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Address for correspondence: Dr Pedram Gerami, Professor of Dermatology and Pathology, Northwestern University, Department of Dermatology, 676 N St Clair Street, Suite 1765, Chicago, IL 60611, USA.
Spitz neoplasms continue to be a diagnostic challenge for dermatopathologists and are defined by distinctive morphological and genetic features. With the recent advancements in genomic sequencing, the classification, diagnosis, and prognostication of these tumours have greatly improved. Several subtypes of Spitz neoplasms have been identified based on their specific genomic aberrations, which often correlate with distinctive morphologies and biological behaviour. These genetic driver events can be classified into four major groups, including: (1) mutations [HRAS mutations (with or without 11p amplification) and 6q23 deletions]; (2) tyrosine kinase fusions (ROS1, ALK, NTRK1-3, MET and RET); (3) serine/threonine kinase fusions and mutations (BRAF, MAP3K8, and MAP2K1); and (4) other rare genomic aberrations. These driver genomic events are hypothesised to enable the initial proliferation of melanocytes and are often accompanied by additional genomic aberrations that affect biological behaviour. The discovery of theses genomic fusions has allowed for a more objective definition of a Spitz neoplasm. Further studies have shown that the majority of morphologically Spitzoid appearing melanocytic neoplasms with aggressive behaviour are in fact BRAF or NRAS mutated tumours mimicking Spitz. Truly malignant fusion driven Spitz neoplasms may occur but are relatively uncommon, and biomarkers such as homozygous 9p21 (CDKN2A) deletions or TERT-p mutations can have some prognostic value in such cases. In this review, we discuss the importance and various methods of identifying Spitz associated genomic fusions to help provide more definitive classification. We also discuss characteristic features of the various fusion subtypes as well as prognostic biomarkers.
Historically, the diagnosis of Spitz neoplasms has been one of the greatest challenges for pathologists. Many studies have documented the considerable lack of interobserver consensus in diagnosing Spitz neoplasms using only morphological criteria.
Further, there are many anecdotes that describe melanocytic tumours diagnosed as a Spitz neoplasm resulting in aggressive clinical behaviour with metastasis and subsequent patient mortality. New molecular studies which have identified the primary genetic drivers of Spitz neoplasms as being predominantly the result of chimeric fusion kinases have provided an opportunity to go beyond morphology in diagnosing Spitz neoplasms.
The identification of a Spitz associated fusion kinase or alternatively a HRAS activating point mutation allows for a definitive classification of neoplasms into the Spitz family. Alternatively, the presence of BRAF or NRAS activating mutations or activating point mutations in other genes in the MAPKinase pathway known to be primary drivers of melanocytic tumours excludes these lesions from the Spitz family.
Some of the Spitz associated kinase fusions have been associated with specific phenotypic patterns. Familiarity with these patterns can improve the accuracy and confidence of a diagnostician in designating a tumour in the Spitz family. Therefore, in this review, we will discuss some of the various morphological patterns that have been associated with specific chimeric fusion kinases. Additionally, there are some novel biomarkers that have been shown to have some prognostic value of Spitz neoplasms and hence may influence whether a diagnosis of Spitz melanoma or Spitz tumour/Spitz naevus is favoured.
Molecular pathogenesis of spitz neoplasms
In a study of 102 Spitzoid neoplasms, translocations involving ROS1, ALK, NTRK1, BRAF or RET were found in 51% of the evaluated cases.
The proposed mechanism involves a chromosomal translocation involving the aforementioned tyrosine kinases in which the 3′ kinase domain of the protein is preserved while the 5′ end of the gene where the regulatory unit resides is replaced by a variable number of potential partners. It is the loss of the regulatory unit that results in constitutive activation of the 3′ kinase and proliferative of Spitzoid melanocytes (Fig. 1 demonstrating a common fusion). A subsequent study also identified NTRK3 and MAP3K8 as well as several other novel fusions as key drivers in Spitz neoplasms.
MAP3K8 can develop a constitutively active kinase from a fusion event as described above or a truncation in which the 5′ regulatory is simply lost also results in constitutive activation of the 3′ kinase.
There is a small remaining percent in which the drivers may not yet be described. Hence it seems overall 70–80% are fusion related and 10–20% are related to activating point mutations in HRAS.
Fig. 1Diagram of chimeric structure in the MAP3K8-SVIL fusion Spitz neoplasms. Functional domains are displayed. Breakpoints are indicated by the orange arrows.
