Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature

Abstract

Background

Spitz tumors are relatively uncommon melanocytic lesions, typically affecting a relatively younger population but can be encountered at any age. They are characterized by a proliferation of melanocytes with epithelioid and/or spindled cytomorphology features, and interpretation is often challenging. The majority of these tumors are driven by kinase fusions or HRAS mutations. MAP3K8 fusions, although rare, are characteristic genomic events in Spitz tumors, especially in more atypical or malignant lesions.

Case presentation

Here, we present the case of a 43-year-old woman with a clinically cystic mass in her right groin, histologically characterized as a spindle and epithelioid cell malignant tumor. Immunohistochemistry revealed diffuse expression of S100 protein, tyrosinase and SOX10, patchy weak PRAME, HMB45 and Melan-A reactivity, and negative staining for BRAF V600E. Next-generation sequencing analysis revealed the presence of a MAP3K8::ABLIM1 fusion gene, as well as GRIN2A and TERT promoter mutations. The morphology, immunohistochemistry and molecular analysis confirmed Spitz melanoma with molecular features suggesting a worse prognosis.

Conclusion

This case introduces a novel fusion partner of MAP3K8 in the context of Spitz melanoma and expands the morphologic and molecular spectrum of Spitz melanoma.

Introduction

Spitz tumors are challenging melanocytic lesions in daily practice, as the morphologic features frequently overlap with those of melanoma [1]. They exist within a spectrum that goes from benign Spitz nevi to malignant Spitz tumors, passing through intermediate lesions (Atypical Spitz tumors / Spitz melanocytomas) [1,2,3,4]. We now recognize specific molecular determinants of these lesions, namely HRAS mutations [1] and translocations involving tyrosine and serine/threonine kinases [1], while the presence of conventional melanocytic lesion molecular determinants, such as BRAF V600E mutations, excludes these lesions from the Spitz category [1,2,3,4].

While documentation of the Spitz pathway aids in identifying Spitz tumors, it does not directly determine their benign or malignant nature [2]. However, it offers invaluable diagnostic insights. For instance, given the rarity of melanomas exhibiting HRAS aberration or specific kinase fusion, detecting such aberrations reduces the probability of a malignant melanoma, unless compelling clinical or histopathological contexts suggest otherwise, or co-existing mutations or genomic aberrations are present [2].

Malignant Spitz tumors, also known as Spitz melanomas, are rare and are characterized by additional molecular determinants, such as TERT promoter mutations, CDKN2A mutations, and other aberrations [2,3,4].

In this report, we present a unique case of Spitz melanoma in which a kinase fusion gene involving MAP3K8::ABLIM1 was identified. The ABLIM1 fusion partner has not been described before in the literature in the context of Spitz melanoma.

Case presentation

A 43-year-old woman with a medical history of hypertension sought care at a general surgery clinic due to a painful and itchy ulcerated cystic mass on her right groin. The mass had been present for over a year but had grown larger in the last six months, measuring around 5 cm. It had a firm base underneath and ulceration on top, surrounded by redness without purulent drainage. Magnetic resonance imaging (MRI) of the pelvic muscular tissue (Fig. 1) revealed a lobulated mass within the subcutaneous soft tissues of the right inguinal region measuring 4.4 × 3.9 × 2.3 cm. The mass demonstrated significant enhancement, consistent with a neoplastic process. The deep surface margin of the lesion abutted the superficial myofascial margin of the pectineus. There was no evidence of intramuscular signal abnormality or invasion, and the mass was otherwise completely contained within the subcutaneous soft tissues. Additionally, there were some mildly prominent lymph nodes around the peripheral margins of the lesion.

Fig. 1

Spitz melanoma. MRI of the pelvic muscular tissue (T1 axial, post-contrast phase) shows a subcutaneous, soft tissue-enhancing mass in the right groin/ inguinal region, medial to the right femoral neurovascular bundle. The deep surface margin of the mass abuts the superficial myofascial margin of the right pectineus muscle, with mildly prominent lymph nodes around the peripheral margin of the mass

A needle biopsy performed on the right groin mass (Fig. 2) revealed a diffuse sheets of malignant pleomorphic spindled and epithelioid cells exhibiting elongated to ovoid hyperchromatic nuclei associated with moderate to abundant amounts of eosinophilic cytoplasm. Mitoses, including atypical forms, were present, and areas of necrosis were observed. Immunohistochemical stains showed that the tumoral cells were strongly positive for S100 protein, and SOX10. H3K27Me3 and INI1 were retained. The malignant cells tested negative for cytokeratin AE1/AE3, cytokeratin OSCAR, desmin, muscle-specific actin, smooth muscle myosin, caldesmon, tyrosinase, Melan-A, PRAME, HMB45, CD117, ERG, myogenin, myo-D1, BRAF V600E, and CD3. The differential diagnosis centered predominantly around malignant peripheral nerve sheath tumor, versus malignant melanoma. The clinical impression of a lymph node metastasis favored malignant melanoma. Next-generation sequencing analysis was performed to further characterize this lesion, and a multidisciplinary team recommended excision of the mass.

