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Pathology of Melanocytic Tumors E-Book

Pathology of Melanocytic Tumors E-Book

Klaus J. Busam | Richard A Scolyer | Pedram Gerami

(2018)

Additional Information

Book Details

Abstract

Constituting a large percentage of everyday diagnostic practice, melanocytic pathology is a complex and challenging area with many difficult-to-diagnose lesions. This highly illustrated reference, written by three of the world’s leading dermatopathologists, provides authoritative guidance in the accurate diagnosis of even the most challenging pigmented skin tumors, helping you avoid pitfalls and recognize mimics.

  • Covers nearly every variant of melanocytic tumors you’re likely to see.
  • Emphasizes how to arrive at an efficient, accurate diagnosis, and includes dermoscopic findings for optimal diagnostic precision.
  • Discusses modern analytic techniques (cytogenetics, molecular studies) and how to use them for diagnosis.
  • Includes numerous case examples to illustrate the differential diagnoses and work-up; how to use ancillary techniques, along with their pros, cons, and limitations; and clinical follow-up.
  • Presents the knowledge and experience of Klaus Busam, Pedram Gerami, and Richard Scolyer, – three dermatopathologists who are globally renowned for their expertise in melanoma pathology and analysis of melanocytic tumors by modern ancillary diagnostic techniques.

Table of Contents

Section Title Page Action Price
Front Cover cover
IFC_ExCon page IFC2
Pathology of Melanocytic Tumors i
Copyright Page iv
Dedication v
Contributors vi
Preface viii
Table Of Contents ix
I Benign Cutaneous Melanocytic Proliferations 1
1 Melanotic Macules 2
Outline 2
Solar Lentigo 2
Clinical Features 2
Histopathologic Findings 2
Differential Diagnosis 4
Lentigo Simplex 5
Clinical Features 5
Histopathologic Findings 5
Differential Diagnosis 5
Miscellaneous Melanotic Macules 5
Primary Acquired Melanosis 7
References 7
2 Acquired Melanocytic Nevi 8
Keywords 8.e1
Outline 8
Origin of Melanocytes 8
Ultraviolet (UV) Radiation and Nevi 8
Clinical Findings 8
Common Acquired Junctional Melanocytic Nevi 8
Common Acquired Compound Melanocytic Nevi 9
Common Acquired Intradermal Melanocytic Nevi 9
Histopathologic Findings 9
Common Acquired Junctional Melanocytic Nevi 9
Acquired Compound and Intradermal Melanocytic Nevi 10
Halo and Eczematous Nevi 14
Dysplastic Nevi 14
Major Criteria 17
Minor Criteria 17
Differential Diagnosis 22
Melanocytic Nevus With Atypical Features Versus Melanoma In Situ Associated With a Nevus 22
Dysplastic Nevus Versus Melanoma 22
References 24
3 Congenital Melanocytic Nevi 26
Keywords 26.e1
Outline 26
Clinical Findings 26
Dermoscopy 28
Histopathologic Findings 28
Nevus Spilus 30
Proliferative Nodules 30
Molecular Findings 31
Cytogenetics of Proliferative Nodules 34
Differential Diagnosis 34
Prognosis and Treatment 34
References 36
4 Spitz Nevi 37
Keywords 37.e1
Outline 37
Clinical Findings 37
Histopathologic Findings 38
Histopathologic Variants of Spitz Nevi and Related Differential Diagnosis 40
Angiomatoid Spitz Nevus 41
Desmoplastic Spitz Nevus 42
Epithelioid Spitz Nevus 42
Pagetoid Spitz Nevus 42
Pigmented Spindle Cell Nevus 43
Plexiform Spitz Nevus 45
Other Variants of Spitz Nevus 45
Molecular Findings and Correlation With Histopathologic Phenotype 45
HRAS Aberrations 45
BAP1-Deficient/Inactivated Spitzoid Neoplasms 45
