update on molecular genetics, diagnosis, staging, sentinel lymph … · 2019. 9. 5. · hanly 2001...
TRANSCRIPT
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Merkel cell carcinoma
Update on molecular genetics,
diagnosis, staging, sentinel lymph
node processing
Michael T. Tetzlaff MD, PhDAssociate Professor
Departments of Pathology (Section of Dermatopathology) and Translational and
Molecular Pathology
The University of Texas MD Anderson Cancer Center
Houston Texas
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Disclosure of Relevant Financial Relationships
I report no relevant financial relationships.
I have served on Advisory Boards for Novartis LLC, Myriad Genetics and Seattle Genetics, but
these are all unrelated to the topics I will present today.
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Merkel Cell Carcinoma
• Diagnosing Merkel Cell Carcinoma
• Histopathologic mimics
• Immunohistochemical studies that aid in the diagnosis
• Pitfalls: CK20-negative and combined morphologies
• Demographics of the disease
• Who gets Merkel cell carcinoma and why?
• Molecular genetics of Merkel cell carcinoma
• Staging Merkel cell carcinoma: Updates to 8th Edition AJCC
• Prognostic biomarkers in Merkel cell carcinoma
• Therapeutic advances in Merkel cell carcinoma
• Biomarkers predictive of response
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Case 1
• 52 year old Caucasian woman
• No past medical history
• Rapidly enlarging erythematous
papule
• Right malar cheek
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Cam5.2 CK20
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CHG Synaptophysin
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CD45 (LCA) TTF-1
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Case 2
• 76 year old Caucasian man
• Rapidly enlarging red-blue papule
• Left proximal pretibial region
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CK20Pan-CK
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CHG Synaptophysin
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TTF-1NF
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Diagnosis: MERKEL CELL CARCINOMA
MERKEL CELL CARCINOMA, ULCERATED
TUMOR SIZE: 3.1 x 1.75 MM
TUMOR THICKNESS: 1.75 MM
MITOTIC COUNT: 39/MM2
PATTERN OF GROWTH: PUSHING
LYMPHOCYTIC INFILTRATE: NON-BRISK
VASCULAR INVASION: PRESENT
INVASION BEYOND SUBCUTANEOUS TISSUE
(BONE, MUSCLE, FASCIA, OR CARTILAGE):
NOT IDENTIFIED
ASSOCIATED MALIGNANCY: NOT IDENTIFIED
SURGICAL MARGINS: CARCINOMA PRESENT
AT DEEP TISSUE EDGE
MERKEL CELL CARCINOMA
TUMOR SIZE: AT LEAST 5.8 X 2.9 MM
TUMOR THICKNESS: AT LEAST 6.0 MM
MITOTIC COUNT: 25/MM2
PATTERN OF GROWTH: NOT AVAILABLE
LYMPHOCYTIC INFILTRATE: NON-BRISK
VASCULAR INVASION: NOT IDENTIFIED
INVASION BEYOND SUBCUTANEOUS TISSUE
(BONE, MUSCLE, FASCIA, OR CARTILAGE):
NOT AVAILABLE
ASSOCIATED MALIGNANCY: NOT IDENTIFIED
SURGICAL MARGINS: CARCINOMA PRESENT
AT PERIPHERAL AND DEEP TISSUE EDGES.
Case 1 Case 2
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Aggressive Epidermal MalignanciesMerkel Cell Carcinoma
• Diagnosing Merkel Cell Carcinoma
• Histopathologic mimics
• Immunohistochemical studies that aid in the diagnosis
• Pitfalls: CK20-negative and combined morphologies
• Demographics of the disease
• Who gets Merkel cell carcinoma and why?
