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1 Challenging Melanocytic Lesions Carlos N. Prieto-Granada M.D. Assistant Professor University of Alabama at Birmingham (UAB) Department of Pathology 2017 AAD Annual Meeting 3/2/17 - Orlando, FL None Conflicts of Interest Acknowledgments Jane Messina M.D. Moffitt Cancer Center Maria Auxiliadora Franco M.D. Moffitt Cancer Center Geling Li M.D. Pathology Department, Children s Hospital of Alabama Amy Theos M.D. Dermatology Department, Children s Hospital of Alabama Peter Pavlidakey M.D. UAB Dermatology Department 1
2 Objectives Case-based overview of salient features of commonly and not-so-commonly encountered related melanocytic lesions Update in molecular findings Quick overview on other related pediatric lesions Case #1- Clinical Features Picture courtesy of Dr. Martin C. Mihm Case #1- Histopathology 2
3 Case #1 - Diagnosis A. Juvenile Xanthogranuloma B. Dysplastic Nevus C. Spitz Nevus D. Melanoma E. Atypical Spitz Tumor Case #1 - Diagnosis A. Juvenile Xanthogranuloma B. Dysplastic Nevus C. Spitz Nevus D. Melanoma E. Atypical Spitz Tumor Classic Spitz Nevus AKA Spindle and Epithelioid Cell Nevus First known description from Darier and Civatte back in 1910 Characterized by Sophie Spitz in 1948 as Melanomas of Childhood with a series of 13 cases with 1 patient dying of widely metastatic disease anticipating problems to come Usually arises in the head and neck area (particularly cheeks), trunk and lower limbs as a rapidly growing papule that is either flesh-colored (mimicking DF/JXG) or red/vascular (mimicking PG) 3
4 Spitz S. Am J Pathol. 1948;24: McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations Philadelphia Elsevier Mosby; 2005 Architecture Classic Spitz Nevus Usually compound - predominantly junctional (Reed), dermal (desmoplastic Spitz) Junctional component: Well-circumscribed large nests of spindle cells on a raining down pattern Epidermal hyperplasia Kamino bodies Dermal component: Symmetrical, imparting a dome-shape to the lesion Inverted triangle shape with evident maturation ( zonation ) Cytology Inherently atypical cytomorphology Epithelioid and spindle cells with pink/ hyalinized cytoplasm and large, often pleomorphic nuclei with vesicular chromatin and prominent nucleoli bizarre forms and giant cells can be seen Pagetoid is often seen ( Pagetoid variant ) OK as far as it is well circumscribed and within the lesion Grow rapidly: mitoses are commonly seen OK as far as they are not marginal Busam KJ, Barnhill RL. Am J Surg Pathol Sep;19(9): Barnhill RL. Mod Pathol. 2006;19 Suppl 2:S Dermal component: Symmetrical, imparting a dome-shape to the lesion Inverted triangle shape with evident maturation ( zonation ) 4
5 Junctional component: Well-circumscribed large nests of spindle cells on a raining down pattern Epidermal hyperplasia HBM45 p16 HMB45 positivity only in the junctional/superficial dermal components and retention of p16 immunoreactivity, reassuring features Spitz Nevus Spitz Nevus Spitzoid Melanoma 5
6 Kamino bodies Case #2 Clinical/Dermoscopic Features Pedrosa AF et al Dermatol Pract Concept Apr 30;6(2):37-41 McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations Philadelphia Elsevier Mosby; 2005 Case #2 Histopathology Pictures courtesy of Dr. Martin C. Mihm 6
7 Case #2 - Diagnosis A. Common Acquired Nevus B. Dysplastic Nevus C. Spindle Cell Melanoma D. Pigmented Spindle Cell Nevus of Reed E. Atypical Spitz Tumor Case #2 - Diagnosis A. Common Acquired Nevus B. Dysplastic Nevus C. Spindle Cell Melanoma D. Pigmented Spindle Cell Nevus of Reed E. Atypical Spitz Tumor Pigmented Spindle Cell Nevus of Reed AKA Pigmented Spindle Cell Tumor of Reed First described by Dr. Richard J. Reed in 1975 Dark brown-black macular or papular domeshaped lesion appearing in the lower limbs of females in the first 4 decades of life Reed RJ et al. Semin Oncol Jun;2(2):