Spitzoid Neoplasms With Deletions in 6q23 49
Fusion-Related Spitzoid Neoplasms 49
Spitz Nevus Versus Atypical Spitz Tumor Versus Spitzoid Melanoma 56
Spitzoid Melanoma 56
Atypical Spitz Tumor 56
Ancillary Methods for Diagnosis 56
Immunohistochemistry 56
Cytogenetic Studies 56
Gene Expression Studies 56
Mutation Analysis 57
Prognosis and Treatment 57
References 59
5 Blue Nevi and Dermal Melanocytosis 61
Keywords 61.e1
Outline 61
Dermal Melanocytosis 61
Clinical Variants 61
Mongolian Spot. 61
Nevus of Ota (a.k.a. “Oculo-Dermal Melanocytosis” or “Nevus Fuscoceruleus Ophthalmomaxillaris”). 61
Nevus of Ito (a.k.a. “Nevus Fuscoceruleus Acromiodeltoideus”). 62
Nevus of Sun (Nevus Fusco-Caeruleus Zygomaticus) and Nevus of Hori (Acquired Bilateral Nevus of Ota-Like Macules). 62
Acquired Dermal Melanocytosis of the Face and Extremities. 62
Dermal Melanocyte Hamartoma. 62
Histopathologic Findings 62
Blue Nevi 63
Common Blue Nevus 63
Clinical Findings and Variants of Common Blue Nevus. 63
Histopathologic Findings. 63
Differential Diagnosis of Common Blue Nevus 64
Blue Nevus Versus Melanocytosis. 64
Blue Nevus Versus Melanosis. 64
Blue Nevus Versus Combined Nevus. 65
Blue Nevus Versus Blue Nevi-Like Melanoma. 65
Blue Nevus Versus Metastatic Blue Nevi-Like Melanoma. 65
Sclerosing Blue Nevus 65
Histopathologic Findings. 65
Differential Diagnosis of Sclerosing Blue Nevus 65
Sclerosing Blue Nevi Versus Dermatofibroma. 65
Sclerosing Blue Nevi Versus Other Sclerosing Nevus. 65
Sclerosing Blue Nevi Versus Desmoplastic Melanoma. 66
Hypomelanotic or Amelanotic Blue Nevus 66
Hypermelanotic Blue Nevus 66
Clear Cell or Balloon Cell Blue Nevus 67
Blue Nevus With Epithelioid Cell Features 67
Differential Diagnosis of Blue Nevus With Epithelioid Cell Features 67
Epithelioid Blue Nevi Versus Nodular Dermal Tumoral Melanosis. 67
Blue Nevi With Epithelioid Cell Features Versus Primary Dermal Blue Nevi–Like Melanoma. 67
Epithelioid Blue Nevi Versus Metastatic Blue Nevi-Like Melanoma. 68
Blue Nevi With Epithelioid Cells Versus Pigmented Epithelioid Melanocytoma. 68
Blue Nevi With Epithelioid Cell Features Versus Pigmented Epithelioid Spitz Nevus. 68
“Compound Blue Nevus” 68
Combined Blue Nevus 68
Traumatized Blue Nevus 68
Cellular Blue Nevus 69
Clinical Findings. 69
Histopathologic Findings. 69
Atypical Cellular Blue Nevus 71
Differential Diagnosis of Cellular Blue Nevus. 71
Cellular Blue Nevi Versus Primary Melanoma (Associated With or Simulating a Cellular Blue Nevus). 72
Cellular Blue Nevi Versus Metastatic Melanoma. 73
Cellular Blue Nevi Versus Clear Cell Sarcoma. 73
Cellular Blue Nevi Versus Pigmented Dermatofibrosarcoma Protruberans (DFSP). 74
Cellular Blue Nevi Versus Malignant Melanotic Schwannian Tumor. 74
Plaque-Type Blue Nevus 74
Clinical Findings. 74
Histopathologic Findings. 74
Neurocristic Hamartoma 76
Clinical Findings. 76
Histopathologic Findings. 78
Differential Diagnosis. 78
Extracutaneous Blue Nevi 78
Nodal Blue Nevus. 78
Mucosal or Visceral Blue Nevi. 78
References 79
6 Deep Penetrating Nevi 80
Keywords 80.e1
Outline 80
Clinical Findings 80
Histopathologic Findings 80
Immunohistochemical Findings 83
Molecular Findings 83
Differential Diagnosis 83
Deep Penetrating Nevus Versus Plexiform Pigmented Spindle Cell or Spitz Nevus 83
Deep Penetrating Nevus Versus Blue Nevus 86
Deep Penetrating Nevus Versus Deep Penetrating Nevus–Like Melanoma 86
Deep Penetrating Nevus Versus Tumoral Melanosis 87
