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Hum Pathol 2019 Mar 8. Epub 2019 Mar 8.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.

Spitzoid neoplasms typically affect young individuals and include Spitz nevus, atypical Spitz tumor and Spitzoid melanoma. Spitz tumors can exhibit gene fusions involving the receptor tyrosine kinases NTRK1, NTRK3, ALK, ROS1, RET, or MET, or, the serine-threonine kinase BRAF. Since most studies have been based on adult cases, we studied ALK fusions in Spitz nevi occurring in pediatric patients. Read More

Zhonghua Bing Li Xue Za Zhi 2019 Mar;48(3):215-219

Clinical Pathological Diagnosis Center of Fudan University, Shanghai 200032, China.

To investigate the clinicopathologic features and prognosis of ALK-positive Spitz tumors. Thirteen patients with ALK-positive Spitz tumors diagnosed at Shanghai Cancer Center, Fudan University from October 2016 to December 2017 were collected. All cases were routinely evaluated histopathological features in HE staining and detected ALK protein expression by immunohistochemistry. Read More

SAGE Open Med Case Rep 2019 18;7:2050313X19829630. Epub 2019 Feb 18.

Division of Dermatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Atypical Spitzoid lesions pose a distinct challenge in classification as they may comprise a mixture of both classic benign nevus and cutaneous melanoma characteristics. Immunostaining and molecular analysis, such as comparative genomic hybridization, can assist in narrowing the differential diagnosis. We present a case of a 5-year-old male with an atypical Spitzoid lesion on his back. Read More

J Cutan Pathol 2019 May 14;46(5):310-316. Epub 2019 Feb 14.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Accurate classification of spitzoid melanocytic lesions is difficult due to overlapping clinical and histopathologic features between Spitz nevi, atypical Spitz tumors (ASTs), and spitzoid melanomas. Expression of p16 (CDKN2A) has been used as a marker of spitzoid lesions. However, its expression may be variable. Read More

Dermatol Pract Concept 2018 Oct 31;8(4):320-321. Epub 2018 Oct 31.

Department of Dermatology, Hospital Clínico San Carlos, Madrid, Spain.

Pediatr Dermatol 2018 Nov;35(6):821-822

Ann Transl Med 2018 Jun;6(12):249

First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

Significant progress in the molecular pathology of melanocytic tumors have revealed that benign neoplasms, so-called nevi, are initiated by gain-of-function mutations in one of several primary oncogenes, such as in acquired melanocytic nevi, in congenital nevi or / in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation. Secondary genetic alterations overcome tumor suppressive mechanisms and allow the progression to intermediate lesions characterized by TERT-p mutation or to invasive melanomas displaying disruption of tumor suppressor genes. Currently, melanoma is molecularly regarded as four different diseases, namely , , and the "triple wild type" subtypes, which are associated with particular clinicopathological features. Read More

Skin Res Technol 2019 Jan 18;25(1):106-107. Epub 2018 Jul 18.

Department of Dermatology, Hospital de Santa Maria, Lisboa, Portugal.

Juvenile xanthogranuloma is the most common type of non-Langerhans cell histiocytosis. It appears primarily in infancy, where its differential diagnosis includes Spitz nevus, dermal nevus and molluscum contagiosum. We report the case of a 2-year-old boy with juvenile xanthogranuloma, as diagnosed using real-time, in vivo reflectance confocal microscopy. Read More

Pediatr Dermatol 2018 Sep 26;35(5):e328-e329. Epub 2018 Jun 26.

Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Spitz nevus commonly appears as a solitary lesion. A 12-year-old male patient presented with a 6-month history of several pigmented lesions on his trunk and lower extremities. He had undergone chemoradiotherapy and unrelated umbilical cord blood transplantation against recurring acute lymphoblastic leukemia for 6 years. Read More

Am J Dermatopathol 2018 Jul;40(7):469-478

Chief Resident (A.L.J.D.), Associate Professor (J.M.G., S.C.S.), Assistant Professor (J.R.K.), Professor (W.B.), Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

Recent studies have identified kinase fusions in Spitzoid melanocytic neoplasms, and approximately 10% of Spitzoid neoplasms harbor anaplastic lymphoma kinase (ALK) rearrangements and corresponding ALK immunoreactivity. Deep penetrating nevi (DPN), a subset of melanocytic neoplasms, have histologic and immunohistochemical overlap that have historically supported classification of DPN with blue/cellular blue nevi (CBN). However, HRAS mutations have rarely been detected in DPN, thereby also linking them to Spitz nevi. Read More

J Am Acad Dermatol 2018 Oct 18;79(4):728-735. Epub 2018 Jun 18.

