НАУЧНО-ПРАКТИЧЕСКАЯ КОНФЕРЕНЦИЯ (МАСТЕР-КЛАСС) «ПРАКТИЧЕСКИЕ АСПЕКТЫ ДИАГНОСТИКИ И ЛЕЧЕНИЯ МЕЛАНОМЫ КОЖИ» DIAGNOSTIC AND PITFALLS IN MELANOMA Guy Perrot (Ги Перро) MD PHD pathologist, University Hospital Specialist, Member of International Academy of Pathology (French board) 22 августа Барнаул
RULES CLINICAL INFORMATION DERMOSCOPY ++++ NO PUNCH OR PARTIAL EXCISION!!!!!! STANDARD REPORT 2nd READ IN DIFFICULT CASES 2
TECHNICAL APPROACH TECHNICAL : 2 BLOCKS MINIMUM 2 HES SLIDES IMMUNOCHEMISTRY FIRST STEP: SOX10 OR HMB45, P16, KI67 - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 3
PROBLEMS IN ADULT MELANOMA PROBLEMS IN CHILD MELANOMA PROBLEMS IN PARTICULAR SITE OR CONDITIONS - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 4
ADULTS : Case 1 Woman 47 years old Melanocytic tumor of left leg with recent changes Dermoscopy :irregular pigment, homogenous reticular patterns Suspicion of melanoma - Dr. Guy Perrot Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 5
HISTOLOGY No major intra epidermal spread Asymmetry Atypia with Mitosis upper location
HISTOLOGY No major intra epidermal spread Asymmetry Atypia with Mitosis upper location
Ki67: 4% IMMUNOCHEMISTRY HMB45 P16 MODIFICATION GRADIENT NOT TOTAL REGRESSION Diagnostic and pitfalls in melanoma Dr. Guy Perrot
ADULTS CASE1 Asymmetric lesion Some epidermis spread but not until granular or horny layer Atypical cells mixed with more typical nevus cells Mitosis: < 2 / mm2 and in UPPER LOCATION Ki67 moderate high :4% HMB45 with modification of gradient but persistent by place NO ENOUGH ARGUMENTS FOR MELANOMA SUFFICIENT ARGUMENTS FOR NO MELANOMA Diagnostic and pitfalls in melanoma Dr. Guy Perrot
ADULTS : Case 1 DIAGNOSIS : MELTUMP Melanocytic TUmor of Uncertain Malignant Potential This group is used to define a type of tumor in adults with severe atypia or/and disorganization without clear features of melanoma Others features as necrosis and vascular invasion are rare This term must be used for high grade lesion with Vertical Growth Phase The main criteria to distinguish MM from MELTUMP is mitosis in deep in melanoma Not for dysplastic nevus with mild atypia (clinical context) - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 10
ADULTS : MELTUP Recommendations Give the same schema report as a melanoma report: Breslow Clark margins and so Don't use in your report the term of malignant melanoma complete excision with margins as melanoma, same follow up Sentinel lymph node controversies and no performs today Diagnostic and pitfalls in melanoma Dr. Guy Perrot 11
ANOTHER VARIANT : SAMPUS SAMPUS: Superficial atypical melanocytic proliferation of uncertain significance Junctional +/- superficial dermis. No Spitzoid features Lesion must be < 1 mm in thickness and must lack intradermal mitotic activity, ulceration or obvious regression The differential diagnosis being: T1a melanoma - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 12
ADULTS : DYSPLASTIC NEVUS CLINICALLY Some what irregular pigmented macule, or pigment papule with macular periphery Sizes vary; largest examples may exceed 1 cm in diameter irritative, trauma, excess UV exposure Personal history of melanoma - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 13
ADULTS : DYSPLASTIC NEVUS HISTOLOGY Junctional or (thin) compound melanocytic nevus Richly cellular junctional component with fusion Junctional nests irregularly spaced and shaped Rete ridges irregularly elongated and oriented, with bridging Sub epidermal lamellar sclerosis (Underline) Nuclear pleomorphism and anisochromasia ('random atypia') of junctional component Dermal component usually small cell type, with pigmentation in all levels Dermal melanophages and perivascular lymphocytic infiltrates - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 14
