Blue Melanocytic Proliferations
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1 Blue Melanocytic Proliferations Labib R. Zakka M.D., M.A. Research Fellow Melanoma Program Department of Dermatology Brigham and Women s Hospital Harvard Medical School Conflicts of Interest No conflicts of interest The Blue Melanocytic Proliferations Nevi of Ota and Ito Mongolian spot Common blue nevus Blue nevus with hypercellularity Cellular blue nevus Deep penetrating nevus/ inverted type A/ clonal nevus Pigmented Epithelioid Melanocytoma (PEM) Blue nevus-like melanoma Malignant Melanoma Short-wavelength visible light (blue) is dispersed and reflected more than longwavelength light (red). The blue color of otherwise black melanin is explained by the depth of the pigment in the dermis. The Tyndall Effect Valdebran M et al. Our Dermatology Online
2 Patient 1: 24 yo female Scenario 1 Patient 2: 36 yo female Patient 1: 24 yo female Patient 2: 36 yo female All photographs courtesy of Dr. Keigo Ito All photographs courtesy of Dr. Keigo Ito VOTE: Best Management A. Patient 1: Excisional biopsy Patient 2: Excisional biopsy Patient 1: 24 yo female Patient 1 B. Patient 1: Shave biopsy Patient 2: Observe C. Patient 1: Observe Patient 2: Shave biopsy Patient 2: 36 yo female D. Patient 1: Observe Patient 2: Excisional biopsy 2
3 Patient 1 Patient 1 Patient 2 Patient 2 3
4 Patient 2 Patient 2 VOTE: Diagnosis A. Patient 1: Deep penetrating (Clonal; Inverted type A) nevus Patient 2: Melanoma B. Patient 1: Melanoma Patient 2: Melanoma C. Patient 1: Blue nevus with hypercellularity Patient 2: Melanoma D. Patient 1: Melanoma Patient 2: Pigmented epithelioid melanocytoma (PEM) Blue Nevus with Hypercellularity Clinical Features Blue nevi often with a central area of hypopigmentation and/or firmness Common locations: Dorsum of hands and feet, less often the buttocks, head and neck May occur on mucosal surfaces Typically 3 to 4 millimeters ZembowiczA and Mihm MC. Histopathology Zembowicz A and Phadke PA. Arch Pathol Lab Med
5 Blue Nevus with Hypercellularity Patient 1: 21 yo female Scenario 2 Patient 2: 53 yo male Histological Features Resembles the common blue nevus but with hypercellularity Aggregates of spindled and epithelioid cells with clear cytoplasms with scattered melanophages Dendrites with fine melanin pigmentation Nuclei with blunt oval contours and bland chromatin patterns Mitoses rare ZembowiczA and Mihm MC. Histopathology Zembowicz A and Phadke PA. Arch Pathol Lab Med Photograph courtesy of Dr. Keigo Ito Photograph courtesy of Dr. A. Neil Crowson VOTE: Best Management A. Patient 1: Observe Patient 2: Excisional biopsy Patient 1: 21 yo female Patient 1 B. Patient 1: Shave biopsy Patient 2: Observe C. Patient 1: Observe Patient 2: Shave biopsy Patient 2: 53 yo male D. Patient 1: Excisional biopsy Patient 2: Excisional biopsy 5
6 Patient 1 Patient 1 Patient 1 Patient 2 6
7 Patient 2 VOTE: Diagnosis A. Patient 1: Nevus of Ito Patient 2: Lentigo Maligna Melanoma B. Patient 1: Nevus of Ito Patient 2: Cellular blue nevus C. Patient 1: Mongolian spot Patient 2: Pigmented epithelioid melanocytoma D. Patient 1: Mongolian spot Patient 2: Blue nevus-like melanoma Mongolian Spot Clinical Features Present at birth Present in Asians > African Americans > Caucasians Slate gray colored macule characteristically in natal cleft and adjacent skin but may be ectopic Usually lighten with age Histological Features Affects the entire dermis and subcutaneous fat Hypocellular Consists of dendritic melanocytes with rare melanophages No fibrous response Many melanocytes extend along elastic fibers Mongolian Spot Franceschini D and Dinulos J. Curr Opin Pediatr Franceschini D and Dinulos J. Curr Opin Pediatr