• Molecular genetics of Merkel cell carcinoma
• Staging Merkel cell carcinoma: Updates to 8th Edition AJCC
• Prognostic biomarkers in Merkel cell carcinoma
• Therapeutic advances in Merkel cell carcinoma
• Biomarkers predictive of response
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Pos Total Pos Total Pos Total
Kervarrec 2018 PMID: 30349028 94 103 10 95 73 97
Stanoszek 2018 PMID: 30239030 46 55 42 55
Bobos 2006 PMID: 16625069 13 13 0 13 12 13
Hanly 2001 PMID: 10728812 20 21 0 21
Sidropoulos 2011 PMID: 21571955 35 40 1 40
Cheuk 2001 PMID: 11175640 23 23 0 23
Moll 1992 PMID: 1371204 15 15
Schmidt 1998 PMID: 9700371 43 56 25 40
Llombart 2005 PMID: 15910593 15 20 0 20
Sur 2007 PMID: 17885674 14 15 0 15
Ordonez 2000 PMID: 10976695 16 18 0 18
Leech 2001 PMID: 11533085 10 11 0 11
Chan 1997 PMID: 9042291 33 34
McCalmont 2010 PMID: 20642632 80 100 95 100
Johannson 1990 PMID: 1698390 17 25
Shah 1993 PMID: 7678934 9 9
Metz 1998 PMID: 9717649 6 6 4 6
Yang 2004 PMID: 14984578 19 22 0 22
Jensen 2000 PMID: 11127923 23 26
Kurokawa 2003 PMID: 12727026 6 6
Chu 2000 PMID: 11007036 7 9
Acebo 2005 PMID: 16164706 9 10 8 8
Byrd-Gloster 2000 PMID: 10665914 16 21 0 21
Nicholson 2000 PMID: 10937047 18 27
Scott and Helm 1999 PMID: 10027519 9 10
Totals 570 661 11 299 285 353
Total Percentage
CK20 TTF-1 NF
80.73.786.2 NF
TTF1
CK20
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Pos Total Pos Total Pos Total Pos Total Pos Total
Bobos 2006 PMID: 16625069 4 13 12 13 13 13 10 13 9 13
Sidropoulos 2011 PMID: 21571955 2 40 29 40 39 40
Llombart 2005 PMID: 15910593 20 20 19 20
Sur 2007 PMID: 17885674 4 15 15 15 11 15 13 15 15 15
Jensen 2000 PMID: 11127923 6 26
Kurokawa 2003 PMID: 12727026 6 6 5 6 6 6 6 6
Acebo 2005 PMID: 16164706 5 10 6 8 6 8
Totals 21 104 33 34 84 102 93 102 30 34
Total Percentage 20.2 97.1 82.4 91.2 88.2
CK7 NSE CHG Synaptophysin CD56
CHG SYN
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Differential diagnosis of Merkel cell carcinoma
Diagnosis Morphology IHC
Basal cell carcinoma • Peripheral palisading
• Clefting
• Mucinous tumor
associated stroma
• MCPy-T-antigen negative
• BCC: CK5/6+ and CK20-
• MCC: CK20+ and CK5/6-
Melanoma • Pigmented
• Intraepidermal extension
common
• S100+, MART-1+, Sox-10+, HMB-45+,
MITF+
• Cytokeratin-
Lymphoma/Leukemia • Dishesive • Positive for lymphoid markers
• Negative for cytokeratins
Metastatic
neuroendocrine
carcinoma (SCLC)
• Overlapping • TTF-1+
• CK7+ (20% of MCCs also positive)
• CDX-2+
• MCPy-T-antigen negative
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Basal cell carcinoma may mimic Merkel cell carcinoma
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Stromal retractionPeripheral palisading Mucinous stroma
MCC may exhibit some morphologic features
that closely overlap with those of BCC
Merkel cell carcinoma may show overlapping
morphology with Basal cell carcinoma
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BCC
MCC
CK20 CK5/6
Immunohistochemical studies for CK5/6 and CK20
help to distinguish BCC from MCC
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Differential diagnosis of MCC: Melanoma
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S100 CK20
Mart-1
Rare examples
of S100+ in MCC
2% (3/146)
Differential diagnosis of MCC: MelanomaImmunohistochemical studies support the distinction
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Pos Total Pos Total Pos Total