Fig. 2

Spitz melanoma, needle core biopsy. A Malignant epithelioid and spindled cells exhibit moderate to severe pleomorphism, hyperchromatic nuclei and eosinophilic cytoplasms (x100). B-C Malignant cells also display prominent nucleoli, multiple nuclear inclusions, and mitoses (x200 and x400, respectively). D Malignant cells are diffusely positive for SOX10 immunohistochemical marker (IHC) (x200). E Malignant cells are negative for tyrosinase IHC (x400). F Malignant cells are negative for PRAME IHC (x400). G Malignant cells are negative for Melan-A IHC (x400)

Molecular testing (Table 1), utilizing RNA sequencing, revealed a MAP3K8::ABLIM1 translocation, while next-generation sequencing showed TERT promoter and TP53 pathogenic mutations and a likely pathogenic GRIN2A variant. Other variants of unknown significance are listed in Table 1. In addition, copy number loss was detected in the CDKN2A and MTAP genes. Tumor mutation burden (TMB) was low (3 mut/Mb). No BRAF mutations were detected.

The resected specimen revealed a 7.4 × 4.2 × 3.8 cm well-defined, firm, tan-pink, focally necrotic, bulging mass continuous with a scar-like lesion on the skin surface. The mass was abutting the skin, and 0.5 cm from the closest soft tissue margin.

Microscopic examination (Fig. 3) of the resected mass revealed a deeply-seated mass in the deep dermis and subcutaneous tissue, composed of confluent expansile nests and sheets of malignant epithelioid cells with abundant eosinophilic cytoplasm. The cells exhibited high-grade nuclear atypia with irregular nuclear membranes and enlarged eosinophilic nucleoli. A focal area of melanin pigment was present. Mitoses, including atypical mitoses, and necrosis were observed. Neither neurotropism nor tumor-infiltrating lymphocytes (TILs) were identified. No epidermal or junctional activity was noted in the overlying epidermis. The tumoral cells were diffusely positive for S100, SOX-10 and tyrosinase, weakly positive for PRAME and HMB45, Melan-A and negative for BRAF V600E. In addition, p16 showed a loss of nuclear and cytoplasmic expression.

Fig. 3

Spitz melanoma, resected specimen. A The deep dermal/subcutaneous tumor with overlying epidermis shows mild spongiosis with no epidermal or junctional melanocytic activity, and dermis shows a perivascular inflammatory infiltrate (x20). B Confluent nests of malignant epithelioid cells with abundant eosinophilic cytoplasms and focal necrosis (x100). C-D Epithelioid cells exhibit very prominent nucleoli (x200 and x400, respectively). E Malignant cells with adjacent areas of prominent pigmentation (x400). F Malignant cells are diffusely positive for S100 IHC (x200). G Malignant cells are diffusely positive for tyrosinase IHC (x200). H Malignant cells are weakly positive for PRAME IHC (x200). I Malignant cells are weakly positive for Melan-A IHC (x200). J Malignant cells show loss of p16 expression (x200)

Based on histomorphology, immunohistochemistry and tumor profile analysis with MAP3K8 gene fusion, a diagnosis of Spitz melanoma was rendered. Additionally, the presence of copy number loss of CDKN2A (with p16 null type), GRIN2A and TERT promoter mutations predicted association with rapid disease progression.

Post-surgical follow-up records (1 month later) showed a healing wound with minimal discomfort. Further imaging studies revealed a metastasis to the right lung. The patient is undergoing immunotherapy with nivolumab and ipilimumab.

Table 1 Summary of molecular findings

Discussion

Spitz melanomas (SM), or malignant Spitz tumors, constitute a distinct subtype of spitzoid melanomas, as recently characterized [1, 3]. The features of these lesions include a larger tumor size (> 1 cm), broad ulceration, asymmetry, lack of maturation, nuclear pleomorphism, necrosis and high mitotic activity featuring atypical mitoses. Moreover, it presents spitzoid characteristics, such as the presence of large epithelioid and/or spindle melanocytes [1].

