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A Diagnostic Algorithm for Atypical Spitzoid Tumors: Guidelines for Immunohistochemical and Molecular Assessment Jeong Hee Cho-Vega

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A Diagnostic Algorithm for Atypical Spitzoid Tumors: Guidelines for Immunohistochemical and Molecular Assessment Jeong Hee Cho-Vega Modern Pathology (2016) 29, 656–670 656 © 2016 USCAP, Inc All rights reserved 0893-3952/16 $32.00 A diagnostic algorithm for atypical spitzoid tumors: guidelines for immunohistochemical and molecular assessment Jeong Hee Cho-Vega Department of Pathology, Dermatopathology, University of Miami Miller School of Medicine, Miami, FL, USA Atypical spitzoid tumors are a morphologically diverse group of rare melanocytic lesions most frequently seen in children and young adults. As atypical spitzoid tumors bear striking resemblance to Spitz nevus and spitzoid melanomas clinically and histopathologically, it is crucial to determine its malignant potential and predict its clinical behavior. To date, many researchers have attempted to differentiate atypical spitzoid tumors from unequivocal melanomas based on morphological, immonohistochemical, and molecular diagnostic differences. A diagnostic algorithm is proposed here to assess the malignant potential of atypical spitzoid tumors by using a combination of immunohistochemical and cytogenetic/molecular tests. Together with classical morphological evaluation, this algorithm includes a set of immunohistochemistry assays (p16Ink4a, a dual-color Ki67/MART-1, and HMB45), fluorescence in situ hybridization (FISH) with five probes (6p25, 8q24, 11q13, CEN9, and 9p21), and an array-based comparative genomic hybridization. This review discusses details of the algorithm, the rationale of each test used in the algorithm, and utility of this algorithm in routine dermatopathology practice. This algorithmic approach will provide a comprehensive diagnostic tool that complements conventional histological criteria and will significantly contribute to improve the diagnosis and prediction of the clinical behavior of atypical spitzoid tumors. Modern Pathology (2016) 29, 656–670; doi:10.1038/modpathol.2016.70; published online 22 April 2016 The term atypical spitzoid tumor applies to a sentinel lymph node biopsies, unnecessary adjuvant morphologically diverse group of rare melanocytic therapies, and emotional and financial strain to the lesions. Majority of atypical spitzoid tumors occur in family. children and young adults, and less frequently in In 1948, it had become apparent that malignant middle-aged or older adults. Atypical spitzoid tumor melanomas in children have different clinical beha- 1 is characterized by a Spitz nevus morphology, but vior than those in adults. This disparity in clinical also displays histological features associated with behavior was obviously a matter of fundamental melanoma. In fact, sometimes it can be nearly importance and Dr Sophie Spitz, a brilliant pathol- impossible to rule out spitzoid melanomas among ogist, raised the following questions: Do histologi- these lesions and is one of the most challenging areas cally malignant melanomas in children differ from in Dermatopathology. Its exact biological potential is those seen in adults? Can the clinical behavior of these lesions be predicted from their histologic also controversial. However, the clinical implica- findings? What factors, if any, influence the clinical tions of diagnosing malignancies are important, as behavior of these lesions? Should the melanomas of failure to recognize melanomas can lead to inade- children be treated any differently from those of quate excisions and recurrence of a neoplasm with adults? She coined the term ‘benign juvenile mela- the potential to metastasize. On the other hand, noma’, which was later renamed as ‘Spitz nevus’ labeling a benign lesion as malignant can lead to based on its benign clinical behavior. morbidity from unwarranted wide re-excisions, Over the years, a subset of cases histologically similar to Spitz nevus cases demonstrated worrisome Correspondence: Dr JH Cho-Vega, MD, PhD, Department of histological features associated with melanomas, Pathology, Dermatopathology The University of Miami Leonard displaying unexpected lymph nodal or distant M. Miller School of Medicine, 1611 N.W 12th Ave, Holtz Building metastasis during a long-term follow-up. These ET Suite 2142A, Miami, FL 33136, USA. E-mail: [email protected] lesions, now called atypical spitzoid tumors, remain Received 8 November 2015; revised 28 February 2016; accepted 6 a controversial entity representing a histologically March 2016; published online 22 April 2016 and clinically heterogeneous group of melanocytic www.modernpathology.org Diagnostic algorithm for atypical spitzoid tumors JH Cho-Vega 657 Table 1 Histological and immunohistochemical features cell proliferation by a dual-color Ki67/MART-1, signifying melanoma in atypical spitzoid tumors a