Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

AIMS: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases. METHODS AND RESULTS: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012). CONCLUSIONS: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status.

Features, management, and outcomes of pediatric scalp melanomas.

Pediatric melanoma of the scalp has the highest mortality of any anatomic location. We describe five pediatric patients with a diagnosis of scalp melanoma receiving care at Massachusetts General Hospital and/or Boston Children's Hospital from 2018 through 2022. Melanoma presented in diverse contexts: cellular blue nevus-associated, compound nevus-associated, spitzoid, nodular, and superficial spreading subtypes. This study describes a range of melanoma presentations and emphasizes the need for additional compilation of data on pediatric scalp melanomas to promote their recognition and improve patient care.

Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology. Limitations: Findings may not be generalizable to nonfamilial melanoma cases. Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.

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

Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as "atypical Spitz tumors" (or Spitz melanocytoma) and malignant Spitz melanoma. More recently a large body of work has uncovered the molecular underpinning of Spitz tumors, including mutations in the HRAS gene and several gene fusions involving several protein kinases. Here we present an overarching view of our current knowledge and understanding of Spitz tumors, detailing clinical, histopathological and molecular features characteristic of these lesions.

Genetic and methylation profiles distinguish benign, malignant and spitzoid melanocytic tumors.

Accurate classification of melanocytic tumors is important for prognostic evaluation, treatment and follow-up protocols of patients. The majority of melanocytic proliferations can be classified solely based on clinical and pathological criteria, however in select cases a definitive diagnostic assessment remains challenging and additional diagnostic biomarkers would be advantageous. We analyzed melanomas, nevi, Spitz nevi and atypical spitzoid tumors using parallel sequencing (exons of 611 genes and 507 gene translocation analysis) and methylation arrays (850k Illumina EPIC). By combining detailed genetic and epigenetic analysis with reference-based and reference-free DNA methylome deconvolution we compared Spitz nevi to nevi and melanoma and assessed the potential for these methods in classifying challenging spitzoid tumors. Results were correlated with clinical and histologic features. Spitz nevi were found to cluster independently of nevi and melanoma and demonstrated a different mutation profile. Multiple copy number alterations and TERT promoter mutations were identified only in melanomas. Genome-wide methylation in Spitz nevi was comparable to benign nevi while the Leukocytes UnMethylation for Purity (LUMP) algorithm in Spitz nevi was comparable to melanoma. Histologically difficult to classify Spitz tumor cases were assessed which, based on methylation arrays, clustered between Spitz nevi and melanoma and in terms of genetic profile or copy number variations demonstrated worrisome features suggesting a malignant neoplasm. Comprehensive sequencing and methylation analysis verify Spitz nevi as an independent melanocytic entity distinct from both nevi and melanoma. Combined genetic and methylation assays can offer additional insights in diagnosing difficult to classify Spitzoid tumors.

Increased incidence of melanoma in children and adolescents in Finland in 1990-2014: nationwide re-evaluation of histopathological characteristics.

BACKGROUND: Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. AIMS: The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. METHODS: Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. RESULTS: A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. CONCLUSIONS: The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed.Key messageA nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.

Spitz Nevus: Review and Update.

The Spitz nevus is an uncommon melanocytic nevus. These lesions classically appear in childhood as a red, dome-shaped papule. They appear rarely in adults and may be pigmented. The Spitz nevus can develop suddenly and grow rapidly, reaching a 1-cm diameter in 6 months or less. There are 3 classes of spitzoid neoplasms: typical Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. The diagnosis should be cautiously differentiated, especially in children. Immunohistochemistry and molecular studies have been helpful in differentiating difficult cases; however, no set of criteria has been accepted to predict biological behavior of atypical Spitz nevi.

An unusual pediatric case of atypical spitzoid neoplasm.