Department of Medicine, University of Padua, Padua, Italy. Electronic address:

Background: ALK receptor tyrosine kinase gene (ALK) rearrangements have been described in spitzoid lesions with a plexiform growth pattern.

Objective: To investigate the prevalence of ALK alterations in a large series of spitzoid lesions.

Methods: ALK immunohistochemical and fluorescence in situ hybridization analyses of 78 spitzoid plexiform lesions including 41 Spitz nevi, 29 atypical Spitz tumors (ASTs), and 8 spitzoid melanomas. Read More

Am J Surg Pathol 2018 Aug;42(8):1042-1051

Department of Dermatology, Feinberg School of Medicine, Northwestern University.

Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. Read More

Clin Exp Dermatol 2018 Oct 20;43(7):782-789. Epub 2018 May 20.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Background: Clonal naevi are characterized by a focal proliferation of pigmented melanocytes in an otherwise banal naevus. These subclones are often composed of aggregates of larger, epithelioid melanocytes with nuclear atypia and dusty-grey cytoplasmic pigmentation, which are referred to as 'pulverocytes', and this finding may lead to a misdiagnosis of malignant melanoma (MM).

Aim: To characterize the significance of subclones of dusty-grey pigmented epithelioid melanocytes within spitzoid neoplasms. Read More

Pathol Res Pract 2018 Jun 11;214(6):821-825. Epub 2018 May 11.

Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Microphthalmia-associated transcription factor (MiTF) is used as a marker of melanocytic differentiation. However, MiTF immunoexpression has also been observed in histiocytes, macrophages, smooth muscle cells and fibroblasts, which raise the concern of fibrohistiocytic (FH) lesions being misdiagnosed as melanoma based on MiTF immunoreactivity. MiTF has been known to be positive in FH tumors, but this is the first study evaluating ninety-three fibrohistiocytic neoplasms to understand and delineate the staining pattern of MiTF in these tumors. Read More

Am J Dermatopathol 2018 Dec;40(12):903-907

Department of Biomedicine, Internal Medicine, and Specialized, Medicine (DIBIMIS), Section of Dermatology, University of Palermo, AOUP Paolo Giaccone, Palermo, PA, Italy.

Spitz nevi, atypical Spitz tumors and Spitzoid melanoma, the three clinicopathologic forms that constitute the spectrum of the Spitz-type melanocytic lesions, share a histologic picture characterized by large spindle and/or epithelioid ganglion-like cells, with various admixtures of multinucleate bizarre cells. This remarkable cytology has always been interpreted as an unusual, as well as unexplained form of atypia. We report a case of atypical Spitz tumor with Homer Wright-like rosettes, a feature characteristic of ganglioneuroblastic proliferation. Read More

J Drugs Dermatol 2018 May;17(5):574-576

Introduction: Pediatric Spitz nevi can pose significant diagnostic challenges to both clinicians and dermatopathologists when the current image-recognition based gold standard is employed. PRAME (preferentially expressed antigen in melanoma) and/or LINC (long intergeneic non-coding RNA 518) gene expression in adult patients in samples obtained non-invasively via adhesive patches differentiates primary melanomas from atypical nevi and other pigmented lesions with a NPV of over 99%, a sensitivity of 91%, and a specificity of 69%, to help clinicians rule out melanoma and the need for surgical biopsies of atypial pigmented lesions with suspicion for melanoma. Surgically obtained melanomas from adult patients show the same gene expression pattern. Read More

Am J Dermatopathol 2018 Dec;40(12):899-902

Clinical Pathology Associates, Austin, TX.

Oncocytic metaplasia represents a histopathologic feature that can be observed in normal tissue such as salivary and lacrimal glands but may also constitute a degenerative metaplastic process as a result of repeated oxidative damage during cellular aging. Although cutaneous oncocytic metaplasia has been considered rare, the finding was seen in over one-third of melanocytic nevi prospectively evaluated, in one study. This case series reports on a small series of oncocytic melanocytic tumors, with the aim of describing this phenomenon in varied contexts and also describing the use of a mitochondrial antigen immunostain, which has not been previously reported. Read More

Int J Surg Pathol 2018 Sep 6;26(6):514-520. Epub 2018 Apr 6.