The molecular alterations of SM are characterized by initiating genomic alterations typical of Spitz nevus, including kinase fusions and HRAS mutations, alongside homozygous loss of 9p21. Mutations in BRAF V600E​​ or other molecular characteristics of conventional melanocytic tumors are not present by definition; that is, presence of such alterations excludes a diagnosis of SM. Furthermore, copy number loss of CDKN2A, GRIN2A and TERT promoter mutations and multiple chromosomal copy number aberrations may be observed, correlating with an adverse prognosis [5, 6]. Additionally, SM usually exhibit a lower tumor mutational burden when compared with conventional melanoma [2].

The differential diagnosis of SM encompasses the spectrum of Spitz melanocytic neoplasms, which share common features such as clinical aspects, histological characteristics like epithelioid and spindled melanocytes, and specific genetic alteration. However, non-melanoma Spitz tumors typically exhibit low to intermediate grade histomorphological features, fewer DNA alterations, and a low risk of progression compared to their malignant counterparts. Atypical Spitz tumors, also known as Spitz melanocytomas, represent intermediate Spitz melanocytic neoplasms that may display some high-grade histomorphological features. Moreover, the umbrella term ‘spitzoid melanomas’ includes melanomas with spitzoid cytomorphology that lack Spitz-defining genetic alterations and demonstrate conventional melanocytic aberrations, most commonly BRAF V600E mutations, as mentioned above [2, 3]. Other differentials to consider, especially in cases of dermal lesions without an epidermal component (as in our case), include clear cell sarcoma, which is characterized by EWSR1 translocations [7]; alveolar soft part sarcoma, which features ASPSCR1-TFE3 fusion [8], epithelioid sarcoma, and epithelioid malignant peripheral nerve sheath tumor, usually demonstrating SMARCB1 (INI1) deletion [9, 10].

Kinase fusions activate downstream cell signaling pathways such as MAP kinase signaling, JAK/STAT signaling, and PI3K/AKT1/MTOR signaling. This activation leads to the promotion of gene transcription, cell growth, proliferation, differentiation, and survival [11, 12]. In Spitz neoplasms, kinase fusions represent important mechanisms of oncogene activation and may serve as therapeutic targets for metastatic SM. Spitz neoplasms frequently harbor fusions involving various receptor tyrosine kinases such as ROS1, NTRK1-3, ALK, RET, MET, as well as serine/threonine kinases including BRAF and MAP3K8 [12, 13].

MAP3K8, a serine-threonine protein kinase, activates extracellular signal-regulated kinase (ERK) 1/2 by phosphorylating its direct substrate, mitogen-activated protein kinase (MEK). High MAP3K8 expression in melanoma leads to resistance against BRAF inhibitors via a MEK-dependent mechanism that does not necessitate BRAF activation upstream [14]. Various MAP3K8 fusion partners have been identified in Spitz neoplasms, with SVIL being the most common 3’ fusion partner [15]. The details of MAP3K8 kinase fusion partners identified in the literature in Spitz tumors are provided in Table 2. Other 3ʹ fusion partners, not mentioned in Table 2, include SFMBT2, MIR3681HG, CDC42EP, SLC4A4, CCNY, LINC00703, and PIP4K2A [15]. MAP3K8-rearranged cases exhibit epithelioid features, amelanotic melanocytes, marked pleomorphism, p16 loss, ulceration, and are more prevalent in atypical Spitz tumors and SM compared to other kinase fusions [4].

Table 2 Summary of MAP3K8 kinase fusion partners identified in the literature in Spitz tumors

ABLIM1, known as Actin-binding LIM protein 1, is a cytoskeletal protein that binds to actin filaments and interacts with cytoplasmic targets [17]. Dysregulation of ABLIM1 is associated with different types of cancers, and its loss in melanoma serves as a tumor suppressor [18]. MAP3K8::ABLIM1 fusion has been previously reported in peritoneal mesothelioma [19]. Interestingly, there have been no previous reports of fusions involving MAP3K8::ABLIM1 in melanoma to our knowledge.

In conclusion, we report an unusual aggressive Spitz melanoma with a novel MAP3K8::ABLIM1 fusion gene and absence of identifiable in-situ component, contributing to the expanding morphologic and molecular spectrum of Spitz melanoma.