic proliferation associated with epidermal hyperplasia (hematoxylin and eosin stain [H&E], original magnification 20×). (B,C): The lesion is composed of predominantly epithelioid cells arranged in nests of various sizes. (H&E, original magnifications 50× and 100×, respectively). (D): Epithelioid tumor cells with hyperchromatic nuclei, increased nuclear-to-cytoplasmic ration, and moderate cellular atypia (H&E, original magnification 200×). (E): Break-apart FISH reveals separation of red and green signals indicative of ROS1 rearrangement. SNP array analysis did not reveal any unbalanced genomic aberrations.

Figure 8

Spitz nevus with PPWWP2A::ROS1 fusion. (A): Low-power view depicting a predominantly intradermal melanocytic proliferation associated with epidermal hyperplasia (hematoxylin and eosin stain [H&E], original magnification 50×). (B): The lesion is composed of spindle-shaped and epithelioid cells arranged in nests within a dense collagenous stroma (H&E, original magnification 100×). (C): The cells display eosinophilic cytoplasm and ovoid-to-round nuclei with conspicuous nucleoli (H&E, original magnification 200×). (D): Immunohistochemical staining for ROS1 shows uniform staining throughout the lesion (ΙHC, original magnification 50×).