complete loss of p16, and/or HMB45 (Table 1), an algorithmic FISH assay will be performed. Atypical Architectural features ‘ Asymmetrya spitzoid tumors positive by FISH for a melanoma Lack of circumscription pattern’ of chromosomal aberrations, isolated homo- Lack of maturation in depth of the dermis zygous loss of 9p21, isolated gain of 6p25, or gain of Ulcera 11q13 will be diagnosed as ‘spitzoid melanoma with High and frequent consumption of epidermis a specific FISH signature’ and further analysis by Cytological features array-based comparative genomic hybridization will Deep dermal mitosisa not be required (Figures 1a and c). For atypical Frequent mitosisa and atypical mitosis in the dermis spitzoid tumors with negative or borderline positive a High-grade cytological atypia FISH results, the array-based comparative genomic Host response hybridization assay will be performed. If the array- Brisk tumor infiltrating lymphocytic infiltrates based comparative genomic hybridization demon- strates a melanoma pattern of chromosomal aberra- Immunohistochemical features tions, the cases will be diagnosed as spitzoid Deep dermal cell proliferation by a dual-color Ki67/MART-1 Complete loss of HMB45 expression melanomas (Figure 1b). If the array-based compara- Complete loss of p16 expression tive genomic hybridization results are negative or show a non-melanoma pattern of chromosomal aHistological features most correlated with disease progression.3 aberrations, the case will be diagnosed as atypical spitzoid tumors (Figure 1d). As both FISH and array- based comparative genomic hybridization assays do lesions with uncertain malignancy potential. There not detect known melanoma molecular signatures is no standardized histological criterion to establish for this particular type of atypical spitzoid tumors, the diagnosis of atypical spitzoid tumor, which these cases can be associated with ‘a low clinical results in occasional disagreement even among ’ 2,3 risk, as in cases of negative FISH. A conservative re- experts. excision and long-term follow-up for cases with non- To address these difficulties, appropriate molecu- melanoma pattern of array-based comparative geno- lar and immunohistochemical tests have been mic hybridization chromosomal aberrations is developed using a panel of selected immunomarkers recommended. and genes that contribute the most to melanoma pathogenesis.4–7 In particular, recent application of fluorescence in situ hybridization (FISH) and array- Histological evaluation based comparative genomic hybridization assays has uncovered an increasing spectrum of potential Although Spitz nevus is a benign melanocytic chromosomal aberrations implicated in atypical neoplasm, its histological features are ‘atypical’ and spitzoid tumors. Using a combination of immuno- can be difficult to distinguish from melanomas. histochemical and cytogenetic/molecular tests, the HRAS activation found in a subset of Spitz nevi, diagnostic algorithm proposed here aims to assess either by amplification of chromosome 11p or by the malignant potential of atypical spitzoid tumors. HRAS activation mutation,6 could give rise to incompletely transformed melanocytes that share several histological features with melanoma cells but Proposed diagnostic algorithm have limited proliferative activity. Atypical spitzoid tumors display both Spitz nevus and spitzoid In addition to classical morphological evaluation, melanoma features. Therefore, it can be very difficult this algorithm applies a set of immunohistochemis- to rule out spitzoid melanoma in these lesions. In try assays (a dual-color of Ki67/MART-1, p16Ink4a, general, Spitz nevus morphology includes features and HMB45), FISH with five probes (covering the such as dome-shaped, plaque-like, wedge-shaped chromosomal loci 6p25, 8q24, 11q13, centromere 9, morphology; little or no asymmetry; epidermal and 9p21; NeoSITE melanoma, Neogenomics hyperplasia; junctional cleavage; presence of Laboratories), and a more comprehensive array- Kamino bodies; evidence of zonation/maturation based comparative genomic hybridization assay deep in the dermis; and a population of enlarged (University of California, San Francisco) for an entire epithelioid and/or spindled melanocytes with abun- chromosomal evaluation. dant opaque or glass cytoplasm. In contrast, mor- Following the identification of histological fea- phological features signifying melanomas include tures associated with melanoma including ulcers, asymmetry, lack of circumscription, lack of matura- asymmetry, high-grade cellular atypia, and frequent tion deep in the dermis, ulcers, high and frequent dermal and deep dermal mitosis from cases with consumption of epidermis, deep dermal mitosis, Spitz nevus-like morphology (Table 1), a set of atypical and frequent mitosis in the dermal compo- immunohistochemistry assays will be performed. If nent, high-grade cytological atypia, and a brisk immunohistochemistry
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