Klinické, morfologické a molekulární vlastnosti Spitzoidních nádorů

Clinical, Morphological and Molecular Features of Spitz tumors

Spitz tumors represent a heterogeneous group of challenging melanocytic neoplasms, displaying a range of biological behaviors, spanning from benign lesions, Spitz nevi (SN) to Spitz melanomas (SM), with intermediate lesions in between known as atypical Spitz tumors (AST). They are histologically characterized by large epithelioid and/or spindled melanocytes arranged in fascicles or nests, often associated with characteristic epidermal hyperplasia and fibrovascular stromal changes. In the last decade, the detection of mutually exclusive structural rearrangements involving receptor tyrosine kinases ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serine threonine kinases BRAF and MAP3K8, or HRAS mutation, led to a clinical, morphological and molecular based classification of Spitz tumors.

The recognition of some reproducible histological features can help dermatopathologist in assessing these lesions and can provide clues to predict the underlying molecular driver.

In this review, we will focus on clinical and morphological findings in molecular Spitz tumor subgroups.

Keywords:

classification – histopathology – melanocytic lesions – genetic alterations – dermoscopy-histopathology correlations – intermediate lesions – melanocytomas – practical recommendations for diagnosis – ALK – Spitz tumor – Atypical Spitz tumor – Spitz melanoma – molecular driver – molecular morphological correlation – ROS1 – NTRK1 – NTRK2 – NTRK3 – RET – MET – BRAF –MAP3K8 fusion – HRAS mutation – MAP2K1 mutation

Autoři: Michele Donati ^1,2; Boulos Mansour ³; Michael Hagstrom ⁴; Pedram Gerami ⁴; Dmitry V. Kazakov ⁵
Působiště autorů: Department of Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy ¹; University Campus Bio-Medico of Rome, Rome, Italy ²; Department of Pathology, Ospedale Israelitico di Roma, Italy ³; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ⁴; IDP Institut für Dermatohistopathologie, Pathologie Institut Enge, Zürich, Switzerland ⁵
Vyšlo v časopise: Čes.-slov. Patol., 60, 2024, No. 1, p. 35-48
Kategorie: Přehledový článek

Souhrn

Spitzoidní nádory představují heterogenní skupinu melanocytárních neoplázií vykazujících široké spektrum biologického chování od zcela benigních afekcí typu névu Spitzové až po maligní léze v podobě spitzoidních melanomů. Mezi těmito dvěma skupinami se pak nacházejí léze s nejistým biologickým chováním v podobě atypických spitzoidních tumorů. Histologicky jsou charakterizované objemnými epiteloidními a/nebo vřetenitými melanocyty uspořádanými do fasciklů nebo hnízd a často s charakteristickou epidermální hyperplázií a fibrovaskulárními stromálními změnami v okolí.

Rozpoznání specifických strukturálních přestaveb v genech pro tyrozinkinázové receptory ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serin threoninové kinázy BRAF a MAP3K8 či HRAS mutací v posledním desetiletí umožnilo přesnější klinickou, morfologickou a molekulární subklasifikaci spitzoidních tumorů. Rozpoznání specifických histologických rysů pak může dermatopatologům napomoct nejen v hodnocení těchto lézí, ale může i nepřímo poukazovat na konkrétní molekulární změny.

Tento doškolovací článek se zaměřuje na klinické a morfologické nálezy u molekulárně definovaných podskupin spitzoidních tumorů.

Klíčová slova:

ALK – Spitzoidní tumor – atypický spitzoidní tumor – spitzoidní melanom – molekulární změna – molekulárně-morfologická korelace – ROS1 – NTRK1 – NTRK2 – NTRK3 – RET – MET – BRAF – MAP3K8 fúze – HRAS mutace – MAP2K1 mutace