Kervarrec 2018 PMID: 30349028 mulitple types 4 65 37 63 3 69
Stanoszek 2018 PMID: 30239030 multiple types 25 61 2 61
Bobos 2006 PMID: 16625069 SCLC 1 13 11 13 0 13
Hanly 2001 PMID: 10728812 SCLC 11 33 28 33
Sidropoulos 2011 PMID: 21571955 SCLC 0 36 27 36
Cheuk 2001 PMID: 11175640 SCLC 0 52 43 52
Cheuk 2001 PMID: 11175640 Extrapulmonary NEC 2 50 21 50
Moll 1992 PMID: 1371204 SCLC 3 15
Schmidt 1998 PMID: 9700371 SCLC 0 18 0 22
Ordonez 2000 PMID: 10976695 SCLC 1 28 27 28
Ordonez 2000 PMID: 10976695 Extrapulmonary NEC 1 36 4 36
Leech 2001 PMID: 11533085 SCLC 0 20 10 10
Chan 1997 PMID: 9042291 SCLC 1 37
Chan 1997 PMID: 9042291 Extrapulmonary NEC 1 52
Johannson 1990 PMID: 1698390 SCLC 0 58
Shah 1993 PMID: 7678934 SCLC 0 28
Shah 1993 PMID: 7678934 Extrapulmonary NEC 0 9
Metz 1998 PMID: 9717649 SCLC 0 22 0 22
Yang 2004 PMID: 14984578 SCLC 0 9 9 9
Chu 2000 PMID: 11007036 SCLC 0 7
Byrd-Gloster 2000 PMID: 10665914 SCLC 1 36 35 36
Nicholson 2000 PMID: 10937047 SCLC 0 5
Scott and Helm 1999 PMID: 10027519 SCLC 0 6
Totals all cases 51 601 252 366 5 282
Total Percentage all cases
Totals SCLC 18 337 190 217 0 143
Total Percentage SCLC
Total Extrapulmonary NEC 4 138 25 86 0 9
Total Percentage Extrapulmonary NEC
NFTTF-1CK20
CK20
2.9 29.1 0.0
0.087.65.3
TTF-1 NF
CK20 TTF-1 NF
8.5 68.9 1.8
Pos Total Pos Total Pos Total
Kervarrec 2018 PMID: 30349028 94 103 10 95 73 97
Stanoszek 2018 PMID: 30239030 46 55 42 55
Bobos 2006 PMID: 16625069 13 13 0 13 12 13
Hanly 2001 PMID: 10728812 20 21 0 21
Sidropoulos 2011 PMID: 21571955 35 40 1 40
Cheuk 2001 PMID: 11175640 23 23 0 23
Moll 1992 PMID: 1371204 15 15
Schmidt 1998 PMID: 9700371 43 56 25 40
Llombart 2005 PMID: 15910593 15 20 0 20
Sur 2007 PMID: 17885674 14 15 0 15
Ordonez 2000 PMID: 10976695 16 18 0 18
Leech 2001 PMID: 11533085 10 11 0 11
Chan 1997 PMID: 9042291 33 34
McCalmont 2010 PMID: 20642632 80 100 95 100
Johannson 1990 PMID: 1698390 17 25
Shah 1993 PMID: 7678934 9 9
Metz 1998 PMID: 9717649 6 6 4 6
Yang 2004 PMID: 14984578 19 22 0 22
Jensen 2000 PMID: 11127923 23 26
Kurokawa 2003 PMID: 12727026 6 6
Chu 2000 PMID: 11007036 7 9
Acebo 2005 PMID: 16164706 9 10 8 8
Byrd-Gloster 2000 PMID: 10665914 16 21 0 21
Nicholson 2000 PMID: 10937047 18 27
Scott and Helm 1999 PMID: 10027519 9 10
Totals 570 661 11 299 285 353
Total Percentage
CK20 TTF-1 NF
80.73.786.2
SCLC
Distinguishing MCC from Small Cell Carcinoma of the LungImmunohistochemical studies for CK20, TTF-1 and NF
MCC
CK20CK20
TTF-1TTF-1
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Differential diagnosis of MCC: Lymphoma/LeukemiaMCC may (aberrantly) express B-cell markers, TdT and CD56
• MCC may stain positively for
hematolymphoid markers:• 70% of MCCs are TdT+
• 94% of MCCs are Pax-5+
MCC
TdT Pax5
Sur M 2007 8/15 ---
Sidiropoulos M 2011 28/40 ---Kohle R 2013 21/27 24/27Zur Hausen A 2013 15/21 21/21
Total72/103
70%
45/48
94%
CD56 positivity of MCCs is an additional pitfall, as CD56 may also highlight
NK/T-cell lymphomas and Blastic plasmacytoid dendritic cell neoplasm
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Aggressive Epidermal MalignanciesMerkel Cell Carcinoma
• Diagnosing Merkel Cell Carcinoma
• Histopathologic mimics
• Immunohistochemical studies that aid in the diagnosis
• Pitfalls: CK20-negative and combined morphologies
• Demographics of the disease
• Who gets Merkel cell carcinoma and why?