Prognosis and Treatment 87
References 89
7 Melanocytic Nevi of Special Sites 90
Abstract 90.e1
Keywords 90.e1
Outline 90
Ear Nevi 90
II Primary Cutaneous Melanoma 130
11 Histopathologic Diagnosis of Melanoma 131
Keywords 131.e1
Outline 131
ABCD Parameters and Cytology 131
Asymmetry 131
Irregular Borders 131
Variation in Color 131
Diameter 131
Cytology 133
Synthesis of Findings and Clinicopathologic Correlation 133
Diagnosis of Melanoma in Situ 135
Differential Diagnosis of Melanoma in Situ 135
Diagnosis of Invasive Melanoma 135
Variants of Melanoma 137
Molecular Classification of Melanoma 138
Ancillary Methods for the Diagnosis of Melanoma 138
Melanocytic Proliferations Reported Without a Precise Diagnosis 138
Atypical Intraepidermal Melanocytic Proliferations 138
MELTUMP 139
References 139
12 Lentigo Maligna Melanoma 140
Abstract 140.e1
Keywords 140.e1
Outline 140
Nomenclature 140
Clinical Findings 140
Obtaining a Biopsy Specimen 141
Histopathologic Findings 142
Lentigo Maligna Melanoma In Situ 142
Lentigo Maligna Melanoma 143
Ancillary Tests 148
Clinical and Dermoscopic Images 148
Immunohistochemistry 148
Molecular Tests 150
Differential Diagnosis 151
Melanocyte Hyperplasia of Sun-Damaged Skin (aka Solar Melanocytosis) Versus Lentigo Maligna 151
Solar Lentigo, Pigmented Seborrheic Keratosis, Lichenoid Keratosis, and Pigmented Actinic Keratosis Versus Lentigo Maligna 151
Junctional Melanocytic Nevus Versus Lentigo Maligna 152
Lentiginous Compound Melanocytic Nevus Versus Lentigo Maligna Melanoma or Lentigo Maligna Colliding With a Nevus 154
Lentigo Maligna Melanoma Versus Lentiginous Melanoma of Skin With Low Cumulative Sun Damage 155
Inflamed Scar Versus Lentigo Maligna Melanoma With Desmoplastic Invasive Tumor 155
Intrafollicular Melanoma In Situ Versus Invasive Melanoma or Satellite Lesion 155
Surgical/Clinical Management and Margin Assessment 156
References 156
13 Superficial Spreading Melanoma 158
Keywords 158.e1
Outline 158
Clinical Findings 158
Histopathologic Findings 158
Differential Diagnosis 165
Superficial Spreading Melanoma Versus Dysplastic Nevus 165
Distinction of Superficial Spreading Melanoma From Superficial Spitz Nevi 165
Distinction of Superficial Spreading Melanoma Versus Other Melanomas 166
Molecular and Cytogenetic Findings 166
Fluorescence In Situ Hybridization for the Diagnosis of Superficial Spreading Melanoma 166
Gene Expression Profiling 166
References 166
14 Acral and Subungual Melanoma 168
Keywords 168.e1
Outline 168
General Comments 168
Site-Specific Microanatomy of Volar Skin and Correlations With Dermoscopy 168
Microanatomy of the Nail Apparatus 168
Melanonychia 169
Clinical Findings 169
Pathologic Findings 171
Melanoma of Volar Skin (Palmar or Plantar Melanoma) 171
Subungal Melanoma 173
Molecular Findings 173
Differential Diagnosis and Pitfalls 173
Differential Diagnosis 177
Melanoma of Volar Skin Versus Melanocytic Nevus of Volar Skin. 177
Subungual Melanoma Versus Subungual Melanocytic Nevus. 177
Subungual Melanoma In Situ Versus Subungual Melanotic Macule. 177
Amelanotic Acral and Subungual Melanoma Versus Nonmelanocytic Tumors. 178
Syringotropic Acral Melanoma In Situ Versus Invasive Melanoma. 178
Pitfalls 178
Difficulty of Measuring Tumor Thickness. 178
Sampling Problems. 179
Treatment and Margin Assessment 179
Prognosis 180
References 180
15 Nodular Melanoma 181
Keywords 181.e1
Outline 181
Clinical Findings 181
