CONTENTS

Introduction: Melanocytes and Their Tumors...... 1 1. Non-Neoplastic Hyperpigmentations...... 5 Ephelides (Freckles)...... 5 Simple Ephelis (Freckle)...... 5 Actinic (Solar) Lentigo...... 6 Miscellaneous Hyperpigmentations...... 9 Mucosal Melanosis (Genital Lentiginosis)...... 9 Café Au Lait Spot...... 11 Becker Nevus...... 12 Dermal Melanocytoses...... 12 Nevus of Ota...... 12 2. Common Acquired Melanocytic Nevi...... 15 Benign Melanocytic Tumors...... 15 Common Acquired Melanocytic Nevi...... 15 Lentigo Simplex...... 20 Junctional Melanocytic Nevus...... 21 Compound Melanocytic Nevus...... 22 Dermal Melanocytic Nevus...... 29 Variants of Acquired Melanocytic Nevi, Nonsite Dependent...... 40 Halo Nevus...... 40 Deep Penetrating Nevus...... 47 Recurrent Melanocytic Nevus...... 49 Nevi of Special Sites...... 55 Nevus of Genital Skin...... 55 Nevus of the Breast...... 61 Nevus of Acral Skin...... 61 Nevus of Flexural Skin...... 64 Nevus of the Head and Neck...... 74 Nevi in Special Physiologic States...... 75 Nevus in Childhood...... 75 Nevus in Pregnancy...... 75 Nevus in the Elderly...... 77 3. Spindle and Epithelioid Cell Melanocytic Tumors/Nevi...... 83 Spindle and Epithelioid Cell Melanocytic Tumor (Spitz Tumor/Nevus)...... 83 Atypical and Malignant Spitz Tumors...... 100 Pigmented Spindle Cell Nevus of Reed...... 103

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4. Blue Nevi and Related Lesions...... 115 Common Blue Nevus...... 115 Plaque Type Blue Nevus...... 121 Neurocristic Hamartoma...... 121 Epithelioid Blue Nevus...... 122 Cellular Blue Nevus...... 124 5. Congenital Melanocytic Nevi...... 135 Small Congenital Nevi...... 135 Intermediate and Giant Congenital Nevi...... 142 Atypical Proliferations in Congenital Nevi...... 146 Cellular and Proliferative Dermal Nodules in Congenital Nevi...... 146 Superficial Atypical Melanocytic Proliferations in Congenital Nevi...... 156 6. Dysplastic Melanocytic Nevi...... 163 Nature and Significance of Dysplastic Nevi...... 163 Clinical Features of Dysplastic Nevi...... 163 Significance of Common and Dysplastic Nevi as Markers of Melanoma Risk...... 166 Clinically Dysplastic Nevi as Melanoma Risk Markers in Familial Melanoma Kindreds...... 166 Clinically Dysplastic Nevi as Melanoma Risk Markers in Random Populations.... 166 Histologically Dysplastic Nevi as Melanoma Risk Markers...... 168 Risk-Based Classification of Dysplastic Nevus Cases...... 170 Significance of Dysplastic Nevi as Potential Precursors of Melanoma...... 170 Dysplastic Nevi in a Model of Tumor Progression...... 171 Cell Biology of Dysplastic Nevi...... 171 Cellular and Molecular Markers of Progression in Dysplastic Nevi...... 173 Critiques of the Concept of Melanocytic Dysplasia...... 175 Pathology of Functional and Compound Dysplastic Nevi...... 176 Microscopic Features...... 176 Histologic Criteria for Diagnosis...... 182 Reproducibility and Controversy Regarding the Diagnosis of Histologic Dysplasia...... 186 Grading of Dysplastic Nevi...... 187 Clinicopathologic Correlation of Melanocytic Dysplasia...... 188 Differential Diagnosis...... 190 Role of the Pathologist in Diagnosis of Dysplastic Nevi...... 193 7. Combined Nevi...... 201 Clinical Features...... 201 Microscopic Findings...... 201

