Update on Merkel cell carcinoma

Transcription

1 Merkel cell carcinoma: Diagnosis, staging, sentinel lymph node biopsy and prognostic markers Michael T. Tetzlaff MD, PhD Associate Professor Departments of Pathology (Dermatopathology) and Translational and Molecular Pathology The University of Texas MD Anderson Cancer Center Executive Officer Translational Research Program The Alliance for Clinical Trials Merkel cell carcinoma Described 5 cases of trabecular carcinoma of the skin Tumors consisted of irregular, angular, anastomosing trabeculae infiltrating among dermal collagen as cords Cells with oval, vesicular nuclei and indiscernible cytoplasm Update on Merkel cell carcinoma Merkel cell carcinoma Diagnosis and molecular pathogenesis Staging Sentinel lymph node Prognostic markers New therapeutics and implications for pathologists

2 Differential diagnosis of Merkel cell carcinoma Immunohistochemical studies inform the diagnosis of Merkel cell carcinoma Diagnosis Morphology IHC BCC Peripheral palisading Clefting Melanoma Pigmented Prominent intraepidermal MCPy-T-antigen negative Lacks prominent CK20+ S100+, MART-1+, Sox-10+, HMB-45+ Cytokeratin- Lymphoma/Leukemia Dishesive Positive for lymphoid markers Negative for cytokeratins Sebaceous carcinoma Metastatic neuroendorcine carcinoma Lacks neuroendocrine chromatin CK7+ CK20- and MCPy-T antigen negative Overlapping TTF-1+ CK7+ CDX-2+ MCPy-T-antigen negative CK20 TTF1 CHG SYN Cam5.2 LCA Differential diagnosis of MCC: Basal cell carcinoma Differential diagnosis MCC vs BCC: Cytokeratin 20 Cytokeratin 20 MCC BCC Moll R / Scott /10 0/6 Hanley AJ /21 Yang DT /22 0/19 McNiff JM /10 Poniecka AW /20 Shirren CG /17 Rekhi B / Bobos M / Llombart B / Leech SN / Chan JK / Sidiropoulos M / Sur M / Nicholson SA / TOTALS 212/ % 0/72 0% Also informative: MCPyV T-Ag

3 Differential diagnosis of MCC: Melanoma Differential diagnosis of MCC: Melanoma Mart-1 S100 CK20 Differential diagnosis of MCC: Small Cell Carcinoma Lung Differential diagnosis of MCC: Small Cell Carcinoma Lung Combination of TTF1- and CK20+ Spectrum of lesions with variable positivity for TTF1 and/or CK20. Diagnosis based on clinical history/exam and where the lesion falls on the IHC spectrum. CK20 CK20 TTF1 TTF1

4 Differential diagnosis of MCC: Lymphoma/Leukemia Differential diagnosis of MCC: Lymphoma/Leukemia Differential diagnosis of MCC: Lymphoma/Leukemia Differential diagnosis of MCC: Lymphoma/Leukemia CD3 MCC may (aberrantly) express B-cell markers MCC may stain positively for hematolymphoid markers 70% of MCCs are TdT+ 94% of MCCs are Pax-5+ CD4 CD30 MCC TdT Pax5 Sur M / Sidiropoulos M / Kohle R /27 24/27 Zur Hausen A /21 21/21 Totals 72/103 70% 45/48 94%

5 Demographics of Merkel cell carcinoma MCC is the most aggressive form of skin cancer ~35% of patients with nodal disease at presentation ~10% of patients with systemic metastases at presentation Estimated mortality rate: 33%-46% MCC affects older Caucasian men and is most commonly on the head and neck 70% of patients are >70 years old 62% of patients are male 43% of patients head and neck Risk factors for MCC are age and immunosuppression Elderly Accumulation of mutations from ultraviolet light Organ transplantation, HIV+, CLL Merkel cell polyomavirus (MCPyV) Mutational signature of Merkel cell carcinoma depends on MCPyV In comparison to MCPyV-positive MCCs (n=7): MCPyV-negative MCCs (n=8) A significantly higher mutational burden A UV-type mutational signature Merkel cell carcinoma driven by polyomavirus infection Mutational signature of Merkel cell carcinoma depends on MCPyV In comparison to MCPyV-positive MCCs (n=12): MCPyV-negative MCCs (n=19) Arise on chronic uv-exposed sites Exhibit a much higher mutational burden