Genomic subtypes of spitz and associated morphological patterns
HRAS and 11p amplifications
Mutations in HRAS (Harvey rat sarcoma viral oncogene homolog), a proto-oncogene located on chromosome 11p, were the first genetic alterations associated with Spitz melanocytic neoplasms.
HRAS belongs to the RAS family of oncogenes, encoding a GTPase that is involved in the MAP kinase signalling pathway. Mutations in HRAS result in constitutive activation and aberrant expression of various transcription factors involved in cell growth and differentiation.
Compared to other Ras proteins, HRAS appears to have higher affinity for the PI3K-AKT pathway, which is thought to contribute to the enlarged epithelioid or spindle cell phenotype of Spitz naevi.
Mutations (most commonly missense) are most often located on exons 2 or 3, including 61Gln to Leu, 61Gln to Arg, and 12Gly to Arg regions, but can also vary widely.
Clinically, Spitz naevi with HRAS mutations commonly present as symmetrical raised lesions with a plaque, wedge, or nodular-shaped silhouette on the head, neck, and extremities.
Morphologically, features of HRAS mutated Spitz naevi are most commonly associated with a desmoplastic Spitz naevi morphology and can vary from having low cellularity in a desmoplastic stroma to having bulky cellularity in a desmoplastic stroma in the dermis.
In cases of naevus spilus there is a germline mosaic mutation in HRAS which results in the naevus spilus. The development of agminated Spitz in a naevus spilus has been associated with secondary copy number gains in 11p, where the HRAS gene resides in the foci of Spitzoid cells.
Tyrosine kinase fusion-associated Spitz neoplasms
ROS1 fusions
ROS1 is a proto-oncogene that resides on chromosome 6q22.1, encoding a tyrosine kinase receptor involved in the following signalling pathways: Ras-Raf-MEK1/2-ERK1/2, JAK3-STAT3, and PI3K-AKT-mTOR.
ROS1 fusions are among the most common type of fusion found in Spitz melanocytic neoplasms, with a large case series finding up to 17% of Spitz naevi or atypical Spitz tumours (AST) harbouring the mutation.
ROS fusions are not exclusive to cutaneous neoplasms, and have been found in non-small cell lung carcinomas, glioblastomas, paediatric gliomas, cholangiocarcinoma, malignant pleural mesothelioma, paediatric inflammatory myofibroblastic tumours, etc. ROS1 fusions have been reported to have several partner genes, including PWWP2A (37% of cases), TPM3 (31% of cases), PPFIBP1, CAPRIN1, MYO5A, PPFIBP1, CLIP1, ERC1, FIP1L1, HLA-A, KIAA1598, MYH9, ZCCHC8, and GOPC.
Spitz tumours with ROS1 fusions: a clinicopathological study of 6 cases, including FISH for chromosomal copy number alterations and mutation analysis using next-generation sequencing.
Clinically, ROS1 fused Spitz naevi are typically dome-shaped, well circumscribed, pink to red papules located throughout the body, with the lower extremities being the most reported site.
Spitz tumours with ROS1 fusions: a clinicopathological study of 6 cases, including FISH for chromosomal copy number alterations and mutation analysis using next-generation sequencing.
ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis.
Morphological features are variable and fairly non-specific, typically showing a compound plaque-like or nodular silhouette with homogeneous epithelioid and spindle cells with mild to moderate cytological atypia along with whirling nests of minimally pigmented melanocytes and mucin.
Spitz tumours with ROS1 fusions: a clinicopathological study of 6 cases, including FISH for chromosomal copy number alterations and mutation analysis using next-generation sequencing.
There is often a prominent junctional melanocytic component containing floating nests or transepidermal elimination of melanocytic nests, with colonisation of the adenexal epithelium.
Spitz tumours with ROS1 fusions: a clinicopathological study of 6 cases, including FISH for chromosomal copy number alterations and mutation analysis using next-generation sequencing.
Diagnostically, FISH studies using a break apart probe targeting the ROS1 gene or immunohistochemistry (IHC) may be used to confirm the presence of a ROS1 fusion. IHC with the monoclonal antibody D4D6 against ROS1 has shown positivity in most (97.4%) of ROS1 fused Spitz naevi and 100% specificity compared to FISH.
ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis.
Various IHC staining patterns have been observed, including diffuse granular cytoplasmic staining, dot-like staining, and nuclear staining, with no specific correlations with cellular localisation of the various ROS1 fusions discovered as of now.
ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis.