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8. Malignant Tumors (Melanomas and Related Lesions)...... 209 Tumor Progression Phases and Classification...... 209 Radial and Vertical Growth Phases (Nontumorigenic and Tumorigenic) Melanomas...... 211 Histogenetic Classification of Melanomas...... 214 Nontumorigenic Melanoma (Radial Growth Phase)...... 219 Tumorigenic Melanoma (Vertical Growth Phase)...... 241 Management of “Uncertain” Melanocytic Neoplasms: Superficial Atypical Melanocytic Proliferations of Uncertain Significance (SAMPUS) and Melanocytic Tumors of Uncertain Malignant Potential (MELTUMP)...... 264 9. Histogenetic Variants of Nontumorigenic Melanoma (Radial Growth Phase)...... 277 Superficial Atypical Melanocytic Proliferations of Uncertain Significance (SAMPUS): Uncertainty in the Diagnosis of Nontumorigenic Melanoma...... 277 Superficial Spreading Melanoma...... 278 Lentigo Maligna Melanoma...... 296 Acral-Lentiginous Melanoma...... 311 Mucosal-Lentiginous Melanoma (Nontumorigenic Compartment)...... 319 10. Histogenetic Variants of Tumorigenic Melanoma (Vertical Growth Phase)...... 325 Nodular Melanoma...... 325 Desmoplastic Melanoma...... 332 Neurotropic Melanoma and Neurotropism...... 343 Malignant Melanomas in Congenital Melanocytic Nevi...... 352 Malignant Blue Nevus...... 356 Nevoid and Minimal Deviation Melanomas...... 360 Pigmented Epithelioid Melanocytic Tumors (Pigmented Epithelioid Melanocytoma).... 371 True Epithelioid Blue Nevus...... 378 Pigmented Epithelioid Melanocytoma of Uncertain Malignant Potential...... 378 Tumoral Melanosis Mimicking Pigmented Epithelioid Melanoma...... 379 Malignant Melanocytic Schwannoma...... 380 Clear Cell Sarcoma...... 381 Dermal Melanocytic Tumors of Uncertain Malignant Potential (MELTUMP)...... 384 11. Metastatic Malignant Melanoma...... 405 General Features...... 405 Epidermotropic Metastatic Melanoma...... 407 Satellites and In-Transit Metastases...... 408 Dermal and Subcutaneous Metastases...... 411 Lymph Node Metastases: Elective and Selective Lymphadenectomy...... 411 Selective Lymphadenectomy: Sentinel Lymph Node Biopsy...... 416 Special Studies for Diagnosis of Oligomelanotic or Amelanotic Melanoma...... 418 Neoplastic Melanin Production...... 418

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Special Stains for Melanin Pigment...... 419 Immunopathology...... 420 Electron Microscopy...... 421 Summary...... 422 12. Prognostic Models for Melanoma...... 427 Staging and Microstaging of Malignant Melanoma...... 427 Microstaging Attributes (Pathologic and Clinical)...... 428 Phase of Tumor Progression...... 428 Clark Levels of Invasion...... 430 Breslow Tumor Thickness...... 432 Dermal Mitotic Rate...... 433 Tumor-Infiltrating Lymphocytes and Other Immunocompetent Cells in the Vertical Growth Phase...... 434 Tumor-Infiltrating Lymphocytes in the Radial Growth Phase...... 437 Radial Growth Phase Regression...... 437 Ulceration...... 439 Microscopic Satellites...... 439 Vascular Invasion...... 439 Morphometric Attributes...... 440 Age, Sex, and Anatomic Location...... 440 Lymph Node Metastases...... 441 Survival Models for Melanoma Patients...... 442 Prognostic Models for Survival in Patients with Localized Melanoma...... 443 Soong Multivariate Prognostic Model...... 443 Cochran Individualized Prognostic Model...... 443 Clark Progression-Based Survival Model (Model Predicting Survival in Stage I Melanoma Based on Tumor Progression)...... 445 TNM Staging System for Melanoma...... 447 Penn Models for Survival Prediction in Thin (AJCC Stage I) Melanoma...... 450 Survival in Patients with Lymph Node Metastatic Melanoma...... 453 Survival in Patients with Distant Metastatic Melanoma...... 453 Surgical Pathology Report for Primary Melanoma...... 453 Index ...... 461

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