8 Ferrara G Arch Dermatol Nov;141(11): McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations Philadelphia Elsevier Mosby; 2005 Picture courtesy of Dr. Martin C. Mihm Pigmented Spindle Cell Nevus of Reed Well-demarcated, predominantly junctional/superficial dermal growth pattern with long axis of the lesion parallel to long axis of epidermis Spindle cells arranged in nests with frequent cleft artifact between nests and epidermis Finely pigmented spindle cells with monomorphous nuclei and small nucleoli Usually accompanied by inflammation and dermal melanophages Slight dermal fibrosis but no lamellar fibrosis or other features of dysplastic nevi Reed RJ et al Semin Oncol Jun;2(2):
9 BRAF Fusion in one case of PSCN of Reed BRAF Wiesner T et al Pathology Feb;48(2): Case #3 Clinical Features Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina Case #3 Histopathology Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina 9
10 Case #3 Clinical Features Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina Case #3 Histopathology Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina Case #3 Histopathology Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina 10
11 Case #3 - Diagnosis A. Giant Congenital Nevus with Proliferative Nodules B. Multifocally invasive Lentigo Maligna Melanoma with incidental congenital nevus C. Multifocal atypical Spitz tumors D. Agminated desmoplastic Spitz Nevi and Congenital Nevus arising in a background of bilateral segmental Nevus Spilus E. Melanocytic lesions with BAP1 aberrations arising in a congenital nevus Case #3 - Diagnosis A. Giant Congenital Nevus with Proliferative Nodules B. Multifocally invasive Lentigo Maligna Melanoma with incidental congenital nevus C. Multifocal atypical Spitz tumors D. Agminated desmoplastic Spitz Nevi and Congenital Nevus arising in a background of bilateral segmental Nevus Spilus E. Melanocytic lesions with BAP1 aberrations arising in a congenital nevus Desmoplastic Spitz Nevus Uncommon Spitz variant, usually presents in the extremities as scaly, erythematous, flesh-colored or occasionally pigmented papulonodule Affected patients are usually in the third decade of life The lesions usually show variable amount of fibrosis/ hyalinization and are often dermal-based Moscarella E et al Br J Dermatol Apr;172(4): Bastian BC et al Am J Pathol Sep;157(3):
12 McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations Philadelphia Elsevier Mosby; 2005 Desmoplastic Spitz Nevus Following pioneering work by Dr. Bastian s group, it was found that the majority of the lesions this Spitz variant show an activation of the HRAS gene, via increased copy number of 11p (amplification) or via activating mutations of HRAS Bastian BC et al Am J Pathol Sep;157(3): HRAS p.g13r,p.a11s HRAS p.g13r,p.a11s Proline for Arginine in position 13 Alanine for Serine in position 11 Pictures courtesy of Dr. Ma. Auxiliadora Franco and Dr. Jane Messina 12
13 Nevus Spilus Nevus Spilus, AKA speckled lentiginous nevus can be congenital or present in the fist decade of life and often affects Caucasians Tends to follow Blaschko lines and the segmental variants are associated with malignant degeneration Spitz nevi arising in the midst of nevus spilus (agminated Spitz) have reported to harbor HRAS mutations Nevus spilus associated with mosaicism syndromes are also associated with HRAS mutations (mosaicism RASopathies) Sarin KY et al JAMA Dermatol Sep;149(9): Luo S, Tsao H J Invest Dermatol Oct;134(10): Segmental Nevus Spilus Regular Nevus Spilus Haenssle HA et al J Am Acad Dermatol Aug;61(2): Sarin KY et al JAMA Dermatol Sep;149(9):
14 Case #4 Clinical/Dermoscopic Features Yoradjian A et al An Bras Dermatol May-Jun;87(3): Case #4 Histopathology Case #4 Which Test Will Likely Give Results to Allow You to Sleep at Night? A. Melan A + Ki-67 Immunohistochmical Cocktail (Mel-Pro/K-Mart) B. p16 Immunohistochemical stain C. Comparative Genomic Hybridization (CGH) or 7-Probe FISH D. SEQUENOM MassARRAY E. Next Generation Sequencing (NGS) Platform 14
