The Dermal Melanocytoses. Conflicts of Interest 5/22/2018. The Nevi of Ota and Ito. Martin C. Mihm M.D.

Transcription

1 The Dermal Melanocytoses Martin C. Mihm M.D. Director Mihm Cutaneous Pathology Consultative Service (MCPCS) Brigham and Women s Hospital Director Melanoma Program Brigham and Women s Hospital and Harvard Medical School Co-Director Melanoma Program Dana-Farber Cancer Institute and Harvard Medical School Conflicts of Interest Chairman Scientific Advisory Board Caliber I.D. Inc. Member Scientific Advisory Board MELA Sciences Inc. Consultant Novartis Consultant Alnylam The Nevi of Ota and Ito Clinical Features Both are defined by a unilateral light gray macule presenting in 1 st -2 nd decades, up to 5 cm diameter which darkens with age in : trigeminal nerve distribution (1/2>3) (OTA, 1939) acromioclavicular nerve distribution (ITO, 1954) Asian descent > African descent > Caucasians Darken as patient ages 1

2 Ota s Nevus Practice point: scleral nevus of Ota is associated with choroidal nevi and melanoma; ophthalmic examination is required The Nevi of Ota and Ito Histomorphology band-like disposition of melanophages and dendritic melanocytes in the upper 1/3rd of the reticular dermis; epidermis spared dendritic cells cytomorphologically similar to those of blue nevus cellularity is sparse and fibrosis is slight scleral lesions also involve nerves and may be more cellular (Ota) Ota s nevus may involve the tympanum and the nasopalatine ganglia 2

3 3

4 Sun s nevus Clinical Features Speckled pattern of bilateral pigmentation in zygomatic region, exclusively in Chinese female predominance 6:1 familial clustering may be seen Histomorphology slender dendritic cells in upper dermis without fibrous response; no blue nevus-like areas Sun, 1990 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 Mongolian Spot Franceschini D and Dinulos J. Curr Opin Pediatr Photograph courtesy of Dr. Keigo Ito Mongolian Spot 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 Franceschini D and Dinulos J. Curr Opin Pediatr

5 5

6 Franceschini D and Dinulos J. Curr Opin Pediatr Mutations & Spectrum of Pigmented Lesions It is clear that in tumor progression several genetic alterations must take place before a lesion acquires the ability to invade and metastasize One mutation, BRAF V600E is sufficient to give rise to a nevus Any further progression requires other genetic alterations 6

7 Mutations & Spectrum of Pigmented Lesions c-kit NRAS BRAF CRAF MEK CDK2 CDK4 CyclinD p16 PI3K PTEN AKT mtor Provided by Dr. Keith Flaherty Class II. The intermediate lesions The growth of the intermediate lesions is not temporally restricted, but the lesions are confined to the tissue compartment of origin Class II lesions do not metastasize. Class II Lesions Examples include: Deep penetrating nevus Pigmented Epithelioid Melanocytoma Some Blue Nevus subtypes Some Spitz nevus/ tumor subtypes BAP1-Inactivated nevus Dysplastic nevus 7

8 Deep Penetrating Nevus The Deep Penetrating Nevus has a characteristic history of an area of blue appearing usually centrally in a previously brown lesion The histology demonstrates a population of pigmented epithelioid cells in the center of a benign acquired nevus These lesions rarely metastasize, especially those with deep proliferative nodules with marked atypia and mitotic activity Deep Penetrating Nevus 30 yo female Photograph courtesy of Dr. Keigo Ito All photographs courtesy of Dr. Keigo Ito 8

9 A darkly pigmented lesion of uncertain duration on the back of a 55 year old man Photos courtesy of Dr. David Elder Photos courtesy of Dr. David Elder Photos courtesy of Dr. David Elder 9

10 Ki67 Photos courtesy of Dr. David Elder Melan-A Melan-A Photos courtesy of Dr. David Elder 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 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 Bender RP et al. Mod Pathol Yeh I et al. Nat Commun

11 Class II Lesions Examples include: Deep penetrating nevus Pigmented Epithelioid Melanocytoma Some Blue Nevus subtypes Some Spitz nevus/ tumor subtypes BAP1-Inactivated nevus Dysplastic nevus Pigmented Epithelioid Melanocytoma 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 No association with familial dysplastic nevus syndrome, sun exposure, or family history of malignant melanoma. Precursor lesion: cellular blue nevus, blue nevus As long as the cytomorphology is well differentiated, the clinical course is in most instances indolent Zembowicz A et al. Am J Surg Pathol Pigmented Epithelioid Melanocytoma Mitotic activity is low A host response is absent Ulceration is uncommon Majority of cells are polygonal and or spindle shaped with abundant cytoplasm/well differentiated Epithelioid cells tend to favor the center with fascicles of large spindle cells extending into the periphery. Intraepidermal involvement is commonly found Cases with an overtly malignant cytology are not categorized as PEM but rather as melanoma Zembowicz A et al. Am J Surg Pathol

12 18 yo male Photograph courtesy of Dr. Keigo Ito PEM from a patient with Carney Complex PEM from a patient with Carney Complex 12

13 PEM 13

14 PRKAR1a PRKAR1a Novel Genetic Findings in PEM PEM are genetically diverse but share common signaling pathways de novo PRKAR1Aa mutations can occur in sporadic PEM PEM subtypes: Combined with BRAFV600 mutation and PRKAR1a alteration Pure PEM with MAP2K1 aberrations PEM with PRKCA fusion Absence of chromosomal copy number changes and TERT promoter mutations are consistent with PEM as a low grade neoplasm rather than a form of melanoma Cohen JN et al. Am J Surg Pathol

