Genomic Landscape of Spitzoid Neoplasms Impacting Patient Management

Abstract

Spitzoid neoplasms are a distinct group of melanocytic proliferations characterized by epithelioid and/ or spindle shaped melanocytes. Intermediate forms that share features of both benign Spitz nevi (SN) and Spitz melanoma, i.e., malignant Spitz tumor (MST) represent a diagnostically and clinically challenging group of melanocytic lesions. A multitude of descriptive diagnostic terms exist for these ambiguous lesions with atypical Spitz tumor (AST) or Spitz tumor of uncertain malignant potential (STUMP) just naming two of them. This diagnostic gray zone creates confusion and high insecurity in clinicians and in patients. Biological behavior and clinical course of this intermediate group still remains largely unknown, often leading to difficulties with uncertainties in clinical management and prognosis. Consequently, a better stratification of Spitzoid neoplasms in benign and malignant forms is required thereby keeping the diagnostic group of AST/STUMP as small as possible. Ancillary diagnostic techniques such as immunohistochemistry, comparative genomic hybridization, fluorescence in situ hybridization, next generation sequencing, micro RNA and mRNA analysis as well as mass spectrometry imaging offer new opportunities for the distinct diagnosis, thereby allowing the best clinical management of Spitzoid neoplasms. This review gives an overview on these additional diagnostic techniques and the recent developments in the field of molecular genetic alterations in Spitzoid neoplasms. We also discuss how the recent findings might facilitate the diagnosis and stratification of atypical Spitzoid neoplasms and how these findings will impact the diagnostic work up as well as patient management. We suggest a stepwise implementation of ancillary diagnostic techniques thereby integrating immunohistochemistry and molecular pathology findings in the diagnosis of challenging ambiguous Spitzoid neoplasms. Finally, we will give an outlook on pending future research objectives in the field of Spitzoid melanocytic lesions.

Keywords: atypical spitz tumor; genetic; malignant spitz tumor; molecular; patient management; spitz melanoma; spitz nevi; spitzoid neoplasms.

Figure 1

Overview of the Molecular Landscape of Melanocytic Neoplasms. Cutaneous melanocytic neoplasms can be clustered into three major lines including conventional melanocytic neoplasms (colored in green), Spitzoid melanocytic neoplasms (colored in turquoise) and blue melanocytic neoplasms (colored in blue). Each group shows distinct molecular genetic alterations. Conventional melanocytic neoplasms (green color) include common melanocytic nevocellular nevi, congenital nevocellular nevi and cutaneous malignant melanoma. Common nevocellular nevi harbor activating hotspot BRAF mutations at codon 600 [~80%, (1)]. The majority of congenital nevocellular nevi harbor activating NRAS hotspot mutations [~75%, (2)]. Cutaneous malignant melanoma has been clustered into four molecular subtypes (3) with the largest subgroup harboring a BRAFV600E mutation (~50%) and the second largest group with an activating NRAS mutation (~25%) as well as HRAS and KRAS mutations (~1%). The third subgroup shows NF1 inactivation (~10%). The last molecular subgroup lacks BRAF, N/H/KRAS or NF1 mutations and represents a heterogeneous so called “triple wild-type subtype”. The second major line of cutaneous melanocytic neoplasms comprises blue melanocytic neoplasms which are also called dermal dendritic melanocytic neoplasms (blue color) and have been shown to harbor activating GNAQ and GNA11 mutations. GNAQ dominates in cutaneous proliferations while GNAQ and GNA11 is found in almost the half of uveal melanomas (4). The third group refers to Spitzoid melanocytic neoplasms (turquoise color) and shows quite different molecular genetic alterations which are rarely observed in the two other groups. Receptor tyrosine kinase translocations involving ALK, ROS1, NTRK1, NTRK3, BRAF, RET, MET (–7) as well as HRAS (5, 8, 9), BAP1 (10), and TERTp mutations (–13) have been described in Spitzoid neoplasms.