6 Mechanisms of Merkel cell carcinomagenesis Common pathways abrogated by distinct mechanisms: mutation or virus Mechanisms of Merkel cell carcinomagenesis Common pathways abrogated by distinct mechanisms: epigenetic or virus MCPyV + MCC Viral inactivation of RB and TP53 related pathways Mutational inactivation of TP53 and RB MCPyV- MCC MCPyV + MCC Viral inactivation of RB and TP53 related pathways Mutational inactivation of TP53 and RB MCPyV- MCC MCPyT MCPyT PRC2 Silences gene regions by methylation (H3K27me) MCPyT MCPyT MCPyVT H3K27me Staging Merkel cell carcinoma Cases with follow-up and complete staging n=9,387 Histopathologic features of Merkel cell carcinoma that correlate with outcome: What do we report and why? Retrospective review of 156 patients with MCC with median follow up 51 months (range: months) Survival directly correlates with overall disease burden Local disease > Nodal metastases > Distant metastases Tumor size (and extent of invasion) define pt-category

7 Histopathologic features of Merkel cell carcinoma that correlate with outcome: What do we report and why? Among patients with lymph node negative early stage MCC (Stage I and II) Pattern of growth (Nodular versus infiltrative) Deepest anatomic compartment of involvement Tumor Lymphovascular invasion Tumor infiltrating lymphocytes (absent vs present) Pathologic staging system for Merkel cell carcinoma Based on pathologic staging of primary and metastatic disease T- pn- pm- Clinical staging system for Merkel cell carcinoma Based on pathologic staging of primary and clinical evidence of metastases T- cn- cm- Metastasis in MCC is relatively common and is an important predictor of survival: The sentinel node Pan-Cytokeratin cocktail Approximately 35% of patients with MCC present with regional nodal metastases

8 Value of immunohistochemical studies in assessing sentinel lymph nodes for MCC 10 patients 23 SLNBs All negative on 1 st H&E IHC for PanCK or CK20 5/23 SLN+ (21.7%) 4/10 patients (40%) Among patients with negative lymph node following examination of initial H&E An additional 40% of patients with lymph node metastases are identified by examining additional tissue levels and immunohistochemical studies with pan-ck or CK20 Pan-Cytokeratin cocktail Value of immunohistochemical studies in assessing sentinel lymph nodes for MCC Pan-Cytokeratin c oc ktail Value of immunohistochemical studies in assessing sentinel lymph nodes for MCC Pan-Cytokeratin cocktail Value of immunohistochemical studies in assessing sentinel lymph nodes for MCC Pan-Cytokeratin cocktail

9 SLN is an important prognostic tool for patients with MCC 59% 76% 42% 26% Lymph node status correlates with outcome Clinically node positive disease fares worst Pathological node negative disease fares best Pattern of sentinel lymph node positivity correlates with survival in Merkel cell carcinoma Pattern 1 Pattern 2 Among patients with lymph node involvement by MCC (H&E or IHC) What are the patterns of involvement? Do these patterns correlate with clinical outcome? What is the significance of metastatic MCC determined only by IHC? Pattern 3 Pattern 4 Pattern 5 Pattern of involvement Metastasis to the SLN in MCC is an important predictor of distant relapse and survival (in most studies) 721 patients 736 SLNBs 218 SLN+ (29.6%) 518 SLN- (70.4%) Regional nodal relapse not significantly different between SLNB+ (11.2%) and SLNB- (8.7%) patients Distant relapse far more frequent among SLNB+ (17.6%) compared to SLNB- (7.3%) patients (p<0.001). Sentinel lymph node status is a robust indicator of distant relapse and overall survival in MCC. Pattern of sentinel lymph node positivity correlates with survival in Merkel cell carcinoma Pattern 1 Pattern 2 Among patients with lymph node involvement by MCC (H&E or IHC) What are the patterns of involvement? Do these patterns correlate with clinical outcome? What is the significance of metastatic MCC determined only by IHC? Pattern 3 Pattern 4 Number of nodes Pattern 5

10 Pattern of sentinel lymph node positivity correlates with survival in Merkel cell carcinoma Pattern 1 Pattern 2 Among patients with lymph node involvement by MCC (H&E or IHC) What are the patterns of involvement? Do these patterns correlate with clinical outcome? What is the significance of metastatic MCC determined only by IHC? Pattern 3 Pattern 4 Age Pattern 5 Prognostic factors in Merkel cell carcinoma: p63 CK20 CHG SYN p63 n= 47 pts with MCC 25 p p63- p63-positive MCCs have worse survival than p63-negative MCCs Pattern of sentinel lymph node positivity correlates with survival in Merkel cell carcinoma Prognostic factors in Merkel cell carcinoma: p63 n= 70 pts with MCC 43 p p63- Assessed for association between survival: Age Gender Anatomic site Tumor size Tumor thickness Cell size LVI Mitotic figures TILS Pattern of growth Stage p63 p53 Ki-67 (MIB1) MCPyVstatus Stage I-II MCC