15 Case #4 Which Test Will Likely Give Results to Allow You to Sleep at Night? A. Melan A + Ki-67 Immunohistochmical Cocktail (Mel-Pro/K-Mart) B. p16 Immunohistochemical stain C. Comparative Genomic Hybridization (CGH) or 7-Probe FISH FISH Negative D. SEQUENOM MassARRAY E. Next Generation Sequencing (NGS) Platform Case #4 - Diagnosis A. Spitzoid Melanoma B. Spitz Nevus C. Atypical Spitz Tumor/Nevus D. Superficial Spreading Melanoma E. Granular Cell Tumor Case #4 - Diagnosis A. Spitzoid Melanoma B. Spitz Nevus C. Atypical Spitz Tumor/Nevus D. Superficial Spreading Melanoma E. Granular Cell Tumor 15
16 Atypical Spitz Nevus/Tumor Barnhill RL. Mod Pathol. 2006;19 Suppl 2:S The ambiguity of Spitzoid Lesions A. Benign Malignant Benign Malignant Malignant Benign B. Malignant Benign Benign Malignant Malignant Benign C. Benign Benign Malignant Benign Benign Benign D. Malignant Malignant Malignant Malignant Malignant Malignant E. Benign Benign Benign Benign Benign Benign Lallas A et al J Am Acad Dermatol Jan;72(1):47-53 The ambiguity of Spitzoid Lesions A. Benign Malignant Benign Malignant Malignant Benign B. Malignant Benign Benign Malignant Malignant Benign C. Benign Benign Malignant Benign Benign Benign D. Malignant Malignant Malignant Malignant Malignant Malignant E. Benign Benign Benign Benign Benign Benign Lallas A et al J Am Acad Dermatol Jan;72(1):
17 Atypical Spitz Nevus/Tumor Chromosomal Copy Number Aberrations CGH/FISH + Benign Spitz Nevus et al Atypical Spitz Tumor SAMPUS MELTUMP (Spitzoid) Melanoma MELTUMP: MELanocytic Tumor of Undetermined Malignant Potential SAMPUS: Superficial Atypical Melanocytic Proliferation of Undetermined Significance Elder DE, Xu X Pathology. 2004;36: Comparative Genomic Hybridization (CGH) Theisen, A. (2008) Microarray-based Comparative Genomic Hybridization (acgh). Nature Education 1(1):45 Fluorescence In Situ Hybridization (FISH) 6p25 11q13 9p21 9p21 CEP9 6p25: RREB1 9p21: CDKN2A (p16) loss (Ras-responsive binding protein) > 2 copies CEP9: centromere of 9 11q13: CCDN1 (cyclin-d1) > 2 copies Gerami P et al Am J Surg Pathol. 2013;37: Gerami P et al Am J Surg Pathol. 2014;38:
18 FISH 1. 6p25: RREB1 (Ras-responsive binding protein) > 2 copies 2. 6q23: MYB (myeloblastosis viral oncogene) loss 3. 11q13: CCDN1 (cyclin-d1) > 2 copies 4. CEP6: centromere of q24: MYC > 2 copies 6. 9p21: CDKN2A (p16) loss 7. CEP9: centromere of 9 Pros: No limit in terms of cellularity, relatively easy to do, quick turnaround time Cons: Technical difficulties, required thresholds, narrow view of the potential aberrations, might be hampered by poly/aneuploidy or senescent changes FISH Vs. CGH CGH Analysis of genomic material of tumor versus normal Pros: Panoramic, comprehensive view of the genome Cons: Special equipment is required, limit in thickness 0.4 mm., certain findings are still of undetermined significance Modified from Dr. Timothy McCalmont s ASDP board review lecture Molecular Taxonomy of Melanocytic Lesions BAP1 Loss ROS1 ALK1 NTRK1 Wiesner T et al Pathology Feb;48(2): Case #5 Clinical Features Nguyen TL et al Am J Dermatopathol Feb;35(1):e
19 Case #5 Histopathology Case #5 Histopathology 19
20 Case #5 Histopathology HMB45 p16 Case #5 A. Nodular melanoma arising in a giant congenital nevus B. Atypical proliferative Nodule with Spitzoid Features arising in a giant congenital nevus C. Collision compound congenital nevus and Spitzoid Melanoma D. Giant congenital nevus with focal area of hypercellularity Case #5 FISH Studies were negaeve 20
21 Case #5 A. Nodular melanoma arising in a giant congenital nevus B. Atypical proliferative Nodule with Spitzoid Features arising in a giant congenital nevus C. Collision compound congenital nevus and Spitzoid Melanoma D. Giant congenital nevus with focal area of hypercellularity Case #5 A. Nodular melanoma arising in a giant congenital nevus B. Atypical proliferative Nodule with Spitzoid Features arising in a giant congenital nevus C. Collision compound congenital nevus and Spitzoid Melanoma D. Giant congenital nevus with focal area of hypercellularity Proliferative Nodules in Giant Congenital Nevi Giant congenital nevi (GCN, > 20 cm) have an estimated 5-10% risk of malignant transformation, particularly during the first 5 years of life. Nevertheless, melanomas arising in this setting are extremely rare On the other hand, proliferative nodules (PN) are benign neoplasms that typically present as papules or nodules within the dermis of GCN in 2.9% to 19% of GCN according to some series Yelamos O et al Am J Surg Pathol. 2015;39:
