Morphologic features in a series of 352 Spitz melanocytic proliferations help predict their oncogenic drivers

Abstract

Spitz nevi are indolent melanocytic tumors arising preferentially during and after childhood. Over the last decades, recurrent oncogenic drivers, sparsely detected in melanoma, were identified in Spitz melanocytic proliferations. Therefore, the detection of such drivers appears as a relevant diagnostic tool to distinguish both entities. Interestingly, morphologic features might correlate with the oncogenic drivers. Thus, the goal of this study was to assess the performances of previously identified morphological criteria to predict the presence of specific drivers. In total, 352 Spitz melanocytic proliferations either with a genetically identified oncogenic driver or investigated for ALK, ROS1, and NTRK1 overexpression by immunohistochemistry were enrolled in the present study. The microscopic features of the cases were assessed blindly with regards to the molecular status and, performances of previously described morphological criteria to predict the molecular status were assessed applying the likelihood-ratio test (LHR). Overall, an oncogenic driver was identified in 76% of the cases (n = 268/352). No microscopic features allowed the reliable prediction of ROS1-and NTRK1-overexpressing cases. By contrast, a plexiform pattern can contribute to the recognition of ALK-overexpressing cases (LHR(+) = 6.14). Importantly, the pseudo-schwannoma variant was highly suggestive of NTRK3-rearranged cases (LHR(+) = 43). Moreover, atypical/malignant tumor (LHR(+) = 5.18), severe cellular atypia (LHR(+) = 5.07), and p16 loss (LHR(+) = 14) contribute to the recognition of MAP3K8-rearranged cases, while the presence of a sheet-like architecture (LHR(+) = 5.39) and a marked fibrosis of the stroma (LHR(+)=5.06) were predictive of BRAF-fused tumors. To conclude, our study confirms ALK-overexpressing, NTRK3-, MAP3K8-, and BRAF-rearranged cases harbored distinct morphologic features allowing their microscopic recognition.

Cutaneous Melanomas: A Single Center Experience on the Usage of Immunohistochemistry Applied for the Diagnosis

“…), but this is beyond the scope of this article [ 6 ]. Since these genetic alterations lead to an over- and/or aberrant expression of specific molecules, and the latter are associated with well-defined histological features of the melanocytic lesion, an expert dermatopathologist could suspect a specific genetic alteration from just the H&E exam and prove it with the immunohistochemistry [ 6 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. In our routine practice, we do not use standard panels; the choice of immunohistochemical panels is performed case-by-case, based on the H&E exam.…”

“…Specifically, the antibodies we use in our laboratory and specific histological entities, related to their over- and/or aberrant expression, are the following: -BRAF V600E: melanocytic lesions in intermittently sun-exposed skin (superficial spreading cM, simple lentigo, conventional and/or lentiginous cN, and dysplastic cN), deep-penetrating cN, BAP1 -inactivated melanocytic lesions, pigmented epithelioid melanocytoma (PEM), acral melanocytic lesions (especially cM), nodular cM (less frequent), and nevoid cM (less frequent); -c-Kit/CD117: acral melanocytic lesions (especially cM), and lentigo maligna; -ALK, ROS1, pan-TRK (NTRK1, NTRK2, and NTRK3), RET, and MET: Spitz lesions (also Reed cN) and acral melanocytic lesions (especially cM); -β-catenin: deep-penetrating cN, rare cases of cM with a “deep-penetrating like silhouette”; -PRKAR1A: PEM; -BAP-1: BAP1 -inactivated melanocytic lesions, cM arising in blue cN and atypical cellular blue tumor (rare cases); -NF1: lentigo maligna, desmoplastic cM, and acral melanocytic lesions (especially cM); -IDH1: recently introduced category of melanocytoma. In this diagnostic setting, although the immunohistochemistry has shown excellent concordance rates with molecular biology techniques (PCR, FISH, and NGS) and, therefore, represents a reliable, feasible, time- and money-saving tool for investigating these lesions, it is usually adopted as a “screening tool”, and the molecular biology techniques are adopted to confirm and expand the genetic background of the analyzed lesions [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. These techniques, differently from the immunohistochemistry, are able to identify the specific mutations and/or fusion partners; these data could provide relevant pathogenetic, prognostic, and therapeutic indications (specific mutations are associated with pharmacological resistances; additionally, specific fusions are associated with marked pharmacological sensitivity to kinase inhibitors) [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ].…”

“…In this diagnostic setting, although the immunohistochemistry has shown excellent concordance rates with molecular biology techniques (PCR, FISH, and NGS) and, therefore, represents a reliable, feasible, time- and money-saving tool for investigating these lesions, it is usually adopted as a “screening tool”, and the molecular biology techniques are adopted to confirm and expand the genetic background of the analyzed lesions [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. These techniques, differently from the immunohistochemistry, are able to identify the specific mutations and/or fusion partners; these data could provide relevant pathogenetic, prognostic, and therapeutic indications (specific mutations are associated with pharmacological resistances; additionally, specific fusions are associated with marked pharmacological sensitivity to kinase inhibitors) [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. A summary of these immunohistochemical markers and the histological entities related to their over- and/or aberrant expression is presented in Table 2 ; illustrative examples of some of these immunohistochemical markers and the corresponding histological entities are shown in Figure 2 .…”

The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification

“…Furthermore, even with the assistance of ancillary studies, there is generally poor concordance between dermatopathologists on the diagnosis of these lesions ( 19 – 22 ). However, correlations between lesion morphology with recently characterized genetic oncologic drivers can assist in identifying these lesions, facilitating accuracy of future epidemiologic studies ( 23 ).…”

Wholistic approach: Transcriptomic analysis and beyond using archival material for molecular diagnosis

“…This integrative management of transcriptomic data allowed the first description and refinement of several neoplastic entities in the field of mesenchymal, melanocytic, mesothelial, and rare tumors, using almost exclusively archived FFPE material: alternative rearrangement of PDGFD in dermatofibrosarcoma protuberans , 28 endometrial stromal sarcoma in general, 6 sarcoma with CIC::NUTM1 rearrangement, 29 perivascular myoid neoplasm with SRF fusion , 30 well‐differentiated rhabdomyosarcomas with SRF fusion, 31 heterogeneity of rhabdomyosarcomas, 32 undifferentiated round cell sarcoma with CRTC1::SS18 fusion, 5 superficial pleomorphic tumors with PRDM10 fusion, 33 giant cell tumor with NCOR2 fusion, 34 acral fibrochondromyxoid tumor with THBS1 fusion, 35 unclassified sclerosing malignant melanomas with AKAP9::BRAF gene fusion, 36 cutaneous melanocytoma with CRTC::TRIM11 fusion, 37,38 melanocytic myxoid spindle cell tumor with ALK rearrangement (MMySTAR), 39 melanocytoma with concomitant mutation of IDH1 and NRAS , 40 CYSLTR2 ‐mutant cutaneous melanocytic neoplasms, 41 agminated melanocytic Spitz nevi arising in a giant congenital hyperpigmented macule with three‐way complex rearrangement of TRPM1::PUM1::LCK , 42 agminated Spitz nevi with GOPC::ROS1 mosaicism, 43 primary melanoma of the lung with FNBP1::BRAF fusion, 44 melanocytic tumors with either RASGRF1 45 or RASGRF2 fusion, 46 melanocytic Spitz neoplasms with MAP3K8 fusion, 47 melanocytic spitz tumors in general, 43,48–50 clear cell tumor with melanocytic differentiation and MITF::CREM 51 and ACTIN::MITF fusion, 52 and solid papillary mesothelial tumor 53 …”