Update on 8 th Edition Cutaneous AJCC Staging of Primary Cutaneous Melanoma Michael T. Tetzlaff MD, PhD Associate Professor Departments of Pathology (Dermatopathology) and Translational and Molecular Pathology Director, Pathology Imaging Laboratory The University of Texas MD Anderson Cancer Center Executive Officer Translational Research Program The Alliance for Clinical Trials
Disclosures Seattle Genetics, Advisory Board Myriad Genetics, Advisory Board Novartis LLC, Advisory Board None related to topics presented
Update on 8 th Edition AJCC staging: Primary cutaneous melanoma Does not apply to melanomas of the conjunctiva, uvea, or mucosal melanomas of the head/neck, vulva/vaginal, or anorectum. Conjunctival Anorectal Urothelial Vulvar
Performing the biopsy and sending the requisition: Help us help you
Pathologic reporting for primary cutaneous melanoma * (A) RIGHT SHOULDER, SKIN PUNCH BIOPSY: * * * * * * * * * * MELANOMA, INVASIVE, SUPERFICIAL SPREADING TYPE CLARK LEVEL, IV BRESLOW THICKNESS, 2.25 MM RADIAL (NON-TUMORIGENIC) GROWTH PHASE, PRESENT VERTICAL (TUMORIGENIC) GROWTH PHASE, PRESENT MITOTIC FIGURES/MM 2, 6 ULCERATION, PRESENT (3.2 MM) REGRESSION, PRESENT VASCULAR INVASION, PRESENT PERINEURAL INVASION, PRESENT MICROSCOPIC SATELLITOSIS, PRESENT (3 X 2 MM) TUMOR-INFILTRATING LYMPHOCYTES, NON-BRISK ASSOCIATED MELANOCYTIC NEVUS, PRESENT INTRADERMAL) PREDOMINANT CYTOLOGY, EPITHELIOID SURGICAL MARGINS: INVASIVE MELANOMA PRESENT AT PERIPHERAL TISSUE EDGES * Required by CAP * Required by AJCC * Recommended by AJCC
T-category determined by Breslow thickness and ulceration Breslow (Tumor) thickness Ulceration Mitotic figures
T-category determined by Breslow thickness and ulceration All principle T-category ranges are preserved in the 8 th Edition AJCC Major differences: Definition of pt1b Breslow reported to 0.1 mm
7 th vs 8 th Edition AJCC staging of primary cutaneous melanoma Most significant change affects definition of pt1 melanomas pt1a pt1b 1.00 mm 1.00 mm 7 th Edition pt1 NO ulceration and mitotic rate <1/mm 2 With ulceration or mitotic rate>1/mm 2 8 th Edition pt1 pt1a <0.8 mm NON-ulcerated pt1b 0.8-1.0 mm NON-ulcerated pt1b 1.0 mm With ulceration Major differences: Mitotic rate no longer contributes to the determination of pt1b Breslow thickness 0.8 mm major determinant of pt1b along with ulceration Breslow reported to 0.1 mm
Basis for the 0.8 mm cut-off among pt1 melanomas Tumor thickness 0.75 mm among the most influential Tumor thickness > 0.78 mm represented a natural cut-point
Basis for the 0.8 mm cut-off among pt1 melanomas N=6263 patients with thin melanomas Tumor thickness 0.80 mm was a natural and significant cut-point distinguishing particularly adverse 10 year survival.
T-category determined by Breslow thickness and ulceration Breslow thickness Breslow thickness: Measured from: (1) top of granular layer or (2) base of the ulcer to the deepest point of invasion
Additional changes to the Breslow thickness measurements Breslow thickness for pathologic staging Includes: Thickness measured in the biopsy OR Biopsy specimen 2 If the biopsy is transected, Breslow thickness is recorded as AT LEAST Thickness measured in the excision WHICHEVER IS GREATEST (NOT ADDITIVE) Biopsy specimen 1 Biopsy specimen 2 1 2 BT1 + BT2 BT3
Additional changes to the Breslow thickness measurements Breslow thickness for pathologic staging Includes: Thickness measured in the biopsy OR If the biopsy is transected, Breslow thickness is recorded as AT LEAST Thickness measured in the excision WHICHEVER IS GREATEST (NOT ADDITIVE) Tumor thickness now recorded to the nearest 0.1 mm (instead of the nearest 0.01 mm) Due to impracticality and imprecision of 0.01 mm measurements particularly for tumors > 1 mm Important pathologic staging implications: 0.75 mm to 0.84 mm now recorded as 0.8 mm (pt1b) 0.95 mm to 1.04 mm now recorded as 1.0 mm (pt1b)
Important pitfalls in measuring Breslow thickness Avoid measuring around adnexal structrues Compared 257 patients with periadnexal involvement to 514 patients without. Breslow thickness did not include periadnexal extension. No difference in DSS, OSS Slightly more frequent SLN metastases
T-category determined by Breslow thickness and ulceration Clarification on ptis, pt0 and ptx ptis: Melanoma in situ pt0: No evidence of primary tumor ( melanoma of unknown primary ) ptx: Tumor thickness cannot be determined Tangential sectioning or the epidermis is not visualized
T-category determined by Breslow thickness and ulceration Ulceration Absence of intact epidermis with accompanying host reaction overlying invasive melanoma : Fibrin deposition with neutrophil scale/serum crust Based on microscopic examination Must be distinguished from artifactual or traumatic disruption
T-category defines prognosis among node-negative patients pt1a/b pt2a pt2b/3a pt3b/4a pt4b N0 N0
Mitotic figures are still important prognostic indicators Hotspot method. AJCC still strongly recommends a careful tabulation of the mitotic rate. NOT BINARY (0 vs 1) NOT IHC assisted. Mart-1/PHH3 cn0