22 The mean age of the 19 patients with PN was 8.1 years (median 5 y) with a range from 1 day to 20 years Median follow-up was 49 months with a range from 6 months to 14 years One PN showed Spitzoid Features Yelamos O et al Am J Surg Pathol. 2015;39: lethal childhood melanomas, diagnosed over a 41-year period Expansile nodules, sheet-like growth pattern and infiltrative borders were noted in most cases (83%) The majority of the cases (9 cases, 75%) demonstrated classic adult-type melanoma epithelioid morphology without outright Spitzoid features The overall features of these tumors were almost Indistinguishable from adult-type melanomas Prieto-Granada CN et al Pathology Dec;48(7): Brief guide on management of Spitzoid/ Pediatric Melanocytic Lesions Benign Spitz nevi: Conservative re-excision or observation for recurrence Atypical Spitz nevus/tumor: Re-excision (5-10 mm margin) and clinical follow up Nevus spilus/giant congenital nevus with proliferative nodules: Excision if possible, observation and further excisions of new lesions develop Pediatric melanomas: Therapeutic approach similar to melanomas in adults but less aggressively if prepubertal, with sentinel lymph node biopsy and staging procedures 22
23 References 1. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, 'Spitzoid melanoma' and risk assessment. Mod Pathol. 2006;19 Suppl 2:S Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread. Am J Surg Pathol Sep;19(9): McKee PH, Calonje E, Granter SR. Pathology of the skin : with clinical correlations / [edited by] Phillip H. McKee, Eduardo Calonje, Scott R. Granter. Edinburgh: Philadelphia Elsevier Mosby; Pedrosa AF, Lopes JM, Azevedo F, Mota A. Spitz/Reed nevi: a review of clinical-dermatoscopic and histological correlation. Dermatol Pract Concept Apr 30;6(2): Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol Jun;2(2): Wiesner T, Kutzner H, Cerroni L, et al. Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy. Pathology. 2016;48: Moscarella E, Al Jalbout S, Piana S, Argenziano G, Lallas A, Longo C, Hofmann-Wellenhof R, Zalaudek I. The stars within the melanocytic garden: unusual variants of Spitz naevi. Br J Dermatol Apr;172(4): 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: Sarin KY, Sun BK, Bangs CD, Cherry A, Swetter SM, Kim J, Khavari PA. Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus. JAMA Dermatol Sep;149(9): Luo S, Tsao H. Epidermal, sebaceous, and melanocytic nevoid proliferations are spectrums of mosaic RASopathies. J Invest Dermatol Oct; 134(10): Haenssle HA, Kaune KM, Buhl T, Thoms KM, Padeken M, Emmert S, Schön MP. Melanoma arising in segmental nevus spilus: detection by sequential digital dermatoscopy. J Am Acad Dermatol Aug;61(2): Yoradjian A, Enokihara MM, Paschoal FM. Spitz nevus and Reed nevus. An Bras Dermatol May-Jun;87(3): Lallas A, Moscarella E, Longo C, Kyrgidis A, de Mestier Y, Vale G, Guida S, Pellacani G, Argenziano G Likelihood of finding melanoma when removing a Spitzoid-looking lesion in patients aged 12 years or older. J Am Acad Dermatol Jan;72(1): Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology. 2004;36: Theisen, A. (2008) Microarray-based Comparative Genomic Hybridization (acgh). Nature Education 1(1): 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: Gerami P, Busam K, Cochran A, et al. Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up. Am J Surg Pathol. 2014;38: Nguyen TL, Theos A, Kelly DR, Busam K, Andea AA. Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall. Am J Dermatopathol Feb;35(1):e Yelamos O, Arva NC, Obregon R, et al. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. Am J Surg Pathol. 2015;39: Prieto-Granada CN, Lezcano C, Scolyer RA, Mihm MC Jr, Piris A. Lethal melanoma in children: a clinicopathological study of 12 cases. Pathology Dec;48(7):
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