Overall, patients with ROS1 fused Spitz naevi tend to have a favourable prognosis, with one study of 17 cases reporting that all patients were disease free at 30 months post-excision with no evidence of recurrence or metastasis.
A case of acral lentiginous melanoma with the same gene fusion also responded to entrecitinib, another ROS1 targeting tyrosine kinase inhibitor, revealing a possible promising treatment option for melanocytic tumours with GOPC-ROS1 fusions.
The anaplastic lymphoma kinase (ALK) gene is located on chromosome 2p23 and encodes a tyrosine kinase receptor that belongs to the insulin receptor family.
Alterations to this gene can result in constitutive activation of the RAS-ERK, JAK3-STAT3, and PI3K-AKT-mTOR pathways, influencing cell proliferation and survival.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
Corresponding anaplastic lymphoma kinase-tropomyosin 3 (ALK-TPM3) fusion in a patient with a primary cutaneous anaplastic large-cell lymphoma and a Spitz nevus.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
ALK fusions are typically mutually exclusive with BRAF mutations.
There is a subset of ALK fused Spitz melanocytic neoplasms termed melanocytic myxoid spindle cell tumours with ALK rearrangement (MMySTAR) with ALK+/SOX10+/MelanA– spindle cells underneath a superficial naevoid or Spitzoid component.
Clinically, ALK fused Spitz naevi are typically amelanotic and have the largest average diameter compared to Spitz naevi with various other genetic abnormalities.
Morphologically, ALK fusion Spitz tumours do appear to have distinct morphological features, commonly presenting as a compound lesion with a predominant intradermal melanocytic component of plexiform intersecting fascicles of fusiform/spindle cell or mixed spindle and epithelioid cell melanocytes with amphophilic cytoplasm and vesicular nuclei with prominent nucleoli.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
Some cases may have more notable nuclear atypia, have ulceration, and brisk mitotic activity of >5/mm2 but still behave indolently. Hence, ALK fusion Spitz tumours are an excellent example of why conventional criteria utilised to classify a melanocytic tumour as malignant may not be relevant to Spitz neoplasms. Kamino bodies are rare and pigment is typically absent or sparse (Fig. 2).
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
Fig. 2(A,B) Low power magnification of a compound wedge-shaped ALK fusion Spitz tumour. Some junctional component is not uncommon but single cell pagetosis and kamino bodies are infrequent. (D) Intermediate power demonstrates the elongated wavy fascicles of spindle cells with a roughly plexiform arrangement. (C) This particular case has a dumbbell shaped expansile nodule at the base as a result of copy number gains of the chimeric fusion gene resulting in more expansile growth in that focus. (E) Also, appreciate the wavy fascicles of spindle cells at higher magnification.
IHC with monoclonal antibodies D5F3 and 5A4 is a cost effective and reliable ancillary diagnostic tool for potential translocations for cases with diffuse and strong immunopositivity.
A clinicopathological study of 29 spitzoid melanocytic lesions with ALK fusions, including novel fusion variants, accompanied by fluorescence in situ hybridization analysis for chromosomal copy number changes, and both TERT promoter and next-generation sequencing mutation analysis.
However, there are several reports of non-Spitz melanocytic proliferations showing weak and heterogeneous ALK staining with ALK overexpression as a result of other molecular mechanisms, including alternative transcription leading to the expression of ALKATI, a novel ALK isoform.
Next generation sequencing (NGS) and fluorescence in situ hybridisation (FISH) with a break apart probe targeting ALK are other ancillary diagnostic techniques that can be used for the detection of ALK fusions.
Currently, there are no reported cases of ALK fused Spitz melanocytic neoplasms found to be associated with systemic metastases or death from disease. Hence, we believe these are a more indolent type of Spitz neoplasm.
NTRK1-3
The neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, are oncogenes encoding TRK family tyrosine kinase receptors, and are located on chromosomes 1q, 9q and 15q, respectively.
These receptors are single-pass transmembrane proteins involved in various cell signalling pathways, including the PI3K-AKT-mTOR, RAF-MEK1/2-ERK1/2, and phospholipase C-γ pathways.
The majority of NTRK fusions result in a retained 3′ portion encoding the kinase domain and a donated 5′ portion encoding a dimerising domain, resulting in constitutive activation of the pathway.
Although NTRK1, NTRK2 and NTRK3 fusions have all been found in Spitz melanocytic neoplasms, NTRK1 fusions are more common in Spitz naevi (Fig. 3) while NTRK3 is most characteristic of pigmented spindle cell naevus of Reed (PSCNR; Fig. 4).