Stránka z

Zdroje

Zedek DC, McCalmont TH. Spitz nevi, atypical spitzoid neoplasms, and spitzoid melanoma. Clin Lab Med 2011; 31(2): 311-320.
Ludgate MW, Fullen DR, Lee J, et al. The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. Cancer 2009; 115(3): 631-641.
Kamino H, Flotte TJ, Misheloff E, Greco MA, Ackerman AB. Eosinophilic globules in Spitz’s nevi. New findings and a diagnostic sign. Am J Dermatopathol 1979; 1(4): 319-324.
Ackerman AB. Discordance among expert pathologists in diagnosis of melanocytic neoplasms. Hum Pathol 1996; 27(11): 1115-1116
Kempf W, Haeffner AC, Mueller B, Panizzon RG, Burg G. Experts and gold standards in dermatopathology: qualitative and quantitative analysis of the self-assessment slide seminar at the 17th colloquium of the International Society of Dermatopathology. Am J Dermatopathol 1998; 20(5): 478-482.
Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999; 30(5): 513-520.
Wechsler J, Bastuji-Garin S, Spatz A, et al. Reliability of the histopathologic diagnosis of malignant melanoma in childhood. Arch Dermatol 2002; 138(5): 625-628.
Spitz S. Melanomas of childhood. Am J Pathol 1948; 24(3): 591-609.
Yagawa K, Nakamura K. An autopsy case of the widely metastasized juvenile malignant melanoma arisen from naevus pigmentosus. Gan 1954; 45(2-3): 278-280.
Brunck J. Uber einen metastasierenden, aber klinisch gutartig verlaufenden Naevus mit blasig entarteten Naevuszellen und über deren Genese. Arch Dermatol Syph 1953; 196(2): 170-175.
Elder DE SR, Willemze R.: WHO Classification of Skin Tumours. Lyon; IARC: 2018.
Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 2014; 5: 3116.
Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 2000; 157(3): 967-972.
Quan VL, Zhang B, Zhang Y, et al. Integrating Next-Generation Sequencing with Morphology Improves Prognostic and Biologic Classification of Spitz Neoplasms. J Invest Dermatol 2020; 140(8): 1599-1608.
Gerami P, Scolyer RA, Xu X, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. Am J Surg Pathol 2013; 37(5): 676-684.
Gerami P, Cooper C, Bajaj S, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. Am J Surg Pathol 2013; 37(9): 1387-1394.
Lee S, Barnhill RL, Dummer R, et al. TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep 2015; 5: 11200.
Quan VL, Zhang B, Mohan LS, et al. Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms. Am J Surg Pathol 2019; 43(4): 538-548.
Houlier A, Pissaloux D, Masse I, et al. Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations. Mod Pathol 2020; 33(5): 846-857.
Busam KJ, Kutzner H, Cerroni L, Wiesner T. Clinical and pathologic findings of Spitz nevi and atypical Spitz tumors with ALK fusions. Am J Surg Pathol 2014; 38(7): 925-933.
Yeh I, de la Fouchardiere A, Pissaloux D, et al. Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions. Am J Surg Pathol 2015; 39(5): 581-591.
Kastnerova L, Martinek P, Grossmann P, et al. A Clinicopathological Study of 29 Spitzoid Melanocytic Lesions With ALK Fusions, Including Novel Fusion Variants, Accompanied by Fluorescence In Situ Hybridization Analysis for Chromosomal Copy Number Changes, and Both TERT Promoter and Next-Generation Sequencing Mutation Analysis. Am J Dermatopathol 2020; 42(8): 578-592.
Donati M, Kastnerova L, Martinek P, et al. Spitz Tumors With ROS1 Fusions: A Clinicopathological Study of 6 Cases, Including FISH for Chromosomal Copy Number Alterations and Mutation Analysis Using Next-Generation Sequencing. Am J Dermatopathol 2020; 42(2): 92-102.
Gerami P, Kim D, Compres EV, et al. Clinical, morphologic, and genomic findings in ROS1 fusion Spitz neoplasms. Mod Pathol 2021; 34(2): 348-357.
Yeh I, Busam KJ, McCalmont TH, et al. Filigree-like Rete Ridges, Lobulated Nests, Rosette-like Structures, and Exaggerated Maturation Characterize Spitz Tumors With NTRK1 Fusion. Am J Surg Pathol 2019; 43(6): 737-746.