8 Mongolian Spot Therapeutic Options Cosmetic camouflage Q-switched Nd-Yag laser Q-switched Alexandrite laser Oshiro T et al. Laser Ther Kagami S et al. Dermatol Surg Franceschini D and Dinulos J. Curr Opin Pediatr Blue Nevus-like Melanoma Also known as Malignant melanoma arising in blue nevus. Previously designated Malignant Blue Nevus Clinical Features M>F ; Mid 40s Scalp most common site Large blue-gray nodule with mean size of 2.9 cm Progressively increase in size May ulcerate History of pre-existing blue nevus at the site Barnhill RL and Gupta K. Clin Dermatol Blue Nevus-like Melanoma Histology Epidermis uninvolved Large sheets or nodules (>3 cm in thickness) extending to subcutaneous fat Spindled and epithelioid cells with pleomorphism May resemble cellular blue nevus (CBN) but with malignant features Malignant features include: Nodules with very large diameters and asymmetry Hypercellularity with large nuclear to cytoplasmic ratios Hyperchromatic nuclei with spiculation Few atypical mitoses (1-2/mm 2 ) Barnhill RL and Gupta K. Clin Dermatol
9 9
10 Blue Nevus-like Melanoma Patient 1: 30 yo female Scenario 3 Patient 2: 67 yo male Prognosis and Therapy True prognosis is unknown, but may have a worse outcome than patients with more conventional melanoma Treated the same as conventional melanoma Barnhill RL and Gupta K. Clin Dermatol All photographs courtesy of Dr. Keigo Ito Patient 1: 30 yo female Patient 2: 67 yo male VOTE: Best Management A. Patient 1: Shave biopsy Patient 2: Observe B. Patient 1: Excisional biopsy Patient 2: Excisional biopsy Patient 1: 30 yo female C. Patient 1: Observe Patient 2: Shave biopsy Patient 2: 67 yo male All photographs courtesy of Dr. Keigo Ito D. Patient 1: Observe Patient 2: Excisional biopsy 10
11 Patient 1 Patient 1 Patient 1 Patient 2 11
12 Patient 2 Patient 2 Patient 2 Patient 2 12
13 VOTE: Diagnosis A. Patient 1: Blue nevus Patient 2: Melanoma B. Patient 1: Compound dysplastic nevus with severe atypia Patient 2: Compound Spitz nevus C. Patient 1: Combined compound dysplastic/ Deep penetrating (Clonal; Inverted type A) nevus Patient 2: Melanoma D. Patient 1: Sclerosing blue nevus Patient 2: Blue nevus-like melanoma Deep Penetrating Nevus Also known as Clonal nevus Inverted type A nevus common variant Clinical Features Brown/gray/tan dome-shaped papule <1cm; rarely >0.6cm Proximal extremities, trunk or face, 2 nd -4 th decade; rarely congenital Do not metastasize Deep Penetrating Nevus Histological Features Wedge-shaped, symmetrical lesion Vertically-oriented, orderly fascicles Follow adventitia of eccrine coil/ follicles and neurovascular bundles May penetrate subcutis Nuclei bland, often with pseudoinclusions Mitoses sparse and typical Melanophages delimit edges of fascicles Magro CM et al. Eur J Dermatol Patient 1: 18 yo male All photographs courtesy of Dr. Keigo Ito Scenario 4 Patient 2: 25 yo female 13
14 Patient 1 Patient 1 Patient 1 Patient 1 14
15 Patient 1 Patient 1 MART1 HMB45 Patient 2 Patient 2 15
16 Patient 2 Patient 2 Patient 2 VOTE: Diagnosis A. Patient 1: Pigmented epithelioid melanocytoma (PEM) Patient 2: Cellular blue nevus B. Patient 1: Blue nevus with hypercellularity Patient 2: Melanoma C. Patient 1: Clonal (Inverted type A) nevus Patient 2: Melanoma D. Patient 1: Compound dysplastic nevus with severe atypia Patient 2: Blue nevus with hypercellularity 16
17 Cellular Blue Nevus Clinical Features: Tumefactive multinodular blue-black nodule Mean size cm (up to 6 cm reported) Anywhere on body but classically dorsa hands/feet, buttocks Some with palpable lymph node deposits ZembowiczA and Mihm MC. Histopathology Zembowicz A and Phadke PA. Arch Pathol Lab Med Cellular Blue Nevus Histological Features: Nodule with Dumb-bell architecture in vertical orientation, with adjacent common blue nevus Lower pole in deep dermis/subcutis Alternating cellular and collagenized zones Cellular nodules + fascicles of cuboidal cells with round/spindled nuclei and clear cytoplasms surrounded by dendritic cells Collagenized zones contain melanophagesand dendritic cells Liquefaction degeneration resulting in spaces filled with blue nevus cells Mitoses may be seen: (<1/10 40X HPF) ZembowiczA and Mihm MC. Histopathology Zembowicz A and Phadke PA. Arch Pathol Lab Med Pigmented Epithelioid Melanocytoma (PEM) Clinical Features: Blue plaques or nodules averaging greater than one centimeter in diameter. Frequently on acral surfaces, buttocks, and scalp Skewed to the younger population As long as the cytomorphology is well differentiated, the clinical course is in most instances indolent However, may metastasize to sentinel lymph nodes and rarely exhibit malignant transformation. Vyas R et al. JAAD Pigmented Epithelioid Melanocytoma (PEM) Histological Features: Large aggregates of polygonal and or spindle shaped cells with abundant melanin-laden cytoplasm Epithelioid cells tend to favor the center with fascicles of large spindle cells extending into the periphery. Intraepidermal involvement is commonly found. Mitotic activity is low. A host response is absent. Zembowicz A, Carney JA, and Mihm MC. Am J Surg Pathol Ulceration is uncommon. Zembowicz A et al. Am J Surg Pathol Vyas R et al. JAAD