• Molecular genetics of Merkel cell carcinoma
• Staging Merkel cell carcinoma: Updates to 8th Edition AJCC
• Prognostic biomarkers in Merkel cell carcinoma
• Therapeutic advances in Merkel cell carcinoma
• Biomarkers predictive of response
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Demographics of Merkel cell carcinoma
• Risk factors for MCC are advanced age
and immunosuppression• Elderly
• Accumulation of mutations from ultraviolet light
• Organ transplantation, HIV+, CLL
• Merkel cell polyomavirus (MCPyV)
• Older Caucasian men
• Head and neck• 70% of patients >70 years old
• 62% of patients male
• 43% of patients head and neck
Image courtesy of Isaac Brownell MD PhD
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Merkel cell carcinoma incidence is increasing
• SEER database study of 6600 cases of
MCC from 2000-2013 in the United States
95.2%
56.5%
15.5%
Overall incidence of MCC rising Especially among older patients
J Am Acad Dermatol. 2018. 78(3):457-463.
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Most Merkel cell carcinomas are driven by
polyomavirus infection
• Merkel cell polyomavirus
integrated in the genome of
~70-80% of MCCs.
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Detecting Merkel cell carcinoma polyomavirus in tissue?Immunohistochemistry may be the most sensitive and specific
• MCPyV- vs MCPyV+o Increased PFS
o Reduced MSS
• MCPyV status NOT
independent of stage.
• CM2B4 IHCo Best sensitivity (88.2%)
and specificity (94.3%)
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In comparison to MCPyV-positive MCCs (n=7):
• MCPyV-negative MCCs (n=8)
• A significantly higher mutational burden
• A UV-type mutational signature
Mutational signature of MCC depends on MCPyV statusMCPyV-negative tumors have high uv-induced mutational burden
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In comparison to MCPyV-positive MCCs
(n=12):
• MCPyV-negative MCCs (n=19)
• Arise on chronic uv-exposed sites
• Show a much higher mutational burden
Mutational signature of MCC depends on MCPyV statusMCPyV-negative tumors have high uv-induced mutational burden
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Mechanisms of Merkel cell carcinomagenesisCommon pathways abrogated by distinct mechanisms:
Virus or uv-induced mutations
Viral inactivation
of RB and TP53
related pathways
Mutational
inactivation of
TP53 and RB
MCPyV
+ MCC
MCPyT
MCPyV
- MCC
Starett et al. MBio. 2017 Jan 3;8(1). pii: e02079-16.
Geographic distribution of MCPyV+ MCC often different from MCPyV- MCC.
MCPyT
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Aggressive Epidermal MalignanciesMerkel Cell Carcinoma
• Diagnosing Merkel Cell Carcinoma
• Histopathologic mimics
• Immunohistochemical studies that aid in the diagnosis
• Pitfalls: CK20-negative and combined morphologies
• Demographics of the disease
• Who gets Merkel cell carcinoma and why?