Spitzoid melanocytic lesions describe a spectrum of pediatric melanocytic proliferations ranging from benign Spitz nevi to malignant spitzoid melanomas typically arising within the first two decades of life. Atypical spitzoid neoplasm (ASN) is a poorly defined category within this spectrum that poses a unique diagnostic challenge due to histologic findings with insufficient atypical characteristics to make the diagnosis of melanoma. This report presents an exceptionally rare case of an ulcerative atypical spitzoid neoplasm mimicking an infantile hemangioma in a two-month-old girl treated with pulse dyed laser (PDL) and surgical excision. Our patient ultimately underwent five excisions over a 2-year period, with successful maintenance of function and dexterity of the affected fingers.

What's new in pediatric melanoma and Spitz tumors? Pretty much everything.

LAY SUMMARY: Pathologists sometimes have great difficulty in determining whether a mole biopsied from the skin of a child is benign or malignant. New molecular technologies have helped pathologists to identify pediatric melanomas, but there are still some atypical moles that cannot be definitively classified as benign or malignant. With further research, it is hoped that the number of these atypical tumors can be decreased and that the treatment for all children with moles and melanoma can be improved.

Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation.

Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib-but not selumentinib-and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.

Molecular pathology as a diagnostic aid in difficult-to-classify melanocytic tumours with spitzoid morphology.

Accurate classification of melanocytic proliferations has important implications for prognostic prediction, treatment and follow-up. Although most melanocytic proliferations can be accurately classified using clinical and pathological criteria, classification (specifically distinction between nevus and melanoma) can be challenging in a subset of cases, including those with spitzoid morphology. Genetic studies have shown that mutation profiles differ between primary melanoma subtypes and Spitz nevi. These differences may aid in distinguishing benign from malignant in some melanocytic tumours. Here, we present a selection of melanocytic proliferations with equivocal histopathological criteria, wherein genetic analysis was requested to help guide classification. In two of four cases, the genetic results offered valuable insights, allowing a definitive diagnosis, indicating the diagnostic value of mutation profiling in a real-world routine clinical setting. Although histopathological assessment remains decisive in melanocytic proliferation classification, we recommend including genetic profiling in cases of borderline or atypical lesion to support accurate classification.

Pediatric melanoma in the Hispanic population: An analysis of institutional and national data.

BACKGROUND/OBJECTIVES: Pediatric melanoma is rare and remains poorly characterized, especially in racial/ethnic minorities of whom Hispanics are the largest and fastest growing in the United States. The health care burden of melanoma in Hispanics, who often present with more advanced disease, is rising and has even been called an early epidemic in California. We sought to document key clinicopathologic features of melanoma in Hispanic pediatric patients and to compare these parameters to pediatric non-Hispanic whites (NHWs) under the a priori hypothesis that Spitzoid melanomas occur in greater proportions in Hispanics. METHODS: Single-institution cross-sectional study of pediatric melanoma cases (age < 20 years) with Hispanic stratification and comparison with matched Surveillance, Epidemiology, and End Results (SEER) data from the same time frame (1988-2016). RESULTS: Of our 61 institutional cases of pediatric melanoma, Hispanics (11), compared with NHWs (40), presented significantly younger (11.7 years, 95% CI: 2.77-8.00 years; P = .001), with lower limb predominance (46%; P < .05), mostly Spitzoid melanomas (82%; P < .05), and thicker tumors (2.34 mm, CI: 0.26-2.19 mm; P < .05). Similarly, SEER data (2499 cases) showed greater proportions of childhood/pre-pubertal adolescent melanomas (<15 years), lower limb involvement, Spitzoid subtype (36.5% vs 22.5% in NHWs; P = .001), and advanced (regional/distant) disease stages in Hispanics (212) compared with NHWs (2197). CONCLUSIONS: Pediatric melanomas may present differently in Hispanics, and heightened awareness/lower threshold to biopsy high-risk Spitzoid tumors on the lower limb may be warranted. Further investigations are needed to aid prevention and early detection in a vulnerable minority population less likely to seek outpatient dermatology specialty care.