ADULTS : DYSPLASTIC NEVUS HISTOLOGY DYSPLASTIC NEVUS MELANOMA Fusion of theca with fibrosis and inflammation The spread is more horizontal and the rete are disorganized - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 15
ADULTS case 2 : HISTOLOGY ACRAL MELANOMA Proliferation of spindle and epithelioid cells Atypical cells among the basa,l mitosis Hyperacanthosis of the epidermidis with disorganized spread proliferation Elongation of rete ridges and extension along sweat ducts Atypia and mitosis - Dr. Guy Perrot Diagnostic and pitfalls in melanoma Dr. Guy Perrot 16
ADULTS : ACRAL MELANOCYTIC TUMOR differential diagnosis Melanocytic proliferation with epidermal ascent cells Atypia, no mitosis Diagnostic and pitfalls in melanoma Dr. Guy Perrot 17
ADULTS case 2 : ACRAL MELANOCYTIC TUMOR differential diagnosis HBM45 P16: no regression DIAGNOSTIC :MANIAC Melanocytic Acral Naevi with Intraepidermal Ascent of Cells This occurs after irritation or trauma 18
MANIAC Desmoplastic features possible
ADULTS case 3: DESMOPLASTIC MELANOMA Malignant melanoma cells with fibrosis Desmoplastic melanoma is more common in males (65%) than females. Most are elderly. Sun exposure Abundant collagenous matrix scar Morphologic disparity paucicellular Amelanotic No epidermal extension generally!! Nerve involvement 20
ADULTS : DESMOPLASTIC MELANOMA IMMUNOCHEMISTRY DIFFERENTIAL DIAGNOSIS Immunohistochemical stain Desmoplastic melanoma Spindle cell carcinoma Sarcoma Epithelioid sarcoma S100 protein Diffusely positive Usually negativea Usually negativea Negative Melanocyte Differentiation antigens May be focally positive or Negative Negative Negative (gp100, Melan-A/Mart-1, tyrosinase, weak +/- Sox10 more + Usually negative May be positivec Negative Positive Usually negative +/_ Positive MITF) Sox10 Muscle markers (SMA, Desmin) Usually negative; may be positive Epithelial Markers (p63, CK5/6, MNF116, Negative 34BE12) 21
ADULTS : DESMOPLASTIC MELANOMA PARTICULAR SITE DIFFERENTIAL DIAGNOSIS VULVAR MELANOMA SMARCB1- deficient vulvar neoplasm Special epithelioid sarcoma 22
ADULTS : RECURRENT NEVUS REGRESSIVE MELANOMA OR RECURRENT NEVUS? CLINIC +++++ Histology: Central scar surrounded by melanocytes s with mild atypia and mitosis Epidermis Hyperacanthosis SCAR Pseudo melanoma Mitotically melanocytic tumor and so.. After trauma or partial excision (!!) (5-6 months) 23
REGRESSION ptis MELANOMA Melanocytes proliferation only in epidermis Dermis without malignant component. Inflammation with pigments melanophages, particular fibrosis with angiogenesis
ADULTS: PREGNANCY AND ACTIVATED NEVUS Superficial Micronodules (SMOPs) Clinically It s a nevus that have some changes with increasing size, superficial nodules. Histology : No or mild atypia but mitosis +++ (A) Nodules are superficial No epidermal changes In the deep the cells become normal (B) 25
INTERMEDIATE ADULT CHILD : DEEP PENETRATING NEVUS Age: child young adults, rare after 40 years old Man 28 years old back papuloid pigmented lesion Histology: circumscribed, often symmetrical and wedge-shaped configuration of the lesion, with the base toward the epidermis and the tip toward the reticular dermis/ sub cutis The cells are epithelioid or spindle in nests with pigments deposits The epidermal component can be absent or classically present with lentiginous features This component is formed by regular cells without atypia or mitosis 26
DEEP PENETRATING NEVUS FEATURES Lentiginous junctional component Wedge shape Fibrous stroma Extension to adnexal and arrector muscle 27
DPN AGE DISTRIBUTION 77% BEFORE 30 YEARS OLD : majority head and neck 28
DPN: NO CLASSICAL FEATURES DON T MEANS MALIGNANCY! These features CAN occur in 30% in child Asymmetry of the lesion, Expansible melanocytic nests in the dermis, Random cytological atypia with nuclear pleomorphism, BUT no diffuse Conspicuous eosinophilic nucleolus, Nucleus hole Absence of maturation, Presence of dermal mitoses, (upper) Inflammation 29