• Molecular genetics of Merkel cell carcinoma
• Staging Merkel cell carcinoma: Updates to 8th Edition AJCC
• Prognostic biomarkers in Merkel cell carcinoma
• Therapeutic advances in Merkel cell carcinoma
• Biomarkers predictive of response
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Staging Merkel cell carcinoma:
Survival associates with stage at presentation
Cases with follow-up
and complete staging
n=9,387
• Survival directly correlates
with disease burden• Local disease > Nodal metastases
> Distant metastases
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cN0 or pN0
AJCC 8th Edition clinical staging of Merkel cell carcinomaT-category (based on clinical measurement) has not changed
• T-category based on clinical measurement• Tumor size (and extent of invasion) define T-category
• Gross and histologic measurements can be used but subject to underestimation
T Category T criteria
TX Primary tumor cannot be identified
T0 No primary tumor
T1 Tumor ≤ 2 cm in greatest dimension
T2 Tumor > 2 cm but ≤ 5 cm in greatest dimension
T3 Tumor > 5 cm
T4 Tumor invades fascia, muscle cartilage, or bone
Cases with follow-up
and complete staging
n=9,387
Increasing tumor
diameter:
OS (p=0.003)
DSS (p=0.008)
Cancer. 2015. 121: 3252-60.
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cN0 or pN0
• T-category based on clinical measurement• Tumor size (and extent of invasion) define T-category
• Gross and histologic measurements can be used but subject to underestimation
T Category T criteria
TX Primary tumor cannot be identified
T0 No primary tumor
T1 Tumor ≤ 2 cm in greatest dimension
T2 Tumor > 2 cm but ≤ 5 cm in greatest dimension
T3 Tumor > 5 cm
T4 Tumor invades fascia, muscle cartilage, or bone
Cases with follow-up
and complete staging
n=9,387
AJCC 8th Edition clinical staging of Merkel cell carcinomaT-category (based on clinical measurement) has not changed
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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: 3-224
months)
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• 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 thickness (< vs ≥ 5 mm)
• Lymphovascular invasion
• Tumor infiltrating lymphocytes (absent vs present)
Histopathologic features of Merkel cell carcinoma that
correlate with outcome: What do we report and why?
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AJCC 8th Edition clinical staging of Merkel cell
carcinoma regional metastasesN-category based on clinical evidence of regional metastases
Definitive surgical management
Clinical staging• Clinical measurement of
primary MCC
• Clinical assessment of
metastasis +/- pathologic
confirmation
Pathologic staging• Clinical measurement of
primary MCC
• Pathologic confirmation
• Nodal metastases (pN)
• Distant metastases (pM)
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N Category Clinical N criteria
cNX Regional lymph nodes cannot be assessed
cN0 No evidence of lymph node metastasis
cN1 Clinically detected regional lymph node metastasis
cN2 Clinically detected in-transit metastasis without lymph node metastasis
cN3 Clinically detected in-transit metastasis AND lymph node metastasis
Based on clinical assessment of metastatic nodal disease
AJCC 8th Edition clinical staging of Merkel cell
carcinoma regional metastasesN-category based on clinical evidence of metastases
Imaging studies are not required for every patient• If thorough history and physical exam do not reveal metastatic disease (N0 M0).
• If there is clinical suspicion for or evidence of metastatic disease, and radiographic
studies confirm this, then cN (1, 2, 3) or cM1 (a, b, c)
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AJCC 8th Edition clinical staging of Merkel cell
carcinoma regional metastasesN-category based on pathologic evidence of regional metastases
Definitive surgical management
Clinical staging• Clinical measurement of
primary MCC
• Clinical assessment of
metastasis +/- pathologic
confirmation
Pathologic staging• Clinical measurement of
primary MCC
• Pathologic confirmation
• Nodal metastases (pN)
• Distant metastases (pM)
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Based on pathologic evidence of metastatic disease
N Category Pathologic N criteria
pNX Regional lymph nodes cannot be assessed
pN0 No evidence of lymph node metastasis (negative SLNB, etc)
pN1a (sn) Clinically occult lymph node metastasis on SLN biopsy (NO completion LND)
pN1a Clinically occult lymph node metastasis on SLN biopsy (WITH completion LND)
pN1b Clinically detected lymph node metastasis, pathologically confirmed
pN2 In-transit metastasis without lymph node metastasis
pN3 In-transit metastasis plus lymph node metastasis
AJCC 8th Edition clinical staging of Merkel cell
carcinoma regional metastasesN-category based on pathologic evidence of metastases
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8th Edition AJCC staging of Merkel cell carcinomaClinical versus pathologic staging highlights important survival differences
cN0 only (pNX)
Patients with clinically evident
regional MCC metastases have
worse survival compared to those
with clinically occult involvement
of the regional lymph nodes
Patients presenting with MCC metastases
to lymph nodes without a known primary
MCC have better survival compared to
those with known primary MCC
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• Approximately 35% of patients with MCC present with regional
lymph node metastases
Mol Clin Oncol. 2015. 3(2):299-302.
