Search Results (12)

Background: Spitz tumors (STs) are a diverse group of melanocytic lesions that range from benign to malignant. STs pose significant classification challenges due to overlapping histological and immunohistochemical (IHC) features among the STs with different malignant potential. This study aimed to assess the diagnostic value of a melanoma-specific next-generation sequencing (NGS) panel (MelArray) combined with IHC analysis to improve the assessment of diagnostically challenging ST cases. Methods: Patients with STs and available MelArray results were included in this retrospective analysis. Molecular analysis (genetic alterations, tumor mutational burden (TMB), and copy number variations (CNV)), clinical data (demographics and clinical course), and IHC data (scores for markers such as p16, Ki-67, HMB45, PRAME, and Melan A) were evaluated in conjunction and correlated with patient outcomes. Results: Atypical Spitz tumors (ASTs, n = 20) predominantly exhibited heterozygous deletions in melanoma-relevant genes, but these were not accompanied by the multiple damaging mutations commonly associated with melanoma. IHC scores were higher in ASTs compared to Spitz nevi (SN, n = 3), suggesting an intermediate biologic potential. SN exhibited minimal genetic alterations and low IHC scores, reflecting a benign profile. Genetic analysis of the Spitz melanoma (SM, n = 1) revealed a distinct molecular profile with damaging mutations affecting the key regulatory pathways involved in tumor progression, along with a high TMB, and an IHC score comparable to ASTs. During a median follow-up of 36 months (range: 6–48 months, n = 23), no recurrences, distant metastases, or tumor-related deaths were observed. Conclusions: The integration of NGS analysis with the MelArray panel, histology, and immunohistochemistry, enhances the diagnostic accuracy of challenging STs by identifying the genetic alterations linked to malignancy risk. This aids in the detection of high-risk lesions that need a more detailed work-up and more stringent follow-up, and those that will follow a benign course. Larger studies are needed to validate the clinical utility and broader applicability. Full article

Background and Aim: Ex vivo fluorescence confocal microscopy (FCM) systems are innovative optical imaging tools that create virtual high-resolution histological images without any standard tissue processing, either freezing or fixing in formalin and embedding in paraffin. These systems have opened an era that would revolutionize pathological examination by providing rapid, real-time assessments across various pathology subspecialties, potentially replacing conventional methods that are tissue- and time-consuming. This study aimed to present the first utilization of FCM in pediatric surgical oncology, focusing on assessing the benefits, particularly in facilitating rapid and accurate diagnosis. Methods: This preliminary study comprised five consecutive patients undergoing surgical biopsy for disease characterization and surgical strategy selection. After biopsy, tissue samples were prepared and analyzed using FCM without sectioning. A pathologist who evaluated macroscopic and microscopic images, once obtained remotely, could promptly indicate any interventions that require timeliness. Samples were then evaluated with conventional methods. Results: All five lesions were deemed suitable for evaluation. Preliminary diagnoses utilizing FCM included atypical Spitz nevus (1), Wilm’s tumor (1), lymph node reactive hyperplasia (1), malignant germ cell tumor of the testis (1), and Hodgkin’s lymphoma (1). Final histopathological analyses revealed atypical Spitz nevus (1), Wilm’s tumor (1), hyperplastic lymphadenopathy with a prevalent marginal pattern (1), mixed nonseminomatous malignant germinal neoplasm consisting of embryonal carcinoma (90%) and yolk sac tumor (10%), and Hodgkin’s lymphoma nodular sclerosis variant (1). In the case of diagnosis of atypical Spitz nevus, the widening of the resection margins was performed in the same surgery. In the case of testicular neoplasm, radical orchiectomy was performed. A high level of agreement between FCM evaluation and definitive histological examination was observed for all parameters evaluated. Conclusions: FCM represents a significant advancement in pathological imaging technology, offering potential benefits in enhancing traditional tissue processing methods. This preliminary report marks the first application of FCM in pediatric surgical oncology. Our findings underscore the promising role of FCM as an adjunctive tool in pediatric oncology, facilitating prompt diagnosis and treatment initiation. Full article

Background: Atypical Spitz tumor (AST) is an intermediate category among Spitz melanocytic neoplasms. Sentinel node biopsy (SNB) has been proposed in the clinical management of AST patients, but this approach remains the subject of debate. This systematic review aims to summarize the available evidence on SNB procedures in AST patients. Methods: A comprehensive search was conducted, including MEDLINE/Pubmed, EMBASE, and SCOPUS, through April 2023. Case series, cohort studies, and case–control studies of AST patients were eligible for inclusion. PRISMA guidelines were followed. Results: Twenty-two studies with a total of 756 AST patients were included. The pooled SNB prevalence was 54% (95% CI 32 to 75%), with substantial heterogeneity (I2 90%). The pooled SNB+ prevalence was 35% (95% CI 25 to 46%) with moderate heterogeneity (I2 39%). Lymphadenectomy was performed in 0–100% of SNB+ patients. Overall survival rates ranged from 93% to 100%, and disease-free survival ranged from 87% to 100% in AST patients. Overall and disease-free survival rates were 100% in SNB patients. Pooled survival estimates were not calculated due to the heterogeneous timing of the survival assessment and/or the small size of the subgroups. All studies clearly reported inclusion criteria and measured the condition in a standard way for all participants, but only 50% indicated valid methods for the identification of the condition. Conclusions: The oncologic behavior of AST is related to an almost always favorable outcome. SNB does not seem to be relevant as a staging or prognostic procedure, and its indication remains debatable and controversial. Full article