Additional factors of the primary tumor recommended for clinical care Clark level (II, III, IV, V) Tumor infiltrating lymphocytes (TILs) recorded as: Absent Non-Brisk Brisk Lymphovascular invasion IHC aided detection may assist in the detection Neurotropism Defined as melanoma cells abutting nerve sheaths, usually circumferentially (perineural invasion) or within nerves (intraneural invasion) Best identified at the periphery of the tumor MiTF/D2-40
Melanoma of unknown primary origin: pt0 Patient presents with a lymph node or distant visceral metastasis but no known primary melanoma. Iatrogenic or non-iatrogenic procedures caused regression Spontaneously regressed primary melanoma Patients with metastases restricted to lymph node should be considered as regional stage III disease. Such patients have a prognosis and natural history similar to if not MORE FAVORABLE than those same staging characteristics from a known primary cutaneous melanoma
N-category determined by number and extent of nodal disease and satellites Major modifications: Clinically occult replaces microscopic [pnxa] Clinically evident replaces macroscopic [pnxb] Microsatellite, satellite or in-transit metastasis [pnxc]
N-category determined by number and extent of nodal disease and satellites N1a N2a N3a 1 2-3 4 Clinically occult Lymph node N1b N2b N3b Clinically evident Lymph node N1c N2c N3c Microsatellite Satellite In-transit met
N-category determined by sentinel node evaluation in most cases Most lymph node metastases are detected by examination of the sentinel lymph node. Sentinel lymph nodes in melanoma About 20% positive 16% initial H&E 4% additional sections/ihc <5% with extracapsular extension
Subcapsular cluster of cells in the lymph node
Isolated cells in the SLN are significant Criteria for positive lymph node: Any tumor deposit size Isolated IHC+ tumor cell acceptable H&E confirmation not required Positive for at least one melanocytic marker (HMB45, Melan-A/Mart-1, Sox- 10, MITF, S100) Cells have malignant morphology (similar to primary tumor) and in the correct location (subcapsular versus intracapsular) No unequivocal evidence for a minimum size threshold of microscopic tumor burden that is applied to define node positive disease.
N-category and capturing the extent of SNL disease burden Extent of sentinel lymph node disease burden correlates with non-sentinel lymph node positivity and predicts survival. Number of positive SLNs Size of the largest discrete deposit (at least one dimension) Anatomic location of the SLN deposit Subcapsular Intraparenchymal Both
Extracapsular extension Defined as the presence of nodal metastasis extending through the lymph node capsule into adjacent tissues usually seen as microscopic extension of metastatic melanoma into the perinodal adipose tissue.
Microsatellites, Satellites and In-transit metastases Each represents a discrete deposit of melanoma separated from the primary melanoma by normal tissue and each considered to represent lymphatic spread of tumor. 8 th Edition AJCC does not require minimum size threshold or minimum distance from the primary lesion. Microsatellites situated close to the primary lesion should be subjected to additional sections to exclude a connection.
Microsatellites, Satellites and In-transit metastases Microsatellite: clinically occult (microscopic) focus of metastatic melanoma in skin/subcutis adjacent or deep to the primary melanoma. The tumor cells are discontinuous from the primary tumor and separated from the primary lesion by normal tissue (rather than fibrosis or inflammation) Detected during examination of the primary resection specimen.
Microsatellites, Satellites and In-transit metastases Satellite: clinically evident focus of metastatic melanoma in the skin or subcutis within 2 cm but discontinuous from the primary tumor. In transit metastasis: clinically evident metastasis in the skin or subcutis located > 2 cm from the primary tumor in the region between the tumor and the regional lymph node basin.
Microsatellites, Satellites and In-transit metastases Satellite: clinically evident focus of metastatic melanoma in the skin or subcutis within 2 cm but discontinuous from the primary tumor. In transit metastasis: clinically evident metastasis in the skin or subcutis located > 2 cm from the primary tumor in the region between the tumor and the regional lymph node basin. In transit Metastasis Microsatellite Satellite Primary Melanoma
8 th Edition AJCC primary cutaneous melanoma Stage III groups robustly stratify survival
Melanoma staging M-category: site and LDH
Thank you Section of Dermatopathology, UTMDACC: Victor G. Prieto MD, PhD Jonathan L. Curry MD Carlos A. Torres-Cabala MD Priya Nagarajan MD, PhD Phyu Aung MD, PhD Doina Ivan MD Departments of Melanoma Medical and Surgical Oncology, UTMDACC: Jeff Gershenwald MD Michael A. Davies MD, PhD