DPN DIFFERENTIAL DIAGNOSIS : ATYPICAL, MELANOMA, CELLULAR BLUE NEVUS Female, 11 years. Pigmented papule, skin of cheek ATYPICAL Compound deep penetrating nevus. Areas of unusually pronounced nuclear atypia and with increased pigmentation. REGARDED AS BENIGN. Courtesy Seab JA Jr, 30
BLUE NEVUS CLASSICAL Ill defined deep dermal proliferation of spindled melanocytes with abundant pigment and melanophages, dissecting dermal collagen Extending into sub cutis No junctional or superficial dermal involvement S100, HMB45, MelaA / Mart1 + 31
BLUE NEVUS EPITHELIOID AND ATYPICAL Atypical : Pleomorphic and vesicular nuclei, evident nucleoli, cellular, and occasional mitosis (<2/mm2) Large and cellular and epithelioid blue nevus. 32
MALIGNANT BLUE NEVUS Melanoma arising in a blue nevus 2 cells components: Benign upper malignant under 33
PEDIATRIC MELANOCYTIC TUMORS PAYA (Pediatric And Young Adults) Pediatric melanomas are rare 2% of all malignancies in patients below 20 years of age, 75% were seen to occur in patients between 15 and 19 years 3 types : CM (Common Melanoma) : BRAF and TERT-p mutations CNM (Congenital Nevus Melanoma) : NRAS mutations SM (Spitz Melanoma): kinase fusion 34
PEDIATRIC MELANOCYTIC TUMORS PAYA (Pediatric And Young Adults) CM are similar to adult melanoma: SUN EXPOSURE As adult melanoma, pediatric CM is associated with a high somatic mutation load, high frequencies of activating BRAF mutations, ( and PTEN copy number changes, with resulting activation of MAPK and PI3K/AKT cellular signaling pathways) Pediatric CNM and SM are distinct clinical entities. CNM :The high incidence of NRAS mutations, high somatic mutation burden, and grim prognosis SM: absence of BRAF/NRAS mutations, kinase fusion (low-somatic mutation burden,) and potentially more benign prognosis 35
PAYA : COMMON MELANOMA Generally post puberty after sun damage and particularly phototype I or II CDKN2 (chromosome 9) and CDK4 (chromosome 12) Same clinic than adult: ABCDE Same histology features Same therapy CLINICAL CASE FOLLOW UP SINCE 1998 CLINICAL HISTORY : Woman, multiples suspects nevi Nov 1998 SSM Clark III Breslow 0.7 mm (18 years old) Aug 2000 SSM Clark III Breslow 0.65 mm Sept 2002 SSM Clark II Breslow 0.5 mm Nov 2010 SSM CLARK3 Breslow 0.7 mm on pre existent nevus Oct 2014 in situ melanoma on preexistent nevus 36
PAYA : COMMON MELANOMA 37
PAYA : COMMON MELANOMA CDKN2 MUTATION NEVI EXCISIONS 2014 AND 2016 Be careful never classical in these patients They have nevus with some nuclear modifications Nuclear hole 38
PAYA CONGENITAL NEVUS Epidemiology 1-2% of newborn infants. 3 Types: Small (less than 1.5 cm), medium (1.5 to 20 cm) and large (over 20 cm) Develop during the first 2 years Characteristics Usually larger than acquired nevi (6-15 mm); may grow rapidly Often large, irregular in contour and pigmentation, hair bearing Associated with higher number of common melanocytic nevi and family history of melanoma, but not with sun exposure May be associated with infantile hemangioma Proliferative nodules but are usually benign and may regress Associated with nevus cells in lymph nodes Overall risk of melanoma is 0.7% 39
PAYA CONGENITAL NEVUS Compound nevus with important dermis component and deep extension (hypodermis) perineural Pigment in upper Some mitosis 40
CONGENITAL NEVUS WITH PROLIFERATIVE NODULES Large model More dark and papuloid Ulceration Acta Dermato-Venereologica 92(2):152-5 41
CONGENITAL NEVUS WITH PROLIFERATIVE NODULES Clinical features Nevus is usually large or giant Age: very young (within the first 2 years of life) Consistency: solid at first, progressive reduction in consistency. Loss of pigmentation over time Regression over time Histology High cellular density Monomorphism of cells Cells gradually merge with the surrounding melanocytes, intermediate forms of cells found at the border to the nevus Maturation of the melanocytes with descent Other: Ulceration possible Necrosis in exceptional cases only Slow growth (rapid growth possible in exceptional cases) 42