Histopathologic Findings 184
Nodular Melanoma Associated With In Situ Melanoma 184
Nodular Melanoma Not Associated With In Situ Melanoma 186
Differential Diagnosis 188
Molecular Findings 188
Treatment and Prognosis 189
Comment 189
References 189
16 Desmoplastic Melanoma 190
Keywords 190.e1
Outline 190
Clinical Findings 190
Histopathologic Findings 190
Pure Desmoplastic Melanoma 195
Mixed Desmoplastic Melanoma 197
Immunohistochemical Findings 197
Molecular Findings 197
Differential Diagnosis 199
Desmoplastic Melanoma Versus Fibrosing Nonmelanocytic Benign Lesions 199
Desmoplastic Melanoma Versus Dermal Scar 199
Desmoplastic Melanoma Versus Dermatofibroma 200
Desmoplastic Melanoma Versus Neurofibroma 200
Desmoplastic Melanoma Versus Plexiform Schwannoma 201
Desmoplastic Melanoma Versus Desmoplastic Cellular Neurothekeoma 202
Desmoplastic Melanoma Versus Desmoplastic Melanocytic Nevus 202
Desmoplastic Melanoma Versus Sclerosing Spitz Nevus 203
Desmoplastic Melanoma Versus Sclerosing Blue Nevus 204
Desmoplastic Melanoma Versus Other Nevi With Sclerosis 206
Desmoplastic Melanoma Versus Nonmelanocytic Malignant Tumors 206
Desmoplastic Melanoma Versus Desmoplastic Spindle Cell Carcinoma 206
Desmoplastic Melanoma Versus Desmoplastic Leiomyosarcoma 206
Desmoplastic Melanoma Versus Spindle Cell Atypical Fibroxanthoma (AFX) or Undifferentiated Dermal Sarcoma 206
Desmoplastic Melanoma Versus Malignant Peripheral Nerve Sheath Tumor 206
Clinical Management and Prognosis 206
References 207
17 Nevoid Melanoma 208
Keywords 208.e1
Outline 208
Clinical Findings 208
Histopathologic Findings 208
Molecular Findings 212
Differential Diagnosis 212
Mitotically Active Melanocytic Nevus 212
Cellular/Proliferative Nodule in a Nevus 212
Superficial Spreading Melanoma With a Nevoid Invasive Component 212
Lentiginous Melanomas With Nevoid Invasive Component 213
References 215
18 Spitzoid Melanoma 216
Keywords 216.e1
Outline 216
Clinical Findings 216
Histopathologic Findings 216
Immunohistochemical Findings 223
Molecular Findings 223
Histopathologic-Genomic Correlations 224
Differential Diagnosis 225
Spitz Nevus and Atypical Spitz Tumor 225
Melanomas With Spitzoid Features 225
Melanoma With Spitzoid Subclones. 225
Conventional Melanoma Arising in a Spitz Nevus. 225
Nevoid Melanoma. 225
Treatment and Prognosis 225
References 225
19 Melanoma Arising in Association With and/or Simulating a Blue Nevus 226
Keywords 226.e1
Outline 226
Clinical Findings 226
Histopathologic Findings 226
Melanoma Associated With a Common Blue Nevus or Melanocytosis (Nevus of Ota or Ito) 226
Melanoma Associated With a Cellular Blue Nevus 226
Melanoma Simulating a Common Blue Nevus 228
Melanoma Simulating a Blue Nevus With Epithelioid Cell Features of Pigmented Epithelioid Melanocytoma 230
Melanoma Simulating a Cellular Blue Nevus 230
Immunohistochemical Findings 230
Molecular Findings 230
Differential Diagnosis 230
Prognosis and Treatment 233
References 234
20 Uncommon Variants of Melanoma and Collision Scenarios 235
Keywords 235.e1
Outline 235
Histopathologic Findings and Differential Diagnosis 235
Balloon Cell/Clear Cell Melanoma 235
Deep Penetrating Nevus-Like (Plexiform) Melanoma 235
Primary Dermal Melanoma 235
Follicular Melanoma 236
Rhabdoid Melanoma 236
Sarcomatoid Melanoma 236
Signet Ring Cell Melanoma 236
Small Cell Melanoma 236
Undifferentiated Melanoma 236
Verrucous (Papillomatous Keratotic Variant of) Melanoma 237