2 Universidade Federal de São Paulo, São Paulo, Brazil.

Background: Spitzoid tumors are a heterogeneous group of melanocytic neoplasms that frequently imposes diagnostic difficulties. Lately, several advances in molecular biology afforded significant discoveries on the pathogenesis of these tumors. BAP1 (BRCA-1 associated protein-1) inactivation and anomalous expression of kinase translocation-related proteins are among the main criteria launched by new classification proposals. Read More

Pediatr Dev Pathol 2018 Mar-Apr;21(2):252-270

1 Lauren V. Ackerman Laboratory of Surgical Pathology, St. Louis Children's Hospital, Washington University Medical Center, St. Louis, Missouri.

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. Read More

Pediatr Dermatol 2018 Jul 26;35(4):e228-e230. Epub 2018 Mar 26.

Department of Pediatrics, Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Angiomatoid and desmoplastic Spitz nevi are rare histologic variants of Spitz nevi that present most frequently on the extremities of children and young adults. Although Spitz nevi are clinically heterogeneous, one presenting as a keloidal nodule has not been previously published. We present a case of an angiomatoid and desmoplastic Spitz nevus clinically akin to a keloid on an African-American teenager and describe its unique histopathologic features. Read More

Br J Dermatol 2018 Sep 19;179(3):769-770. Epub 2018 Jun 19.

Section of Dermatology, Department of Clinical Medicine and Surgery, Dermatology Unit, University of Naples Federico II, Via Pansini, 5, 80131, Napoli, Italy.

Am J Dermatopathol 2018 Sep;40(9):686-689

Departments of Dermatology, and.

Spitz nevus is a type of melanocytic nevus that can arise as a solitary lesion or as multiple lesions either disseminated or agminated (grouped) in different skin backgrounds (eg, grossly normal, hyperpigmented, or hypopigmented). Agminated Spitz nevi have been rarely reported and are even rarer in a background of hypopigmented skin. We present the case of a 2-month-old girl with multiple, grouped, dome-shaped, red papules arising on a hypopigmented patch with a segmental distribution. Read More

Hum Pathol 2018 Oct 4;80:99-103. Epub 2018 Apr 4.

Department of Diagnostic Pathology, Wakayama Medical University, Wakayama, 641-8509, Japan. Electronic address:

Frequent kinase fusions have been reported in spitzoid neoplasms, approximately 10% of which involve ALK rearrangements. Herein, we report a case of atypical Spitz tumor with a novel MLPH-ALK fusion, which has not been previously reported to contribute to cancer development. The tumor was detected in the right arm of a 40-year-old woman. Read More

Arch Dermatol Res 2018 May 7;310(4):329-342. Epub 2018 Feb 7.

Department of Dermatology, Venereology and Allergology, HELIOS-Klinikum Hildesheim, Senator-Braun-Allee 33, 31135, Hildesheim, Germany.

The histopathologic differentiation between Spitz nevus and melanoma is of particular interest in routine diagnostic procedures of melanocytic tumors. Atypical Spitz nevi are sometimes difficult to distinguish from melanoma. There is still no single criterion that ensures a distinction of melanoma and atypical Spitz nevus. Read More

Australas J Dermatol 2018 Aug 5;59(3):e234-e235. Epub 2018 Feb 5.

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

JAMA 2018 01;319(2):194

Department of Dermatology, Peking Union Medical College Hospital, Beijing, China.

JAMA 2018 01;319(2):194

Private practice, Huntingdon Valley, Pennsylvania.

Pediatr Dermatol 2018 Mar 4;35(2):e99-e102. Epub 2018 Jan 4.

Department of Dermatology, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA.

Acral pigmented Spitz nevi are seldom reported in the literature. We report a new case on the palm of a 4-year-old girl that demonstrated correlation between features observed on dermoscopy and reflectance confocal microscopy (RCM). Histopathology revealed a benign intraepidermal Spitz nevus with transepidermal elimination of melanocytes that showed on RCM as focal atypical bright cells concerning for malignancy. Read More

J Am Acad Dermatol 2018 Aug 4;79(2):367-369. Epub 2018 Jan 4.

Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Clin Exp Dermatol 2018 Apr 20;43(3):363-365. Epub 2017 Dec 20.

Victorian Melanoma Service, Alfred Hospital, Melbourne, Victoria, Australia.