Giant lung metastasis of NRAS-mutant melanoma in a 24-year-old patient with a history of BRAF-mutant conventional melanoma harboring Spitzoid morphology: a case report.

BACKGROUND: Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous and overlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or, in some cases, impossible. Among the Spitzoid lesions, there is a lesion termed an atypical Spitz tumour (AST) that has intermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertain malignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitz nevus or an AST with fatal consequences. It is, therefore, advised to perform a molecular characterization in cases where uncertain skin lesions are presented, as it may provide extended set of information with a possible impact on the treatment options. Furthermore, preventive measures, such as regular physical and skin examinations, as well as thorough scheduling of individual follow-up visits, are essential in patients with potentially malignant skin nevi. CASE REPORT: We report a case of a young adult female with a history of AST excision with a negative sentinel lymph node biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis, she presented with a giant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathological examination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequent appearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis of Spitzoid melanoma, however, was not confirmed. Moreover, the molecular examination revealed a major discordance between the initial lesion and the lung tumour, which most likely excluded the possible association of the lung metastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features and termed as AST, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course was complicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless, despite complex specialised medical care, the patient's clinical condition rapidly deteriorated. By this time, no active oncological treatment was possible. The patient was delegated to local hospice for palliative care six months after the surgery and died three weeks later. CONCLUSIONS: Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization, as well as the close clinical follow-up should be always precisely performed in patients with uncertain skin lesions, such as AST.

Metastatic PRAME-Expressing Juvenile Spitzoid Melanoma on the Buttock.

Since the cost of molecular biological methods for Spitzoid neoplasms is expensive, the number of institutes that employ these methods might be limited. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen that is useful to distinguish melanoma from other melanocytic disorders, including pediatric Spitzoid tumors that are difficult to diagnose by conventional methods alone. In this report, we report a case of PRAME-expressing juvenile Spitzoid melanoma with lymph node metastasis. Unexpectedly, there were few PRAME-expressing cells in the primary tumor, whereas most metastatic tumors expressed PRAME in the metastatic lymph node. These observations might suggest that, in Spitzoid melanomas, a limited number of melanoma cells possess metastatic potential and that metastatic lesions possess clonality.

Uncommon Subtypes of Malignant Melanomas: A Review Based on Clinical and Molecular Perspectives.

Malignant melanoma represents the most aggressive type of skin cancer. Modern therapies, including targeted agents and immune checkpoint inhibitors, have changed the dismal prognosis that characterized this disease. However, most evidence was obtained by studying patients with frequent subtypes of cutaneous melanoma (CM). Consequently, there is an emerging need to understand the molecular basis and treatment approaches for unusual melanoma subtypes. Even a standardized definition of infrequent or rare melanoma is not clearly established. For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs-not associated with classical V600E/K BRAF mutations-malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas. Finally, we collected information regarding melanomas from non-traditional primary sites, which emerge from locations as unique as meninges, dermis, lymph nodes, the esophagus, and breasts. The aim of this review is to summarize and highlight the main scientific evidence regarding rare melanomas, with a particular focus on treatment perspectives.

Spitz Nevus and Other Spitzoid Tumors in Children. Part 2: Cytogenetic and Molecular Features. Prognosis and Treatment. / Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 2: características citogenéticas y moleculares. Pronóstico y tratamiento.

Melanocytic neoplasms with spitzoid morphology (Spitz nevi, atypical Spitz tumors, and spitzoid melanomas) may be benign or malignant. Because the malignant potential of atypical Spitz tumors is uncertain, the proper therapeutic approach has been much debated over the years. Promising new techniques for molecular analysis have enabled better predictions of the biological behavior of these tumors. We review their cytogenetic features and prognosis and also provide an update of the most recent recommendations for management.

Spitzoid cutaneous melanoma is associated with favorable clinicopathological factors and outcome.