The sentinel node is the most common site for
clinically occult Merkel cell carcinoma metastases
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• H&E
• Pan-Cytokeratin IHC
• Unstained slide
200mm
Among patients with negative SLN following examination of initial H&E:
Approximately 20-30% of patients with lymph node metastases are identified after
examination of additional tissue levels and IHC for pan-Cytokeratin or CK20
IHC for PanCK
or CK20
• 5/23 SLN+ (22%)
• 4/10 patients (40%)
• 10 patients
• 23 SLNBs
• All negative on 1st H&E
The sentinel node is the most common site for
clinically occult Merkel cell carcinoma metastases
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• H&E
• Pan-Cytokeratin IHC
• Unstained slide
200mm
The sentinel node is the most common site for
clinically occult Merkel cell carcinoma metastases
Among patients with negative SLN following examination of initial H&E:
Approximately 20-30% of patients with lymph node metastases are identified after
examination of additional tissue levels and IHC for pan-Cytokeratin or CK20
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Sentinel lymph node assessment in MCCPositivity on initial H&E stained tissue sections spans a spectrum of
disease burden
• H&E
• Pan-Cytokeratin IHC
• Unstained slide
200mm
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Sentinel lymph node assessment in MCCImmunohistochemical studies facilitate the detection of clinically
occult lymph node involvement
• H&E
• Pan-Cytokeratin IHC
• Unstained slide
200mm
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Sentinel lymph node assessment in MCCImmunohistochemical studies facilitate the detection of clinically
occult lymph node involvement
No minimal size threshold defined for metastatic deposits of Merkel cell
carcinoma to qualify as positive
• H&E
• Pan-Cytokeratin IHC
• Unstained slide
200mm
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Extent of disease burden in lymph node status correlates with survival
• Clinically evident lymph node positive disease fares worst
• Pathological node negative disease fares best
SLN is a critical prognostic tool for patients with MCC:
Pathologically negative patients fare the best
59%
26%
76%
42%
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Prognostic factors in Merkel cell carcinoma: p63
• n= 47 pts with MCC
• 25 p63+
• 22 p63-CK20
CHG SYN
p63
n= 70 pts with MCC
• 43 p63+
• 27 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)
• MCPyV status
Stage I-II MCC
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Stage I Stage II Stage III Stage IV
No significant correlation with p63 status within a given stage
?
• n= 128 pts with MCC
• 42 p63+
• 86 p63-
All patients
Prognostic factors in Merkel cell carcinoma: p63
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Prognostic factors in Merkel cell carcinoma: Integrity of the immune system
• Advanced patient age and male sex associate with worse
prognosis(Laryngoscope. 2012. 122:1283-90.)
• Immunosuppression is a risk factor for developing MCC and correlates
with worse outcome independent of stage.
• 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
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Prognostic factors in Merkel cell carcinoma: Tumor associated immune infiltrate correlates with survival
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Prognostic factors in Merkel cell carcinoma: Composition, density and distribution of the tumor
associated immune infiltrate correlates with survival
• n=62 MCCs and 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-quantified/mm2
-
Prognostic factors in Merkel cell carcinoma: Composition, density and distribution of the tumor
associated immune infiltrate correlates with survival
• n=62 MCCs and 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-quantified/mm2
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Aggressive Epidermal MalignanciesMerkel Cell Carcinoma
• Diagnosing Merkel Cell Carcinoma
• Histopathologic mimics
• Immunohistochemical studies that aid in the diagnosis
• Pitfalls: CK20-negative and combined morphologies
• Demographics of the disease
• Who gets Merkel cell carcinoma and why?