VandenBoom T, Quan VL, Zhang B, et al. Genomic Fusions in Pigmented Spindle Cell Nevus of Reed. Am J Surg Pathol 2018; 42(8): 1042-1051.
Amin SM, Haugh AM, Lee CY, et al. A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms. Am J Surg Pathol 2017; 41(4): 491-498.
Kim D, Compres EV, Zhang B, et al. A Series of RET Fusion Spitz Neoplasms With PlaqueLike Silhouette and Dyscohesive Nesting of Epithelioid Melanocytes. Am J Dermatopathol 2021; 43(4): 243-251.
Mansour B, Vanecek T, Kastnerova L, Nosek D, Kazakov DV, Donati M. Spitz Tumor With SQSTM1::NTRK2 Fusion: A Clinicopathological Study of 5 Cases. Am J Dermatopathol 2023; 45(5): 306-310.
Drilon A, Jenkins C, Iyer S, Schoenfeld A, Keddy C, Davare MA. ROS1-dependent cancers biology, diagnostics and therapeutics. Nat Rev Clin Oncol 2021; 18(1): 35-55.
Raghavan SS, Kapler ES, Dinges MM, Bastian BC, Yeh I. Eruptive Spitz nevus, a striking example of benign metastasis. Sci Rep 2020; 10(1): 16216.
Robertson SJ, Orme L, Teixeira R, et al. Evaluation of Crizotinib Treatment in a Patient With Unresectable GOPC-ROS1 Fusion Agminated Spitz Nevi. JAMA Dermatol 2021; 157(7): 836-841.
Church AJ, Moustafa D, Pinches RS, Hawryluk EB, Schmidt BAR. Genomic comparison of malignant melanoma and atypical Spitz tumor in the pediatric population. Pediatr Dermatol 2022; 39(3): 409-419.
Cesinaro AM, Gallo G, Manfredini S, Maiorana A, Bettelli SR. ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis. Histopathology 2021; 79(6): 966-974.
Mariño-Enríquez A, Dal Cin P. ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages. Cancer Genet 2013; 206(11): 357-373.
Iwahara T, Fujimoto J, Wen D, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 1997; 14(4): 439-449.
Pulford K, Morris SW, Turturro F. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 2004; 199(3): 330-358.
Slupianek A, Nieborowska-Skorska M, Hoser G, et al. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/ anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 2001; 61(5): 2194-2199.
Newman S, Fan L, Pribnow A, et al. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nat Med 2019; 25(4): 597-602.
Fujimoto M, Togashi Y, Matsuzaki I, et al. A case report of atypical Spitz tumor harboring a novel MLPH-ALK gene fusion with discordant ALK immunohistochemistry results. Hum Pathol 2018; 80: 99-103.
Chung CT, Marrano P, Swanson D, Dickson BC, Thorner PS. Fusion of ALK to the melanophilin gene MLPH in pediatric Spitz nevi. Hum Pathol 2019; 87: 57-64.
Busam KJ, Sung J, Wiesner T, von Deimling A, Jungbluth A. Combined BRAF(V600E)-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol 2013; 37(2): 193-199.
Kiuru M, Jungbluth A, Kutzner H, Wiesner T, Busam KJ. Spitz Tumors: Comparison of Histological Features in Relationship to Immunohistochemical Staining for ALK and NTRK1. Int J Surg Pathol 2016; 24(3): 200-206.
Perron E, Pissaloux D, Charon Barra C, et al. Melanocytic Myxoid Spindle Cell Tumor With ALK Rearrangement (MMySTAR): Report of 4 Cases of a Nevus Variant With Potential Diagnostic Challenge. Am J Surg Pathol 2018; 42(5): 595-603.
Niu X, Chuang JC, Berry GJ, Wakelee HA. Anaplastic Lymphoma Kinase Testing: IHC vs. FISH vs. NGS. Curr Treat Options Oncol 2017; 18(12): 71.
Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 2003; 4(4): 299-309.
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15(12): 731-747.
Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5(1): 25-34.
Coppola V, Barrick CA, Southon EA, et al. Ablation of TrkA function in the immune system causes B cell abnormalities. Development 2004; 131(20): 5185-5195.
Kaplan DR, Martin-Zanca D, Parada LF. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 1991; 350(6314):158-160.
Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 1991; 252(5005): 554-558.
Rubin JB, Segal RA. Growth, survival and migration: the Trk to cancer. Cancer Treat Res 2003; 115: 1-18.
Cappellesso R, Nozzoli F, Zito Marino F, et al. NTRK Gene Fusion Detection in Atypical Spitz Tumors. Int J Mol Sci 2021; 22(22): 12332.
Goto K, Pissaloux D, Tirode F, de la Fouchardière A. Spitz nevus with a novel TFG-NTRK2 fusion: The first case report of NTRK2-rearranged Spitz/Reed nevus. J Cutan Pathol 2021; 48(9): 1193-1196.
Lezcano C, Shoushtari AN, Ariyan C, Hollmann TJ, Busam KJ. Primary and Metastatic Melanoma With NTRK Fusions. Am J Surg Pathol 2018; 42(8): 1052-1058.
Yeh I, Tee MK, Botton T, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol 2016; 240(3): 282-290.
de la Fouchardière A, Tee MK, Peternel S, et al. Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes. Mod Pathol 2021; 34(4): 735-747.
Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J. Regulation of c-Met-dependent gene expression by PTEN. Oncogene 2004; 23(57): 9173-9182.
Kervarrec T, Pissaloux D, Tirode F, et al. Morphologic features in a series of 352 Spitz melanocytic proliferations help predict their oncogenic drivers. Virchows Arch 2022; 480(2): 369-382.
Yeh I, Botton T, Talevich E, et al. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun 2015; 6: 7174.
Czyz M. HGF/c-MET Signaling in Melanocytes and Melanoma. Int J Mol Sci 2018; 19(12): 3844.
Zarabi SK, Azzato EM, Tu ZJ, et al. Targeted next generation sequencing (NGS) to classify melanocytic neoplasms. J Cutan Pathol 2020; 47(8): 691-704.
Tschandl P, Berghoff AS, Preusser M, et al. NRAS and BRAF mutations in melanoma-associated nevi and uninvolved nevi. PLoS One 2013; 8(7): e69639.
Hutchinson KE, Lipson D, Stephens PJ, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res 2013; 19(24): 6696-6702.
Kim D, Khan AU, Compres EV, et al. BRAF fusion Spitz neoplasms; clinical morphological, and genomic findings in six cases. J Cutan Pathol 2020; 47(12): 1132-1142.
Ross JS, Wang K, Chmielecki J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer 2016; 138(4): 881-890.
Perron E, Pissaloux D, Neub A, et al. Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors. Virchows Arch 2018; 472(3):469-476.
Wu G, Barnhill RL, Lee S, et al. The landscape of fusion transcripts in spitzoid melanoma and biologically indeterminate spitzoid tumors by RNA sequencing. Mod Pathol 2016; 29(4): 359-369.
Donati M, Kastnerova L, Ptakova N, Michal M, Kazakov DV. Polypoid Atypical Spitz Tumor With a Fibrosclerotic Stroma, CLIP2-BRAF Fusion, and Homozygous Loss of 9p21. Am J Dermatopathol 2020; 42(3): 204-207.
Raghavan SS, Peternel S, Mully TW, et al. Spitz melanoma is a distinct subset of spitzoid melanoma. Mod Pathol 2020; 33(6):1122-1134.
Roy SF, Bastian BC, Maguiness S, et al. Multiple desmoplastic Spitz nevi with BRAF fusions in a patient with ring chromosome 7 syndrome. Pigment Cell Melanoma Res 2021; 34(5): 987-993.
Roy SF, Milante R, Pissaloux D, et al. Spectrum of Melanocytic Tumors Harboring BRAF Gene Fusions: 58 Cases With Histomorphologic and Genetic Correlations. Mod Pathol 2023; 36(6): 100149.
Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J 1996; 15(4): 817-826.
Hagemann D, Troppmair J, Rapp UR. Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells. Oncogene 1999; 18(7): 1391-1400.
Gándara ML, López P, Hernando R, Castaño JG, Alemany S. The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity. Mol Cell Biol 2003; 23(20): 7377-7390.
Ceci JD, Patriotis CP, Tsatsanis C, et al. Tpl2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Genes Dev 1997; 11(6): 688-700.
Clark AM, Reynolds SH, Anderson M, Wiest JS. Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer 2004; 41(2): 99-108.