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions. Full article

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. Full article

Current diagnostic algorithms are insufficient for the optimal clinical and therapeutic management of cutaneous spitzoid tumors, particularly atypical spitzoid tumors (AST). Therefore, it is crucial to identify new markers that allow for reliable and reproducible diagnostic assessment and can also be used as a predictive tool to anticipate the individual malignant potential of each patient, leading to tailored individual therapy. Using Reduced Representation Bisulfite Sequencing (RRBS), we studied genome–wide methylation profiles of a series of Spitz nevi (SN), spitzoid melanoma (SM), and AST. We established a diagnostic algorithm based on the methylation status of seven cg sites located in TETK4P2 (Tektin 4 Pseudogene 2), MYO1D (Myosin ID), and PMF1-BGLAP (PMF1-BGLAP Readthrough), which allows the distinction between SN and SM but is also capable of subclassifying AST according to their similarity to the methylation levels of Spitz nevi or spitzoid melanoma. Thus, our epigenetic algorithm can predict the risk level of AST and predict its potential clinical outcomes. Full article

After 25 years, “Ackerman’s conundrum”, namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and MAP3K8, or some mutations, such as HRAS and MAP3K8. These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT-p mutation. Since the accumulation of mutations is gradual and progressive, tumors appear to form a bio-morphologic spectrum, in which they show a progressive increase of clinical risk and histological atypia. In this context, a binary classification Spitz nevus-melanoma appears as no longer adequate, not corresponding to the real genomic substrate of lesions. A ternary classification Spitz nevus-Spitz melanocytoma-Spitz melanoma is more adherent to the real neoplastic pathway, but some cases with intermediate ambiguous features remain difficult to diagnose. A prognostic stratification of Spitz tumors, based on the morphologic and genomic characteristics, as a complement to the diagnosis, may contribute to better treatment plans for patients. Full article

Atypical and malignant cutaneous tumors are understudied in the pediatric population, with limited data on long-term follow-up. This study examines pediatric (0–18 years) atypical melanocytic proliferations over a twenty-year period (January 2002–December2022) using the EPIC SlicerDicer at our institution. Over a twenty-year period, there were 55 cases of pediatric melanoma (53 patients). The median follow-up time was 8 years, 11 months. A proportion of 96% were treated with wide local excision (WLE), and 47% had a sentinel lymph node biopsy (SLNB) (35% positive rate). There were 101 atypical Spitz tumor cases (85% atypical Spitz tumors, 15% Spitz melanoma), with a median follow-up duration of 9 years. A proportion of 77% were treated with WLE (with one patient dying of metastatic disease). There were 10 cases of atypical melanocytic proliferations not otherwise specified, including 5 pigmented epithelioid melanocytomas (PEM), 4 deep-penetrating nevi, and 1 atypical cellular blue nevus. This study adds to the growing body of knowledge on pediatric atypical cutaneous melanocytic proliferations, aligning with many described characteristics such as disease location and overall survival rates, with distinct exceptions (higher melanoma positive SLNB rate, lower atypical Spitz tumor WLE rate, and a case of fatal metastatic atypical Spitz tumor). Full article

Over the past several decades, the study of Spitz neoplasms has flourished, with expanded conceptualization and refined terminology, providing a framework for the assessment and classification of Spitz nevi, atypical Spitz Tumors, and Spitz melanoma. Cancer genomics have generated concepts such as driver and passenger genes and clonal evolution, which can be applied to Spitz tumors. Herein, we provide a historical perspective, followed by a summary of current knowledge and clinical approaches for these challenging tumors. Full article

Spitz neoplasms are a heterogeneous group of melanocytic proliferations with a great variability in the histological characteristics and in the biological behavior. Thanks to recent discoveries, the morpho-molecular landscape of Spitz lineage is becoming clearer, with the identification of subtypes with recurrent features thus providing the basis for a more solid and precise tumor classification. Indeed, specific mutually exclusive driver molecular events, namely HRAS or MAP2K1 mutations, copy number gains of 11p, and fusions involving ALK, ROS, NTRK1, NTRK2, NTRK3, MET, RET, MAP3K8, and BRAF genes, correlate with distinctive histological features. The accumulation of further molecular aberrations, instead, promotes the increasing malignant transformation of Spitz neoplasms. Thus, the detection of a driver genetic alteration can be achieved using the appropriate diagnostic tests chosen according to the histological characteristics of the lesion. This allows the recognition of subtypes with aggressive behavior requiring further molecular investigations. This review provides an update on the morpho-molecular correlations in Spitz neoplasms. Full article

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques. Full article

Cutaneous melanomas are exceptional in children and represent a variety of clinical situations, each with a different prognosis. In congenital nevi, the risk of transformation is correlated with the size of the nevus. The most frequent type is lateral transformation, extremely rare before puberty, reminiscent of a superficial spreading melanoma (SSM) ex-nevus. Deep nodular transformation is much rarer, can occur before puberty, and must be distinguished from benign proliferative nodules. Superficial spreading melanoma can also arise within small nevi, which were not visible at birth, usually after puberty, and can reveal a cancer predisposition syndrome (CDKN2A or CDK4 germline mutations). Prognosis is correlated with classical histoprognostic features (mainly Breslow thickness). Spitz tumors are frequent in adolescents and encompass benign (Spitz nevus), intermediate (atypical Spitz tumor), and malignant forms (malignant Spitz tumor). The whole spectrum is characterized by specific morphology with spindled and epithelioid cells, genetic features, and an overall favorable outcome even if a regional lymph node is involved. Nevoid melanomas are rare and difficult to diagnose clinically and histologically. They can arise in late adolescence. Their prognosis is currently not very well ascertained. A small group of melanomas remains unclassified after histological and molecular assessment. Full article