11 Prognostic factors in Merkel cell carcinoma: p63? Prognostic factors in Merkel cell carcinoma: Not all studies support the prognostic significance of p63 Status of the immune system n= 26 pts with MCC 20 p63+ 6 p63- NO ASSSOCIATION Advanced patient age and male sex associate with worse prognosis(laryngoscope : ) Immunosuppression is a risk factor for developing MCC and correlates with worse outcome independent of stage. n= 128 pts with MCC 42 p p63- All patients Stage I Stage II No significant correlation within a given stage Stage III Stage IV n= 471 pts with MCC n= 430 immunocompetent n= 41 immunosuppressed n=21 CLL/hematologic malignancy n=5 HIV/AIDS n=15 iatrogenic transplant autoimmune Composition and density of the immune system is prognostic Merkel cell carcinoma Composition, density and distribution of the immune infiltrate is prognostic Merkel cell carcinoma n=62 MCCs IHC CD3, CD8, PD-1, and PD-L1 Quantified with Aperio automated image analysis Does the composition, density and/or distribution of the associated immune infiltrate associate with survival in MCC? CD3 IHC CD3 IHC-quantified/mm 2

12 Composition, density and distribution of the immune infiltrate is prognostic Merkel cell carcinoma Leveraging the immune system to treat MCC Immunity and Merkel cell carcinoma Immunosuppression Risk factor for the development of MCC Correlates with worse prognosis independent of stage Immune infiltrates correlate with prognosis Increasing CD8+ T-cells at tumor periphery associates with improved survival Robust frequency of neoantigens in MCC (MCPyV or high mutational burden) Density of the CD8+ T-cell infiltrate at the tumor periphery associates with survival Effect appears to be amplified in MCPyV+ compared to MCPyV- MCCs Leveraging the immune system to treat MCC Response to anti-pd-1 in Merkel cell carcinoma Immunity and Merkel cell carcinoma Immunosuppression Risk factor for the development of MCC Correlates with worse prognosis independent of stage Immune infiltrates correlate with prognosis Increasing CD8+ T-cells at tumor periphery associates with improved survival Robust frequency of neoantigens in MCC (MCPyV or high mutational burden) 56% objective response rate to PD-1 inhibitor among stage IIIb or IV MCC patients who had not received prior systemic therapy independent of MCPyV status or the relative expression of PD-L1.

13 Response to anti-pd-l1 in Merkel cell carcinoma 32% (28/88) patients with stage IV MCC who failed at least one prior systemic therapy achieved rapid and sustained response to PD-L1 inhibitor independent of MCPyV status or the relative expression of PD-L1. FDA approval for MCC Thank you.. Department of Pathology, Section of Dermatopathology, MDACC Victor G. Prieto MD, PhD Carlos A. Torres-Cabala MD Jonathan L Curry MD Priyadharsini Nagarajan MD, PhD Phyu Aung MD, PhD Doina Ivan MD Laurence Feldmeyer, MD, PhD Courtney W. Hudgens, BS Department of Pathology, Cleveland Clinic Steven D Billings MD Jennifer S. Ko MD, PhD Merkel cell carcinoma MCC is the most aggressive form of skin cancer Risk factors are age, exposure and immunosuppression Important parameters of the primary lesion Size, depth, lymphocytic infiltrate, LVI, pattern of growth Staging according to TNM criteria MCC is related to infection by Merkel cell polyoma virus Viral T-antigens impact on Rb and TP53-dependent processes MCPyV-negative MCC enriched for UV-mutations (in particular TP53 and RB) Prognostic biomarkers include: Immune infiltrate p63 expression by tumor cells, but utility is questionable MCC responds to immune checkpoint blockade Thus far, independent of PD-L1 or MCPyV status Complex relationships between MCPyV and TP53 and RB RB expression lost in MCPyV- MCCs but preserved in MCPyV+ MCCs TP53 expression detected (surrogate for TP53 mutation) in MCPyV- MCCs but not in MCPyV+ MCCs. Suggest MCPy machinery interferes with RB and TP53-dependent pathways while MCPyV- MCCs rely on mutational inactivation.