Gruosso T, Garnier C, Abelanet S, et al. MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in highgrade serous ovarian carcinomas. Nat Commun 2015; 6: 8583.
Lee JH, Lee JH, Lee SH, et al. TPL2 Is an Oncogenic Driver in Keratocanthoma and Squamous Cell Carcinoma. Cancer Res 2016; 76(22): 6712-6722.
Sourvinos G, Tsatsanis C, Spandidos DA. Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 1999; 18(35):4968-4973.
Newman S, Pappo A, Raimondi S, Zhang J, Barnhill R, Bahrami A. Pathologic Characteristics of Spitz Melanoma With MAP3K8 Fusion or Truncation in a Pediatric Cohort. Am J Surg Pathol 2019; 43(12): 1631-1637.
Pappo AS, McPherson V, Pan H, et al. A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions. Cancer 2021; 127(20): 3825-3831.
Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 2015; 16(5): 281-298.
Martins da Silva V, Martinez-Barrios E, Tell-Martí G, et al. Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS Mutations. J Invest Dermatol 2019; 139(4): 900-908.
Baltres A, Salhi A, Houlier A, et al. Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion. Pigment Cell Melanoma Res 2019; 32(5): 708-713.
LeBlanc RE, Lefferts JA, Baker ML, Linos KD. Novel LRRFIP2-RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications. J Cutan Pathol 2020; 47(12): 1181-1186.
Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature 2017; 545(7653): 175-180.
Moran JMT, Le LP, Nardi V, et al. Identification of fusions with potential clinical significance in melanoma. Mod Pathol 2022; 35(12): 1837-1847.
Donati M, Martinek P, Kastnerova L, Persichetti P, Michal M, Kazakov DV. RAF1 Gene Fusions as a Possible Driver Mechanism in Rare BAP1-Inactivated Melanocytic Tumors: A Report of 2 Cases. Am J Dermatopathol 2020; 42(12): 961-966.
Donati M, Martinek P, Steiner P, et al. Novel insights into the BAP1-inactivated melanocytic tumor. Mod Pathol 2022; 35(5): 664-675.
Donati M, Olivares S, Lemahieu J, Mansour BG, Kazakov DV. Spitz Tumor With RAF1 Fusion: A Report of 3 Cases. Annals of Diagnostic Pathology 2023; 67:152215.
Barbacid M. ras genes. Annu Rev Biochem1987; 56: 779-827.
van Dijk MC, Bernsen MR, Ruiter DJ. Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the differential diagnosis of Spitz nevus and spitzoid melanoma. Am J Surg Pathol 2005; 29(9): 1145-1151.
Ross AL, Sanchez MI, Grichnik JM. Molecular nevogenesis. Dermatol Res Pract 2011; 2011: 463184.
Lezcano CM, Yeh I, Eslamdoost N, et al. Expanding the Spectrum of Microscopic and Cytogenetic Findings Associated With Spitz Tumors With 11p Gains. Am J Surg Pathol 2021; 45(2): 277-285.
van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, Klaasen A, Mooi WJ, Blokx WA. HRAS-mutated Spitz tumors: A subtype of Spitz tumors with distinct features. Am J Surg Pathol 2010; 34(10): 1436-1441.
Donati M, Nosek D, Waldenbäck P, et al. MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology. Am J Dermatopathol 2021; 43(6): 412-417.
Sunshine JC, Kim D, Zhang B, et al. Melanocytic Neoplasms With MAP2K1 in Frame Deletions and Spitz Morphology. Am J Dermatopathol 2020; 42(12): 923-931.
Kerckhoffs KGP, Aallali T, Ambarus CA, Sigurdsson V, Jansen AML, Blokx WAM. Expanding spectrum of “spitzoid” lesions: a small series of 4 cases with MAP2K1 mutations. Virchows Arch 2021; 479(1): 195-202.
Roskoski R Jr. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun 2012; 417(1): 5-10.
Gao Y, Chang MT, McKay D, et al. Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties. Cancer Discov 2018; 8(5): 648-661.
Zhao J, Benton S, Zhang B, et al. Benign and Intermediate-grade Melanocytic Tumors With BRAF Mutations and Spitzoid Morphology: A Subset of Melanocytic Neoplasms Distinct From Melanoma. Am J Surg Pathol 2022; 46(4): 476-485.