Melanoma Associated With Pseudoepitheliomatous Epidermal Hyperplasia 237
Melanoma With Pseudovascular Changes 238
Melanoma With Epithelial Features 238
Spindle Cell Melanoma 238
Polypoid Melanoma 241
Collision Scenarios 241
Melanoma Colliding With a Basal Cell Carcinoma 241
Melanoma Colliding With a Squamous Proliferation 241
References 243
21 Pediatric Melanoma 244
Outline 244
Clinical Findings 244
Adult Subtype 244
Spitzoid Subtype 244
Large/Giant Congenital Nevi–Associated Subtype 244
Histopathologic Findings 245
Adult Subtype 245
Spitzoid Subtype 245
Large/Giant Congenital Nevus–Associated Subtype 247
Molecular Findings 247
Adult Subtype 247
Spitzoid Subtype 248
Giant/Large Congenital Nevus–Associated Subtype 248
Differential Diagnosis 248
Prognosis 249
Treatment 251
References 251
III Primary Extracutaneous Melanocytic Proliferations 253
22 Conjunctival Melanocytic Proliferations 254
Keywords 254.e1
Outline 254
Complexion-Associated Melanosis 254
IV Metastatic Melanoma 313
27 Metastatic Melanoma 314
Keywords 314.e1
Outline 314
Clinical Findings 314
Pathologic Findings 314
Locoregional Metastases 315
Metastatic Melanoma in Regional Lymph Nodes. 315
Sentinel lymph node biopsy. 316
Pathologic examination of sentinel lymph nodes. 316
Locoregional Metastatic Melanoma to Skin and/or Soft Tissue. 317
Metastatic Melanoma to Distant Sites 317
Metastatic Melanoma With Unknown/Undetectable Primary Site 319
Ancillary Studies 319
Immunohistochemistry (IHC) 319
Molecular Pathology 320
Differential Diagnosis 320
Metastatic Melanoma in Lymph Node Versus Other 320
Metastatic Melanoma Versus Nodal Melanocytic Nevus 320
Metastatic Melanoma Versus Nodal Melanosis or Nonmelanotic Pigment in Lymph Node (LN) 322
Metastatic Melanoma Versus Nonmalignant Immunoreactive Cells in LN 322
Metastatic Melanoma Versus Nonmelanocytic Tumor in LN 323
Metastatic Cutaneous Melanoma Versus Metastatic Melanoma of Soft Parts (Clear Cell Sarcoma) 323
Metastatic Melanoma to Skin and Soft Tissue Versus Other 323
Metastatic Melanoma to the Skin Versus Primary Melanoma 323
Metastatic Melanoma Versus Melanocytic Nevus 325
Metastatic Melanoma to the Skin and Soft Tissue Versus Primary Nonmelanocytic Tumor 327
Metastatic Melanoma Versus Clear Cell Sarcoma 327
Metastatic Melanoma Versus Melanotic Schwannoma 327
Metastatic Melanoma to the Skin and Soft Tissue Versus Metastatic Nonmelanocytic Tumor 327
Metastatic Melanoma to Visceral Sites, Brain, or Bone 327
Metastatic Melanoma Versus Nonmelanocytic (Primary or Metastatic) Tumor 327
Metastatic Melanoma Versus Primary Mucosal or Visceral Melanoma 328
Melanosis Associated With Metastatic Melanoma 328
Prognosis and Treatment of Metastatic Melanoma 328
Locoregional Metastases (AJCC Stage III) 328
Distant Metastases (AJCC Stage IV Disease) 329
References 329
V Ancillary Studies 330
28 Dermoscopy for Dermatopathologists 331
Abstract 331.e1
Keywords 331.e1
Outline 331
Using Dermoscopy to Improve Histologic Analysis: the Role of the Clinician 332
Adding Dermoscopic Information and/or Images to the Pathology Requisition Form 332
Marking the Area of Concern 333
Using Dermoscopy to Improve Histologic Analysis: the Role of the Pathologist 333
Ex Vivo Dermoscopy 333
Knowing the Dermoscopic Structures and Colors and Their Histopathologic Correlates 333
Colors in Dermoscopy. 334
Dermoscopic Structures Encountered in Melanocytic Neoplasms. 334
Dermoscopic Features With Special Relevance for the Dermatopathologist 344