Melanoma Res 2018 02;28(1):71-75

Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts.

There is a significant need for the development of diagnostic tools that can precisely distinguish Spitz nevi and spitzoid melanomas. Here, we report the development of a PCR-based quantitative diagnostic assay for spitzoid melanocytic lesions utilizing the expression ratio of neuropilin-2 and melan-A genes in primary tumor specimens. We find that the expression ratio of neuropilin-2/melan-A is significantly increased in spitzoid melanomas compared with Spitz nevi. Read More

J Cutan Pathol 2018 Feb 17;45(2):180-183. Epub 2017 Dec 17.

Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, Florida.

Nevus spilus is a melanocytic neoplasm characterized by a tan macular background punctuated by multiple hyperpigmented macules or papules that represent various types of nevi. These include junctional and compound nevi, Spitz nevi, and rarely blue nevi. We report a unique case of widespread, multiple nevi spili giving rise to agminated Spitz nevi and congenital-pattern compound nevi. Read More

Br J Dermatol 2018 03 19;178(3):804-806. Epub 2018 Feb 19.

Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, U.S.A.

Exp Mol Pathol 2017 12 21;103(3):279-287. Epub 2017 Nov 21.

Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. Electronic address:

Histopathology is the gold standard for diagnosing melanocytic lesions; however, distinguishing benign versus malignant is not always clear histologically. Single nucleotide polymorphism (SNP) microarray analysis may help in making a definitive diagnosis. Here, we share our experience with the Oncoscan FFPE Assay and demonstrate its diagnostic utility in the context of ambiguous melanocytic lesions. Read More

Pediatr Dermatol 2018 Jan 22;35(1):e55-e56. Epub 2017 Nov 22.

Department of Dermatology, Hospital Universitario Fundacion Jiménez Diaz, Universidad Autónoma, Madrid, Spain.

Juvenile xanthogranuloma is the most common form of non-Langerhans cell histiocytosis in childhood. The clinical differential diagnosis of a solitary juvenile xanthogranuloma includes molluscum contagiosum, Spitz nevus, and melanoma. Lesions larger than 2 cm in diameter may be misdiagnosed as hemangiomas, but this is not typical of smaller juvenile xanthogranuloma. Read More

J Eur Acad Dermatol Venereol 2018 Jul 12;32(7):1128-1137. Epub 2017 Dec 12.

1st University Department of Dermatology - Venereology, "Andreas Sygros" Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.

Background: Spitz naevi may present with clinical and histopathological atypical features that do not affect patient prognosis but may become worrisome for patients ≥40 years presenting with newly appearing SN.

Objective: Patient characteristics and sun behaviour patterns were investigated in correlation with age. SN characteristics and histopathological attributes were also investigated in correlation with age. Read More

J Am Acad Dermatol 2018 05 11;78(5):913-919. Epub 2017 Nov 11.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Background: Shiny white streaks (SWSs) are best visualized with polarized dermoscopy and correlate with dermal fibroplasia histopathologically. SWSs have been described at higher frequencies in melanomas than in benign nevi.

Objective: We assessed the diagnostic value of different patterns of SWSs and their histologic correlate in melanocytic lesions. Read More

Ocul Oncol Pathol 2017 Sep 27;3(3):176-180. Epub 2017 Jan 27.

Department of Ophthalmology, New England Eye Center, Tufts Medical Center, Tufts University, Boston, Massachusetts, USA.

Purpose: To report the clinical, pathological, and immunohistochemical features of the first pigmented spindle cell nevus (PSCN) of Reed documented to have appeared in the eyelid.

Methods: The findings of clinical and histopathological examination are presented, along with differential diagnoses and a review of the pertinent literature.

Case: A 3-year-old boy presented with a rapidly growing, heavily pigmented left lower lid papule raising the concern of malignancy, warranting excisional biopsy. Read More

J Cutan Pathol 2018 Feb 28;45(2):136-140. Epub 2017 Nov 28.

Miraca Life Sciences, Newton, Massachusetts.

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. Read More

J Am Acad Dermatol 2018 02 9;78(2):278-288. Epub 2017 Oct 9.

Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: Knowledge regarding the morphologic spectrum of pediatric melanoma (PM) is sparse, and this may in part contribute to delay in detection and thicker tumors.

Objective: To analyze the clinicodermoscopic characteristics of PM.