In fact greater than 50% of PSCNR are the result of NTRK3 fusions. Several fusion partners for both NTRK1 and NTRK3 have been reported, including LMNA,
secretory carcinoma of the breast and salivary gland, infantile fibrosarcoma, congenital mesoblastic nephroma, lung carcinoma, papillary carcinoma and glioma.
Fig. 3(A) Low power magnification of a plaque-shaped NTRK1 fusion Spitz naevus. (B) On intermediate power notice the elongated filigree-like rete ridges and the lobulated nesting pattern which shows many smaller nests organised in a back-to-back pattern creating a larger nest. (C,D) On higher power notice the relatively smaller cell size in the Spitz spectrum, a common feature of NTRK fusions.
Fig. 4NTRK3 fusion pigmented spindle cell naevus of Reed. (A) The lesion has a broad plaque like architecture with fascicles of pigmented spindle cells along the dermal-epidermal junction. (B) Some uniformly distributed pagetoid cells are common. Melanophages fill the superficial dermis.
Clinically, most NTRK1 fused Spitz naevi are symmetric compound or dermal exophytic lesions, with one report demonstrating a regular array of coiled-glomerular vessels admixed with crystalline structures on dermatoscopic exam.
Histologically, NTRK1 fused Spitz naevi show small spindled cell morphology with elongated, thin rete ridges (filigree-like), lobulated dermal melanocytic nests, frequent Kamino bodies, and the formation of pseudorosettes.
Diagnostically, immunohistochemistry with pan-TRK A7H6R and EPR17341 antibodies can be used to screen for the possibility of an NTRK fusion. Although both clones are highly sensitive and specific, the EPR17341 antibody, which specifically reacts against a conserved C-terminal epitope in wild-type and in all chimeric TRK proteins, has slightly higher specificity.
NTRK1 fused Spitz naevi tends to show higher Pan-TRK staining saturation in the cytoplasm, while LMNA-NTRK1 fused Spitz naevi show higher saturation in the nucleus.
NTRK3 fused Spitz naevi have been reported to show cytoplasmic and nuclear pan-TRK ICH staining in up to 50% of tumours, with one report showing more intense nuclear than cytoplasmic immunoreactivity in ETV6-NTRK3 fused Spitz naevi.
Rare cases of Spitz melanomas harbouring NTRK fusions resulting in distant metastasis have been reported. In the rare case of metastasis, targeted TRK inhibitor therapy is a potential treatment option.
This receptor is involved in the PI3K-AKT, RAF-MEK1/2-ERK1/2, PLCγ1, and β-catenin pathways and plays a role in cell growth, motility, and melanocyte homeostasis.
A series of six cases of fused MET Spitz naevi reported a breakpoint in intron 14 in all cases, which contains the auto-inhibitor domain that is localised upstream from the kinase domain.
Morphologically, MET fused Spitz naevi have been found as symmetric dome-shaped lesions, compound or intradermal, with epidermal hyperplasia containing large nests of intermediate to large epithelioid or spindle melanocytes with pericellular clefting.
However, given the limited number of cases of MET fused Spitz naevi, there are currently no distinctive morphological features associated with MET fused Spitz naevi to aid in diagnosis or prognosis. Diagnostically, NGS and FISH are available techniques to detect MET fusions.
Possible therapeutic agents include cabozantinib (inhibitor of c-MET and VEGFR2) or PF-04217903 (c-MET inhibitor), which showed decreased p-MET, p-ERK, p-AKT and p-PLCγ1 in melanocytes expressing TRIM4-MET or ZKSCAN1-MET fusions.
the recent development of MET inhibitors (e.g., crizotinib, tivantinib, savolitinib, tepotinib, and foretinib) and anti-MET antibodies (e.g., emibetuzumab and onartuzumab), thus far primarily used to treat lung cancer, could be a therapeutic option in a case of a true malignant MET fusion Spitz melanoma.
Receptor tyrosine kinase rearranged during translocation (RET) is a proto-oncogene located on chromosome 10q11.21 that encodes a tyrosine kinase involved in several signalling pathways, including MAPK/ERK, PI3K/AKT/mTOR and PLCγ1.
RET fusions have been found in other cutaneous neoplasms such as acral lentiginous melanoma, spindle cell mesenchymal tumour (one case containing a novel NCOA4-RET fusion
) and soft tissue mesenchymal tumours with varying features, including small lipofibromatous-like neural tumour, infantile fibrosarcoma-like tumour and malignant peripheral nerve sheath-like tumour.