• Molecular genetics of Merkel cell carcinoma
• Staging Merkel cell carcinoma: Updates to 8th Edition AJCC
• Prognostic biomarkers in Merkel cell carcinoma
• Therapeutic advances in Merkel cell carcinoma
• Biomarkers predictive of response
-
Response to anti-PD-1 in Merkel cell carcinoma
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.
-
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
Response to anti-PD-L1 in Merkel cell carcinoma
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Response to anti-PD-L1 in Merkel cell carcinoma
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Response to anti-PD-L1 in Merkel cell carcinomaMultifactorial and includes spatial relationships of the TILS
Density of PD-1+ cells and PD-L1+ cells
significantly higher among responders
versus non-responders
Proximity of PD-1+ cells to PD-L1+ cells in a tumor
correlates with response to a-PD-1: Number of PD-1+
cells ≤ 20mm of PD-L1+ cell higher in R versus NR
Greater engagement of PD-1 with PD-L1 implies a greater likelihood that
inhibiting this interaction will exert a positive clinical effect.
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Merkel cell carcinoma
• MCC is among the most aggressive forms of skin cancer• Risk factors are age, uv-exposure and immunosuppression
• MCC responds to immune checkpoint blockade• Thus far, independent of PD-L1 or MCPyV status
• Important parameters of the primary lesion• Size, extent of involvement of underlying structures
• Staging according to TNM criteria
• Depth, lymphocytic infiltrate, LVI, pattern of growth
• MCC is related to infection by Merkel cell polyoma virus• MCPyV-positive MCC lacks high mutational load
• 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
• p63 expression by tumor cells
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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
Steven Billings, MD
Isaac Brownell MD PhD
Paul Harms, MD PhD
Axel zur Hausen, MD, PhD
Jürgen Becker MD, PhD
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• 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
-
CK20
-
AJCC 7th Edition for Merkel cell carcinoma:Clinical and pathologic nodal status were considered together
*
*
*
*
With increasing application of sentinel lymph node biopsy (SLNB), this
system created a selection bias for stage IB and IIB (cN0 patients) to consist
of patients in whom SLNB was not performed due to underlying
comorbidities, and unclear if these comorbidities contribute to their survival.
-
Definitive surgical management
Clinical staging• Clinical measurement of
primary MCC
• Clinical assessment of
metastatic disease (+/-
pathologic confirmation)
Pathologic staging• Clinical measurement of
primary MCC
• Pathologic confirmation
• Nodal metastases (pN)
• Distant metastases (pM)
AJCC 8th edition more accurately distinguishes the prognostic
significance of the extent of nodal disease burden with less
emphasis on the extent of nodal evaluation.
AJCC 8th Edition for Merkel cell carcinoma:Clinical and pathologic nodal status considered separately
Cases with follow-up
and complete staging
n=9,387
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T1 (63%)
T2/3 (53%)
T4 (35%)
cN0 only
T1 (45%)
T2/3 (31%)
T4 (27%)
8th Edition AJCC establishes a more sensitive system for prognostication of
survival among pathologically node negative patients that is distinct from
clinically node negative patients.
8th Edition AJCC staging of Merkel cell carcinomaClinical versus pathologic node negative patient survival according to T-category
This underscores the importance of the sentinel lymph node.
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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
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MCC occasionally shows divergent differentiationThese tumors are not associated with MCPy-virus infection
• 44 cases of MCC combined with SCC:
• 0/44 MCPyV-negative
-
CK20
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MCC occasionally shows divergent differentiationThese tumors are not associated with MCPy-virus infection
• 44 cases of MCC combined with SCC:
• 0/44 MCPyV-negative