Figure 2

Prototypic Spitz Nevus. (a) The compound Spitz nevus (SN) has a small size of 3 mm with a symmetric dome shaped morphology and shows sharp lateral demarcation (H.E. staining, magnification factor 2.5x). (b) Higher magnification from A shows regular epidermal hyperplasia with vertically orientated fascicles of spindled and epithelioid melanocytes. Note the numerous epidermal junctional clefts (*) which are formed due to discohesion of the melanocytes (H.E. staining, magnification factor 10x). (c) Higher magnification from B with uniform characteristic epithelioid melanocytes at the epidermal junction (H.E. staining, magnification factor 40x). (d) Higher magnification from B showing regular spindle shaped melanocytes at the epidermal junction with formation of junctional clefts (*) due to discohesion of the Spitzoid melanocytes (H.E. staining, magnification factor 40x). (e) Schematic sketch of a prototypic epithelioid shaped melanocyte which is characteristic for a SN. (f) Schematic sketch of a prototypic spindle shaped melanocyte which is characteristic for a SN.

Figure 3

Diagnosis and Management of Spitzoid Melanocytic Neoplasms. Histopathologic evaluation is the initial step in diagnosing a Spitzoid neoplasm. In case of evident benign histologic characteristics, the diagnosis of a Spitz nevus (SN) can be made. If the lesion has been completely excised a clinical follow up is not necessary. In cases of evident malignant histopathology, the diagnosis of Spitz melanoma, i.e., malignant Spitz tumor (MST) is made and clinical management according to conventional malignant melanoma protocols should be followed. The diagnosis of MST necessitates a re-excision with a margin of at least 1 cm, in high risk cases a sentinel node procedure, clinical staging and follow up. If the histopathology is ambiguous stepwise ancillary studies such as immunohistochemistry (IHC), comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) should be performed. If histopathology as well as ancillary studies still remain inconclusive the diagnosis per exclusionem of atypical Spitz tumor (AST) is made. A reexcision with a margin of 0.5–1 cm should follow. The value of a sentinel node procedure, the follow up time, and the extent of clinical staging in this setting remains a topic of ongoing debate.

Figure 4

The Spitz classifier: Stepwise Implementation of Immunohistochemistry and Molecular Pathology in Ambiguous Spitzoid Neoplasms. In cases with ambiguous histopathological features that give suspicion for malignancy stepwise ancillary studies are performed to render the diagnosis of a Spitz nevus (SN), atypical Spitz tumor (AST) or malignant Spitz tumor (MST) with more security. Step 1 is immunohistochemistry (IHC) with a panel of MIB-1-, HMB45-, and p16 antibody. In dependence of the obtained result a diagnosis of SN or MST can be made. A MIB-1 IHC index < 2% with diminished expression in the deep dermal component as well as diminished HMB45 IHC expression in the deep dermal component and patchy to strong p16 IHC expression throughout the lesion favors the diagnosis of SN. Cases with MIB-1 IHC expression >10%, persisting HMB45 IHC expression in the deep dermal component as well as loss of p16 IHC expression favor the diagnosis of MST although exceptions of this rule are possible. If results of IHC investigation are intermediate with a MIB-1 IHC index of 2–10%, and/or variable HMB45- and p16 IHC expression one should proceed to step 2 with implementation of molecular pathology. Comparative genomic hybridization (CGH) analysis or if not available fluorescence in situ hybridization (FISH) are performed. Next generation sequencing (NGS) is of help as well. No detectable chromosomal aberration or isolated gain of Chr. 7p or 11p as well as activating HRAS mutation favor the diagnosis of a SN. The presence of at least one chromosomal abnormality (excluding Chr. 7p or 11p gain), especially homozygous loss of Chr. 9p11 as well as PTEN and TERTp mutations argue for MST. If the afore mentioned findings are only partly present with ≥1 chromosomal abnormality (including heterozygous and very rarely homozygous loss of Chr. 9p21), or PTEN mutations AST as a diagnosis per exclusionem is to be considered. Adapted from WHO 2018 classification (14).

Figure 5

Overview of the Classification Systems of Spitzoid Neoplasms. Over time there have been many different diagnostic approaches to classify Spitzoid neoplasms. The proposed three- and four- tiered classification system best reflect the existence of the group op ambiguous Spitzoid neoplasms with atypical Spitz tumor (AST, gray color) with intermediate features in between complete benign Spitz nevi (SN, green color) and clear cut malignant Spitz melanoma, i.e., malignant Spitz tumor (MST, blue color). The application of ancillary diagnostic techniques and implementation of findings from molecular pathology might help to reduce the uncertain diagnostic category of AST to a minimum and improve and clarify patient management in the future.