NCOA4-RET and TRIM27-RET are characteristic gene fusions in salivary intraductal carcinoma, including invasive and metastatic tumours: is "intraductal" correct?.
Morphologically, the features of RET fused Spitz naevi are not specific, but are often reported as being well-circumscribed, symmetric, compound lesions with a plaque-like silhouette containing large expansile nests of small to intermediate-sized predominantly epithelioid cells with prominent dyscohesion of melanocytes within the nests. Nuclear atypia was observed to be mild to moderate.
RET fused Spitz melanocytic neoplasms typically have a good clinical outcome and no Spitz melanoma with reported follow-up has had widespread metastases or death from disease.
In the rare instance that metastasis occurs, RET inhibitors such as vandetanib and cabozantinib, approved for the treatment of medullary thyroid cancer, serve as possible therapeutic agents.
Activating point mutations in BRAF occur in most common acquired naevi, dysplastic naevi, and melanoma. The presence of such an activating mutation excludes the tumour from the Spitz family. On the contrary, BRAF fusions are commonly found in Spitz melanocytic neoplasms.
BRAF is a proto-oncogene located on chromosome 7q that encodes a serine/threonine kinase with three domains. The CR1 domain contains N-terminal RAS-binding and cysteine-rich domains, the CR2 domain contains serine-threonine-rich domains, and both CR1 and CR2 auto inhibit the CR3 kinase domain.
In the event of a BRAF fusion, the resultant chimeric protein only contains the CR3 domain, which is the functional kinase domain of the BRAF gene, and loses the autoinhibitory domains. This results in increased activity of the kinase enzyme with subsequent activation of downstream MEK1/2 and ERK1/2 pathway.
BRAF fusions are not exclusive to Spitz naevi, and have been found in various other neoplasms, such as thyroid cancer, non-small cell lung adenocarcinoma, colorectal carcinoma, and gliomas.
Recently, there was a report of multiple desmoplastic Spitz naevi with BRAF fusions in a patient with ring chromosome 7 syndrome, which identified two novel BRAF fusion partners, TMEM106B and WDR91.
Histologically, BRAF fused Spitz naevi are commonly intradermal with a plaque-like, nodular, or wedge-shaped silhouette containing epithelioid or mixed, epithelioid and spindle morphology with amphophilic cytoplasm and vesicular nuclei with predominant nucleoli. Cytological atypia is typically moderate to severe and nuclear pleomorphism is frequently marked.
BRAF fusion-specific morphology has previously been described, which includes a dense cellular sheet-like melanocytic proliferation superficially, with a desmoplastic base containing prominent dermal sclerosis.
Among the various genomic fusion subtypes of Spitz, BRAF and MAP3K8 are typically the most morphologically atypical with large atypical epithelioid cells, prominent nuclear atypia, and pleomorphism. Hence, BRAF fusions are only second to MAP3K8 fusions in their likelihood of being classified as Spitz melanoma. Diagnostically, NGS or FISH analysis are used for the detection of BRAF fusions.
While most cases are indolent, there are more examples of aggressive behaviour in BRAF and MAP3K8 fusions reported in the literature compared to other fusion types. Widespread metastasis of BRAF fused malignant Spitz tumours has been reported in multiple cases.
There are also several reported cases of non-Spitz BRAF fused melanomas, including the following subtypes: acral, mucosal, superficial spreading, and melanoma arising within a giant congenital naevus.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
The mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2, COT) gene is located on chromosome 10p11 and encodes a serine/threonine and tyrosine kinase involved in the direct activation of the RAF-MEK1/2-ERK1/2 pathway.
The inhibitor domain has two functions: first, to sterically inhibit the kinase domain in its inactive state; and second, to target the enzyme for proteolytic degradation.
MAP3K8 fusions and truncations result in the loss of the inhibitor domain, resulting in subsequent unopposed kinase activity and loss of proteolytic degradation, leading to increased MEK1/2-ERK1/2 pathway involved in cell proliferation, division, and differentiation.
MAP3K8 fusions and truncations are not exclusive to Spitz melanocytic neoplasms, and have been found in various tumours, including acral melanomas, squamous cell carcinomas, cutaneous myxoinflammatory fibroblastic sarcoma, ovarian cancer, lung carcinoma, breast carcinoma, and mesothelioma.
Clinically, Spitz neoplasms with MAP3K8 fusions typically present as asymmetric exophitic pigmented lesions in the lower extremities of patients of all ages, showing a slight female predominance.
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