18 PEM: Therapy Blue Nevi: Role for Molecular Tests? Excision with at least a 1 cm. margin depending on thickness is recommended Sentinel Lymph Node Biopsy and Completion Lymphadenectomy: Zembowicz et al. (2004): 11/24 (46%) PEMs metastasized to SLN parenchyma. 5/11 had positive parenchymal deposits on completion. Mean 36 month follow-up with no death. Therefore, prognosis is much better than melanoma and SLN biopsy is recommended The Melanoma Sentinel Lymph Node Trial 2 (MSLT-2) did not demonstrate an increase in melanoma specific survival for completion lymphadenectomy in melanoma Completion lymphadenectomy requires further study in PEM In some centers, patients draining basins are followed with ultrasound Longer follow-up with diagnoses based on pathology review are required for a more accurate therapeutic recommendation GNAQ and GNA11 encode for α subunits of G- protein-coupled receptors GNAQ and GNA11 mutations have been described in the various types of blue nevi Detection of GNAQ or GNA11 in lesions with histopathologic ambiguity would favor benign blue nevus versus melanoma Zembowicz A, Carney JA, and Mihm MC. Am J Surg Pathol Faries MB et al. N Engl J Med Gerami P and Busam KJ. Dermatol Clin Blue Nevi: Role for Molecular Tests? Blue Nevi: Role for Molecular Tests? ABN: Amelanotic/ Hypomelanotic Blue Nevus; BN: Blue Nevus; CBN: Cellular Blue Nevus; MM: Malignant Melanoma; IDMN: Intradermal Melanocytic Nevus Emley A et al. Human Pathol Chan MP et al. Mod Pathol
19 Blue Nevi: Role for Molecular Tests? Deep Penetrating Nevus: Role for Molecular Tests? Study analyzed DPNs for GNAQ, GNA11, and HRAS mutations: DPN: 0/38 demonstrated GNAQ or GNA11; 2/38 (6%) demonstrated HRAS Blue Nevi: 26/30 (87%) - GNAQ, 1/28 (4%) - GNA11; 0/30 HRAS Spitz Nevi: 0/30 GNAQ or GNA11, 5/30 (17%) HRAS New study demonstrated that the combination of activation of MAP Kinase and β catenin signaling caused DPN Mutations of the β-catenin pathway changed the phenotype of a common nevus with BRAF mutation into that of DPN, with increased pigmentation, cell volume and nuclear cyclin D1 levels. β-catenin pathway activation may promote tumorigenesis by overriding dependencies on the microenvironment that constrain proliferation of common nevi. Suggested that DPN is an intermediate lesion in a transformation to melanoma Gammon B et al. J Cutan Pathol Bender RP et al. Mod Pathol Yeh I et al. Nat Commun PEM: Role for Molecular Tests? Loss of expression of Protein Kinase A Regulatory Subunit 1α (PRKAR1A) Located on chromosome 17q /34 (82%) PEMs exhibited loss of PRKARA1A using immunohistochemistry FISH analysis using 4 probes reported in 2 studies on a total of 7 PEMs 1/7 showed an extra copy of chromosome 6 (CEP6 probe) Patient 1: 29 yo female Scenario 5 Patient 2: 48 yo male Zembowicz A et al. Am J Surg Pathol Urso et al.melanoma Res Battistella et al. Dermatology Photograph courtesy of Dr. Keigo Ito Photograph courtesy of Dr. Martin C. Mihm Jr. 19
20 VOTE: Diagnosis A. Patient 1: Blue nevus Patient 2: Something else B. Patient 1: Something else Patient 2: Melanoma Patient 1: 29 yo female Patient 1 C. Patient 1: Clonal (inverted type A) nevus Patient 2: Blue nevus Patient 2: 48 yo male D. Patient 1: Cellular blue nevus Patient 2: Blue nevus-like Melanoma Patient 1 Patient 1 20
21 Patient 1 Patient 2 Patient 2 Patient 2 HMB45 21
22 Acknowledgments Martin C. Mihm Jr., MD Jennifer Lin, MD Keigo Ito, MD Carlos Nicolas Prieto-Granada, MD Adriano Piris, MD THANK YOU!! 22
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