Methods: Retrospective study of 52 melanomas diagnosed in patients before the age of 20 years. Read More

Rev Paul Pediatr 2017 Oct-Dec;35(4):476-479. Epub 2017 Sep 21.

Universidade Estadual de Campinas, Campinas, SP, Brasil.

Objective: To report the clinical evolution and handling of a Spitz nevus, from its initial flat feature to becoming an irregular, nodular, reddish lesion.

Case Description: Female child, phototype II, with a small congenital nevus on the left lower limb and other sustained small nevi. The patient went through annual clinical and dermoscopic evaluations between the ages of three and seven, period during which the nevi located on the left thigh grew rapidly. Read More

JAMA 2017 Sep;318(11):1059-1060

Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China.

Dermatol Clin 2017 Oct 28;35(4):525-536. Epub 2017 Jul 28.

University of Colorado School of Medicine, 12605 E 16th Avenue, Aurora, CO 80045, USA. Electronic address:

The assessment of melanoma by light microscopy with hematoxylin-eosin staining remains an often subjective process. However, there are additional diagnostic measures that may be of utility, such as immunohistochemical staining and genetic evaluation. Adjunctive genetic assessment to augment the diagnosis of melanoma includes comparative genomic hybridization or fluorescent in situ hybridization to assess for gains or losses in genetic material, or gene expression profiling in some form, to ascertain the expression of genes associated with malignancy. Read More

Pediatr Dermatol 2017 09;34(5):628-629

Provincial Health Care Services, Institute of Pathology, Santa Maria del Carmine Hospital, Rovereto, Italy.

J Eur Acad Dermatol Venereol 2018 Mar 15;32(3):e101-e102. Epub 2017 Sep 15.

Dermatology Unit, Nuovo Policlinico (edificio 9C), University of Campania, Naples, Italy.

Clin Lab Med 2017 09;37(3):473-484

Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Molecular evaluation of melanocytic tumors can be diagnostically useful to confirm malignancy or benignancy. Molecular tools are ancillary and supplemental to histopathologic evaluation and do not replace conventional microscopy. Immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, and massively parallel short-read sequencing, often referred to as next-generation sequencing, each provide varied (and often incomplete) additional information, and careful planning is necessary if tissue is limited. Read More

Clin Lab Med 2017 09;37(3):431-448

Section of Dermatopathology, Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX, USA.

The histopathologic spectrum of Spitzoid neoplasms includes Spitz nevi, atypical Spitz tumors, and Spitzoid melanomas. Advances in molecular genetics have evolved to the point that Spitzoid lesions can now be reasonably classified according to their distinctive molecular-genetic alterations: Spitzoid lesions with (1) 11p amplification and/or HRAS mutations; (2) isolated loss of 6q23 by fluorescence in situ hybridization (FISH); (3) homozygous deletion of 9p21 by FISH; (4) BAP1 loss and BRAFV600 E mutation; (5) translocations involving any of a number of different oncogenic kinase drivers, including ROS1, ALK, NTRK1, NTRK3, MET, BRAF, and RET; and (6) TERT promoter mutations. Read More

Am J Surg Pathol 2017 Oct;41(10):1333-1346

Departments of *Pathology §Dermatopathology ∥Dermatology †Clinical Cancer Genomics Laboratory ‡Helen Diller Cancer Center, University of California, San Francisco, CA ¶Department of Pathology, Lahey Clinic, Burlington, MA.

Pigmented epithelioid melanocytoma (PEM) is a rare cutaneous melanocytic tumor first described as epithelioid blue nevus in patients with the Carney Complex (CC). PEM was among the first established examples of an intermediate class of melanocytic tumors, including atypical Spitz tumors, with frequent metastasis to lymph nodes but only rare extranodal spread. Sporadic and CC-associated PEM are essentially histologically indistinguishable. Read More

Indian J Dermatol Venereol Leprol 2017 Sep-Oct;83(5):612-614

Department of Dermatology, Katihar Medical College and Hospital, Katihar, Bihar, India.

Pediatr Dermatol 2017 Jul 30;34(4):438-445. Epub 2017 Jun 30.

Department of Dermatology, Bezmialem Vakif University, Istanbul, Turkey.

Background/objectives: Spitz nevi are melanocytic lesions with clinical, dermoscopic, and histopathologic presentations that may resemble those of melanoma. The evolution of Spitz nevi is a well-known feature. The objectives of this study were to investigate the clinical and dermoscopic features of Spitz nevi and define their evolution. Read More