BACKGROUND: Spitzoid melanoma is one of the rare subtypes of melanoma, whose clinical and pathological characteristics have yet to be understood. OBJECTIVE: Understanding the histopathologic features and behavior characteristics of Spitzoid cutaneous melanoma. METHODS: A total number of 11 Turkish Caucasian patients with pathologically diagnosed Spitzoid melanoma were analyzed retrospectively. RESULTS: The median age of patients was 24 years (ranging from 16 to 54 years), and the females outnumbered the males (90%). The extremities, especially lower limbs (67%), were the most commonly affected primary areas (64% of patients). Median depth and mitotic rate were 2.2 mm and 3 /mm2 , respectively. The presence of ulceration and regression were observed in a few lesions (14%). While tumor-infiltrating lymphocytes were expressed in all of the lesions, none of the lesions was associated with lymphovascular invasion and/or neurotropism. The regional lymph nodes were involved only in minority of the patients (27%), and no patients had metastatic disease. Recurrences occurred in only two patients (18%) that affected merely distant areas, that is, lung and brain. The median disease-free survival time and 5-year disease-free survival rate were 20.5 months and 80.6%, respectively. Only one (9%) death occurred; and the median overall survival time was 26.2 months, and 5-year overall survival rate was 90.7%. CONCLUSION: Spitzoid cutaneous melanoma is correlated with favorable histopathologic and clinical characteristics, and therefore, it is associated with better survival rates.

Neoplasias melanocíticas spitzoides: estudio clínico-histopatológico de 62 lesiones en un hospital universitario chileno / Spitzoid melanocytic neoplasms: clinical-histopathological study of 62 lesions in a Chilean university hospital

INTRODUCCIÓN: Las neoplasias spitzoides son tumores melanocíticos con un espectro biológico variable, que constituyen un desafío diagnóstico. Los estudios en población latinoamericana son muy escasos, no contando con series chilenas. OBJETIVO: Caracterizar clínica e histopatológicamente a los pacientes con neoplasias spitzoides en el Hospital Clínico de la Universidad de Chile. METODOLOGÍA: Estudio retrospectivo, basado en revisión de fichas clínicas y biopsias de pacientes con diagnóstico confirmado de nevo de Spitz (NS), tumor de Spitz atípico y melanoma spitzoide, entre 1995-2018. Se analizó: edad, sexo, características clínicas e histopatológicas. RESULTADOS: Se estudiaron 62 neoplasias spitzoides. 39 mujeres (62,9%). Edad promedio de 18,9 (+14,3) años. Localización de lesiones: 8 (12,9%) cabeza, 6 (9,7%) tronco, 17 (27,4%) extremidades superiores y 22 (35,5%) extremidades inferiores; en 9 (14,5%) no se registró. Tamaño promedio 5,5 mm. Respecto al diagnóstico clínico: 21 (33,9%) nevo melanocítico, 16 (25,8%) nevo atípico, 12 (19,4%) NS, 7 (11,3%) lesiones vasculares, 3 (4,8%) melanoma y 3 (4,8%) otro. En cuanto al diagnóstico histopatológico: NS clásico 38 (61,3%), Nevo de Reed 9 (14,5%), NS desmoplásico 2 (3,2%), NS atípico 8 (12,9%) y melanoma spitzoide 5 (8,1%). CONCLUSIÓN: El presente estudio constituye la primera serie chilena de neoplasias spitzoides, según la literatura revisada. Destaca el mayor número de lesiones en mujeres y en extremidades, lo que ya había sido informado en otras series similares. Considerando la dificultad en el diagnóstico clínico preoperatorio, destaca un número mayor de sospecha de neoplasias spitzoides comparado a otros estudios.

