Molecular Pathology of Skin Tumors Selected Topics

2015-02-04

Prof. Dr. med. Katharina Glatz Pathologie UV LIGHT AND SKIN CANCER UVA 100x less mutagenic than UVB, but more abundant UVB DNA-damage: direct photocemical reactions  UV photoproducts

UV signature: C-T transitions and CC-TT tandem base substitutions Nucleotide excision repair: repairs pyrimidine dimers photoproducts

Immune system: proinflammatory and immunosuppressive effects

Melanin pigment: Predominant mechanism of photoprotection UV-induced stress response: tanning response

NMSC causative link between UV light and NMSC frequent mutations of TP53 (UV signature)

Melanoma high load of somatic mutations (UV signature) role of UVB and UVA (tanning beds) Fluorescence in situ hybridization MALIGNANT MELANOMA 2011 Fig. 1 Schematic overview of the Fig. 2 Schematic overview of the immune synapse RAS/RAF/MEK/ERK signaling pathway. and therapeutic interventions.

Simone Stadler , Kasia Weina , Christoffer Gebhardt , Jochen Utikal New therapeutic options for advanced non-resectable malignant melanoma Advances in Medical Sciences, Volume 60, Issue 1, 2015, 83 - 88 Sensitivity of 60% and a specificity of 50%

Negative FISH result in histologically and clinically definitive malignant melanomas

Incongruent results of array CGH data and FISH The FISH technique with its present composition of locus-specific probes for RREB1/MYB and CCND1 did not achieve a clinically useful sensitivity and specificity.

Reassessment of the probes and better standardization of the method may lead to a valuable diagnostic tool. Sensitivity of 4-color FISH for the detection of spitzoid Melanomas can be increased to 85% based on homozygous loss of the 9p21 locus

Typical Spitz nevi in patients >50y with retained p16 expression show normal diploid 9p21 FISH signals p16 IHC serves as a screening tool to select IHC-negative spitzoid lesions for FISH analysis targeting the 9p21 locus Clinicpathologic features beat molecular pathology SQUAMOUS CELL CARCINOMA

(CSCC)

• Excellent prognosis after surgery – nodal metastasis (3.7-5.2%) – disease-specific death (1.5-2.1%)

• Clinical and histologic risk factors associated with increased risk

• No specific role of molecular pathology in disease prognostication and prediction of CSCC Cohort: 1818 tumors in 974 patients. Median follow-up time 50 months (2 to 142 months).

Perineural invasion ≥ 0.1mm  indicates diameter of involved nerve. 2.5-5% have Pn1 Lymphovascular invasion is associated with nodal metastases and disease specific death Karia P S et al. JCO 2014;32:327-334 Percentage of local recurrences, nodal metastases and disease specific deaths in low versus high stages of three different staging systems

91% 88% 67% 81% 67% 50% 53% 30% 17%

9% 12% 33% 19% 33% 50% 47% 70% 83%

Cohort: 1818 tumors in 974 patients. Median follow-up time 50 months (2 to 142 months). ADNEXAL TUMORS Brooke Spiegler Syndrome/ Familial cylindromatosis/ Multiple familial trichoepithelioma:

Cylindromas Spiradenomas Cylindroma Spiradenoma Trichoepitheliomas

Autosomal dominant 88% have inactivating germline mutations of CYLD gene Brooke Spiegler Syndrome/ Familial cylindromatosis/ Multiple familial trichoepithelioma:

88% have inactivating germline mutations of CYLD gene  Phenotypic variation of a single defect

A MYB–NFIB fusion-positive dermal cylindroma B Immunostaining of MYB protein

ACC-like areas with cribriform structures in spiradenoma.

Cells in the ACC-like area showed a myoepithelial phenotype with expression of SMA ? ?

? ? Spiradenoma Cylindroma

Adenoidcystic Carcinoma Breast Adenoidcystic Carcinoma Parotid Gland Adenoidcystic carcinoma (N=15): Adenoid Basal Cell Carcinoma (N=15) 40% CD43 + 0% CD43 + 100% CD117 + (moderate/strong) 20% CD117 + (weak/moderate) SEBACEOUS NEOPLASMS AND MUIR TORRE SYNDROME Sebaceous Hyperplasia

Sebaceous hyperplasia is not associated with Muir Torre Syndrome Sebaceous Adenoma

More than 50% of the tumor is composed of sebocytes More than 1 layer of basaloid/germinative cells at periphery of sebocyte-filled lobules Sebaceous adenoma can be associated with Muir-Torre syndrome

Sebaceoma

50% basaloid cells < 50% sebocytes often arranged haphazardly. Basaloid cells may show mild cytologic atypia and mitotic figures. Sebaceous cells do not show significant atypia or mitotic activity Adipophilin Sebaceous Carcinoma

(EMA) Cytologic atypia Pleomorphism Mitotic figures, often atypical High nuclear Ki67 and p53 staining may help in establishing the malignant nature of any sebaceous neoplasm Muir Torre Syndrome

• Skin tumors: – Sebaceous neoplasms – Keratoacanthoma and basal cell carcinoma with sebaceous differentiation

• Occurrence of skin tumors – 22–32% precede internal malignancy – 9-12% accompany internal malignancy Muir Torre Syndrome

• autosomal-dominant • subset (1–3%) of the Lynch syndrome • associated malignancies (less aggressive!) – Skin: sebaceous adenoma, sebaceoma, sebaceous carcinoma, keratoacanthoma (seboacanthoma) – Visceral malignancies: colorectal, genitourinary, breast, hematological, upper gastrointestinal neoplasms Muir Torre Syndrome

• MTS related sebaceous lesions: – Keratoacanthoma like changes and/or – increased tumor-infiltrating lymphocytes – association with cystic architecture has been questioned Muir Torre Syndrome

• 2/3 MTS cases associated with hereditary MMR defects and MSI in both visceral and cutaneous neoplasms

• MTS cases exhibiting MSI: – 90% MSH2 mutation – 10% MLH1 mutation – Rare MSH6 mutation – MSH3 , PMS1 , or PMS2 mutations have not been reported MTS Screening

• PCR – MSI-H: MSI in at least two Bethesda markers – less cost-effective than IHC – no information about specific MMR protein defects MTS Screening

• IHC staining for MLH1, MSH2, and MSH6 on lesional tissue from any sebaceous neoplasm – nuclear expression by IHC is highly sensitive (92%) and specific (95%) – good correlation with MSI status (PCR)

MLH1 normal MSH2 loss

Images: Pathol Res Pract. 2014 Oct 23. [Epub ahead of print] Boennelycke M1, Thomsen BM2, Holck S3. Suggested Reading

Molecular Surgical Pathology. Chapter 13 p. 269-306: Molecular Pathology of Cutaneous Melanoma and Nonmelanoma Skin Cancer. Saggini A and Bastian B. Cheng L, Eble JN (eds.), Springer Science+Business Media New York 2013