Conclusion 345
References 346
29 Immunohistochemistry for the Diagnosis of Melanocytic Proliferations 348
Keywords 348.e1
Outline 348
The Reagents 348
Differentiation Markers 348
S100. 348
GP100 (PMEL). 348
Tyrosinase. 350
TRP1. 351
TRP2. 351
Melan-A/MART1. 351
MITF. 352
SOX10. 352
PNL2. 353
Biomarkers 354
Ki-67. 354
PHH3. 354
P16. 355
BAP1. 355
ALK. 356
NTRK. 356
SAC. 357
5-hmC. 357
H3K27me3. 357
PRAME. 358
Mutation Antigens 358
BRAFV600E. 358
RASQ61R. 358
HRAS. 359
Immune-Response Score 359
PD1. 359
PD-L1. 359
Basic Applications of Immunohistochemistry 359
Visualization of Melanocytes 359
Immunohistochemistry for the Distinction of a Melanocytic from Nonmelanocytic Tumor 360
Immunohistochemistry for the Distinction of a Melanocytic Nevus from Melanoma 360
Expression Profile of p16, HMB45 and Ki-67. 361
Expression of Cancer Testis Antigens for the Distinction of Nevi from Melanoma. 361
For the Distinction of a Desmoplastic Spitz Nevus from Desmoplastic Melanoma. 362
For the Distinction of Nodal Nevus from Metastatic Melanoma. 362
Distinction of Proliferative Nodule from Pediatric Nodular Melanoma. 362
Immunohistochemistry for Treatment Selection and/or Staging Purposes 362
References 362
30 Molecular Techniques 364
Keywords 364.e1
Outline 364
Basic Terms and Principles 364
Polymerase Chain Reaction 366
Endpoint Polymerase Chain Reaction 366
Quantitative Polymerase Chain Reaction 366
Gene-Expression–Based Assays 366
DNA Sequencing 367
Sanger Sequencing 367
Next-Generation Sequencing 367
Assays to Detect DNA Copy Number Alterations 370
Array Comparative Genomic Hybridization 370
Single Nucleotide Polymorphism—Arrays and Molecular Inversion Probes 371
Fluorescence In Situ Hybridization 371
Diagnostic Use of Molecular Methods 372
References 372
31 Clinical, Dermoscopic, Pathologic, and Molecular Correlations 374
Keywords 374.e1
Outline 374
Clinical History and Dermoscopy 374
Immunohistochemistry 374
Molecular Methods 378
Cytogenetics: Fluorescence In Situ Hybridization and Comparative Genomic Hybridization 378
mRNA Expression Profiling 381
References 384
VI Prognosis, Staging, and Reporting of Melanoma 385
32 Prognosis, Staging, and Reporting of Melanomas 386
Keywords 386.e1
Outline 386
Clinical Parameters 386
Histopathologic Parameters 386
Tumor Thickness 386
Partial Biopsy. 386
Ulceration. 387
Epidermal Hyperplasia. 387
Adnexotropism/Periadnexal Extension. 388
Lymphatic Invasion and/or Satellites. 388
Fragmentation and Tangential Sectioning. 388
Ulceration 388
Tumor Mitotic Rate 389
Clark Level 389
Microsatellites 391
Tumor-Infiltrating Lymphocytes 391
Blood Vessel and Lymphatic Invasion 392
Neurotropism 392
Regression 392
Staging of Melanoma 392
Reporting of Melanoma 393
Primary Melanoma 393
Metastatic Melanoma in Lymph Node 395
Distant Metastases 395
Reporting Format. 395
Reports With No Definitive Diagnosis. 395
References 396
VII Margin Assessment of Melanomas 397
33 Margin Assessment of Cutaneous Melanoma 398
Keywords 398.e1
Outline 398
Guidelines for Melanoma Margins 398
Tissue Processing and Margin Review 399
Conventional Elliptical Excisions 400
Mohs Surgery 401
Staged Excision 401
Pitfalls in Margin Assessment 403
Margin Reporting 403
References 406
Index 407
A 407
B 407
C 407
D 408
E 409
F 409
G 409
H 409
I 409
J 409
K 409
L 409
M 410
N 412
O 412
P 412
Q 413
R 413
S 413
T 414
U 414
V 414
W 414
Z 414
IBC_Clinical Key ad IBC1