INTRODUCTION: Spitzoid neoplasms are melanocytic tumors with a variable biological spectrum, which are a diagnostic challenge. There are few studies in Latin American population, not finding chilean series. OBJECTIVE: Clinically and histopathologically characterize patients with spitzoid neoplasms in the Hospital Clínico Universidad de Chile. METHODOLOGY: Retrospective study, based on re-view of clinical records and biopsies of patients with confirmed diagnosis of Spitz nevus (SN), atypical Spitz tumors and spitzoid melanoma (SM), between 1995-2018. It is analyzed: age, sex, clinical and histopathological characteristics. RESULTS: 62 spitzoid neoplasms were studied. 39 women (62.9%). Average age of 18.9 (+14.3) years. Location of injuries: 8 (12.9%) head, 6 (9.7%) trunk, 17 (27.4%) upper extremities and 22 (35.5%) lower extremities; in 9 (14.5%) it is not identified. Average size 5.5 mm. Clinical diagnosis: 21 (33.9%) melanocytic nevus, 16 (25.8%) atypical nevus, 12 (19.4%) NS, 7 (11.3%) vascular lesions, 3 (4.8%) melanoma and 3 (4.8%) other. Histopathological diagnosis: classic NS 38 (61.3%), Reed Nevus 9 (14.5%), desmoplastic SN 2 (3.2%), atypical SN 8 (12.9%) and SM 5 (8.1%). CONCLUSION: The present study appears in the first chilean series of spitzoid neoplasms, according to the literature reviewed. It highlights the greatest number of injuries in women and in the extremities, which had already been reported in other similar series. In the preoperative clinical diagnosis, a greater number of suspicion of spitzoid neoplasms stands out compared to other studies.

Common and not so Common Melanocytic Lesions in Children and Adolescents.

The acquired melanocytic nevus is the most common lesion encountered by pediatric pathologists and dermatopathologists in their daily practice. In most cases, there are few difficulties in histopathologic diagnosis. However, it is the acquired melanocytic lesion known as the Spitz nevus, with its intrinsic atypical features which becomes the challenge since it exists along a histopathologic and biologic continuum from the atypical Spitz tumor to spitzoid melanoma. The frustration with some of these spitzoid lesions is that even the "experts" cannot agree as to the differentiation of one from the other even at the level of molecular genetics. Other melanocytic lesions are discussed including the congenital melanocytic nevus with its proliferative nodule(s) and melanoma as the ultimate complication. Although uncommon, cutaneous melanoma in the first 2 decades is emerging as a clinical problem especially in young women in the second decade of life. These are ultraviolet-associated neoplasms whose histopathologic and prognostic features are identical to the adult experience. Considerable progress has been made over the past 15 to 20 years in our understanding of cutaneous melanocytic lesions, but gaps still exist in the important group of spitzoid lesions. It can also be anticipated that more cutaneous melanomas in children will be seen in the future based upon epidemiologic studies.

Atypical ALK-positive Spitz tumors with 9p21 homozygous deletion: Report of two cases and review of the literature.

ALK rearrangements occur in up to 10% of spitzoid melanocytic neoplasms. No reported cases have shown homozygous deletion of 9p21 (CDKN2A) or gains of 6p25 (RREB1) or 11q13 (CCND1), which have been associated with aggressive clinical behavior. Here we report 2 unique cases. Case 1 occurred in a 9-year-old male with a 14-mm nodule on the anterior left thigh. Biopsy revealed an ALK-positive Spitz tumor containing an irregular nodule of densely packed melanocytes with increased mitoses and loss of p16 immunoreactivity. FISH analysis showed homozygous deletion of 9p21 and gain of 6p25. Sentinel lymph node biopsy revealed small subcapsular foci of tumor. Case 2 occurred in a 7-year-old female with a 12-mm nodule on the anterior right ankle. Biopsy revealed an ALK-positive Spitz tumor containing an expansile nodule of pleomorphic epithelioid melanocytes with numerous mitoses and loss of p16 immunoreactivity. By FISH, the nodule showed homozygous deletion of 9p21 and gains of 6p25 and 11q13. Our cases show the transformation of tumors produced by an activating kinase fusion gene (ALK) through secondary genetic changes including loss of tumor suppressor activity (CDKN2A). Long-term follow up will be important to further define the behavior of these unique Spitz tumors.