PAYA: CONGENITAL NEVUS: MELANOMA Deep and intra epidermal Nests or cohesive nodules distinct the nevus cells Nuclear pleomorphism, necrotic cells, and high mitotic activity 43
PAYA : SPITZ NEVUS Solitary acquired nevus childhood, small (<10mm) size, symmetric architecture and uniform (often light) pigmentation. Vertical cells arrangements 44
PAYA: SPITZ NEVUS IN VERY YOUNG CHILD Pagetoid intra epidermal Atypia Upper mitosis FREQUENT NOT MALIGNANCY 45
PAYA : SPITZ NEVUS MAJOR CRITERIA 1. Symmetry and sharp lateral borders (no lateral extension of junctional activity beyond the limits of dermal components). 2. Cell type- epithelioid and spindle cells.spindle cells are more common. These cells are arranged in fascicles with vertical orientation related to the rete ridges. 3. Maturation of cells - Presence of small normal nevus cells in the deeper part of the lesion. 4. Absent pagetoid spread of single cells. 5. Coalescent, pale pink Kamino bodies. 6. 2-3% of cells display Ki-67 46
PAYA : SPITZ NEVUS MINOR CRITERIA 1. Junctional cleavage 2. Hyperkeratosis and acanthosis. 3. Superficial multinucleate nevus cells 4. Perivascular inflammation 5. Absence of nuclear pleomorphism 6. No deep atypical mitoses 7. Deep outlying, solitary nevus cells. Nevus cells drift in between collagen fibers. 8. Superficial edema, telangiectasia present. 47
SPITZ TUMORS: ATYPICAL SPITZ NEVUS (ASN or STUMP) Loss of regular architecture Horizontalisation Atypia Upper mitosis Epidermal spread not in upper layers often in group of naevocytes Fibrosis, melanophages 48
ATYPICAL SPITZ: DIAGNOSTIC CLUE I -Intradermal variant: A. Architectural disorder - 1. Disordered Intraepidermal melanocytic proliferation (lentiginous and junctional nests). - 2. Asymmetry, - 3. Poorly circumscribed, -4. Lateral extension of Intraepidermal component. B. Cytological atypia Nuclear pleomorphism and enlargement. Variation in nuclear chromatin pattern and nucleoli. C. Host response Patchy chronic inflammation and fibroplasias 49
ATYPICAL SPITZ: DIAGNOSTIC CLUE II -Dermal variant: A. Architectural disorder. Expansible nodule, increased cellularity, asymmetry, loss of cellular cohesion, deep extension, lack of maturation, ulceration, necrosis. B. Cytological atypia. C. Numerous atypical mitosis upper D. Ki67 : 10-15% P16 partial regression HMB45 loss of gradient 50
PAYA : SPITZ MELANOMA It s an Atypical Spitz Nevus with: Deep and marginal mitoses, atypical mitoses, Asymmetry, Pleomorphism and prominent epidermal involvement 51
PAYA: OTHERS MELANOCYTIC T IN CHILD Spilus nevus (Congenital Speckled Lentiginous Nevus) Alternating flat and raised areas Flat areas demonstrating elongated epidermal retes, hyperpigmentation, an increased number of melanocytes at the basal layer in association with melanophages in the upper dermis Raised areas showing nests of typical melanocytes at the dermoepidermal junction and angiocentric and adnexocentric nevus cells in the dermis Regions that resemble a blue nevus 52
PAYA: MELANOMA ARISING ON NEVUS SPILUS Acta Dermato-Venereologica 53
TAKE AWAY MESSAGE: STANDARD REPORT TO HAVE THE SAME VOCABULARY BETWEEN PATHOLOGISTS AND WITH CLINICIANS TO MANAGE THE RIGHT AND SAME ITEM AND CLASSIFICATION TO DECIDE THE BEST THERAPY TO SHARE EXPERIENCE TO FOLLOW UP CORRECTLY THE PATIENT TO CREATE A DATA BANK TO STUDIES FOR EPIDEMIOLOGY IT S THE FIRST STEP TO CREATE A CANCER NETWORK! 54
MELANOCYTIC TUMORS NEED A TEAM Standard report PATHOLOGIST DERMATOLOGIST Clinic and dermatoscopy ONCOLOGIST Therapy 55
THANK YOU FOR YOUR ATTENTION 56