15 Class II Lesions Examples include: Deep penetrating nevus Pigmented Epithelioid Melanocytoma Some Blue Nevus subtypes Some Spitz nevus/ tumor subtypes BAP1-Inactivated nevus Dysplastic nevus The Blue Nevus The Blue nevus of Jadassohn-Tieche Mainly a lesion of childhood Most common location: dorsum of hands and feet, less often the buttocks, head and neck; can occur on mucosal surfaces Typically 3 to 4 millimeters Can be multiple and inherited as an autosomal dominant trait Blue Nevus 2 Blue Nevus 3 15

16 Blue nevus in oral cavity Hypomelanotic Blue Nevus 16

17 Blue Nevus with Hypercellularity Blue Nevus with Hypercellularity Clinical blue nevi often with a central areas of hypopigmentation and/or firmness with surrounding dense blue coloration Histomorphology areas of typical blue nevus cellular bands and fascicles of spindle-shaped cells with clear cytoplasms; nuclei with blunt oval contours and bland chromatin patterns; however the lesions are small and the hypocellular blue nevus component still predominates 17

18 Cellular fascicles of spindle cells surrounded by classic blue nevus component 18

19 Plaque-like Blue Nevus 19

20 Plaque-like Blue Nevus Clinical Slightly raised flat blue lesion sometimes associated with small papules. May vary in size from a few centimeters to rarely lesions that cover large areas of skin, such as scalp, trunk, and buttocks. Plaque-like Blue Nevus Histology Concentration of dendritic blue nevus cells with fibrosis in the upper third to upper half of the dermis. Beneath this plaque, there are variable numbers of scattered blue nevus cells with macrophages. There is no nodularity or mitotic activity 20

21 Cellular Blue Nevus Courtesy Dr Mirek Stranc 21

22 Courtesy Dr Mirek Stranc 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 melanocytoma of spinal canal may involve meninges and subjacent brain some with palpable lymph node deposits Cellular Blue Nevus histomorphology dumb-bell architecture, vertical orientation 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 melanophages and dendritic cells 22

23 Cellular Blue Nevus Histomorphology: degenerative cystification may occur : myxoid zones with viable bland cellular elements cystification in malignant CBN = necrosis mitoses may be seen : few in number (<1/10 40X HPF) and typical in type senescent atypia may be seen : nuclei lack discernable chromatin Cellular Blue Nevus: Subcutaneous base of the dumbbell-shaped architecture 23

24 Practice point: Cellular blue nevus with cystification reflects degeneration with viable cell islands lacking necrosis 24

25 Cellular Blue Nevus with Atypia At times cellular blue nevi may manifest significant atypia HALLMARKS: Diffuse growth pattern, asymmetry, hypercellularity, nuclear pleomorphism, focal single-cell necrosis, and mitotic figures, but the dominant background is one of a CBN Practice point: Cellular Blue nevus with atypia lacks confluent necrosis, conspicuous mitoses or high N/C ratios as in malignant blue nevus Blue Nevus-like Melanoma 25

26 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 Photograph courtesy of Dr. A. Neil Crowson 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

27 27

28 Blue Nevus-like Melanoma 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

29 Blue Nevi: Role for Molecular Tests? GNAQ and GNA11 encode for α subunits of G-proteincoupled 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 Gerami P and Busam KJ. Dermatol Clin Blue Nevi: Role for Molecular Tests? ABN: Amelanotic/ Hypomelanotic Blue Nevus; BN: Blue Nevus; CBN: Cellular Blue Nevus; MM: Malignant Melanoma; IDMN: Intrdermal Melanocytic Nevs Emley A et al. Human Pathol Blue Nevi: Role for Molecular Tests? Chan MP et al. Mod Pathol

30 Blue Nevi: Role for Molecular Tests? Gammon B et al. J Cutan Pathol Blue Nevus-like Melanoma BAP1 and SF3B1 mutations were present in Blue Nevus-like Melanoma Their co-existence with GNAQ and GNA11 mutations may be confirmatory of the diagnosis Atypical cellular blue nevi should be subject to these molecular tests Griewank KG et al, Mod Pathol Neurocristic Hamartoma 30

31 Neurocristic Hamartoma Clinical Area of bluish discoloration sometimes highlighted by clearing of pigment around follicles and/or prominent follicular pigmentation Several centimeters in size Rarely may cover large areas of the skin, even half the trunk Malignant degeneration has been reported Careful follow-up of patients is important Neurocristic Hamartoma Histology Prominent deposition of blue nevus cells with variable pigmentation around hair follicles extending even into the papillae Varying degrees of cellularity May be localized to follicles only or, in addition, may show blue nevus proliferation between involved follicles Characteristically schwannian differentiation may be observed Mitoses usually scarce, if increased malignant degeneration must be ruled out 31

32 Dermal Melanocytic Hamartoma Dermal Melanocytic Hamartoma Clinical Features pigmentation of buttocks with superimposed darker macular pigmentation, often extending down leg in dermatomal distribution Histomorphology identical to that of nevi of Ota/Ito low density proliferation of heavily pigmented dendritic melanocytes in upper dermis Burkhart and Gohara,

33 Acknowledgments Cynthia Magro, MD A. Neil Crowson, MD David Elder, MD Richard Scolyer, MD Adriano Piris, MD Labib Zakka, MD, MA Thank you for your kind attention 33