5/25/2013 “Current” Approach to Diagnostic Pathology Uterine Cancer: 1. Understanding how pathologic evaluation allows a surgeon to make the best decisions about current treatment options. Practical Approach to Histologic Subtyping 2. Understanding current criteria to classify tumors and navigate problematic cases. Joseph Rabban MD MPH Associate Professor Pathology Department Treatment Decisions for Uterine Carcinoma Treatment Decisions for Uterine Carcinoma UCSF Gyn Onc Division, 2013 UCSF Gyn Onc Division, 2013 High Risk Tumor Behavior 1. Surgery versus Trial of Hormonal Therapy 2. Extent of Surgery � Advanced stage at presentation � Chemoresistance 3. Type of Adjuvant Therapy � Local recurrence � Distant metastasis 4. Candidacy for Lynch syndrome evaluation � Death 1
5/25/2013 Treatment Decisions for Uterine Carcinoma Treatment Decisions for Uterine Carcinoma UCSF Gyn Onc Division, 2013 UCSF Gyn Onc Division, 2013 High Risk Tumor Behavior Decision 1. Surgery versus Trial of Hormonal Therapy � Advanced stage at presentation Surgery is the default unless: � Chemoresistance � Recurrence locally � Distant metastasis � Grade 1 Endometrioid adenocarcinoma � Death Trial of AND Hormone Therapy High Risk Tumor Criteria � Fertility preservation � Poor surgical candidate � Any grade 3 sub-type (serous, clear cell, carcinosarcoma, endometrioid) Or � Grade 1, 2 endometrioid type with any: � Lymphovascular invasion � Myometrial/cervical/adnexal involvement � Lymph node involvement Treatment Decisions for Uterine Carcinoma Treatment Decisions for Uterine Carcinoma UCSF Gyn Onc Division, 2013 UCSF Gyn Onc Division, 2013 Decision 2. Extent of Surgery Decision 3. Type of Adjuvant Treatment Biopsy / Frozen Section None grade 1, stage 1 endometrioid, no LVI Hysterectomy g1 Endometrioid, no Myoinvasion/LVI Chemotherapy grade 2 or 3 endometrioid / age / LVI / MM invasion considered serous, clear cell, carcinosarcoma Plus pelvic lymph nodes g1 Endometroid, +Myoinvasion Radiation clear cell, serous, carcinosarcoma Plus para-aortic lymph nodes: g1,2 Endometrioid, +Myo / LVI / CX invasion considered higher stage endometrioid g3 Endometrioid Clear cell carcinoma Ifosfamide carcinosarcoma with rhabomyosarcoma elements considered Plus omentectomy: Serous carcinoma Carcinosarcoma Etoposide neuroendocrine carcinoma considered 2
5/25/2013 Treatment Decisions for Uterine Carcinoma Treatment Decisions for Endometrial Carcinoma UCSF Gyn Onc Division, 2013 Decision 4. Candidate for Lynch syndrome screening ? 4 Pathology Variables Drive these Clinical Decisions Any one criteria: � Sub-typing � Age < 50 � Grading � Bethesda Guidelines criteria � Staging Tumor infiltrating lymphocytes Peritumoral lymphocytes � Tumor Morphology � Lynch syndrome tumor morphology and testing Undifferentiated histology Lower uterine segment origin Concurrent ovarian cancer WHO Classification of Uterine Carcinoma Endometrioid adenocarcinoma � Serous carcinoma � Clear cell carcinoma � Transitional cell carcinoma � Mucinous carcinoma � Small cell carcinoma � Squamous cell carcinoma � Undifferentiated carcinoma � Carcinosarcoma � Mixed type (each type must be > 10% overall tumor) � 3
5/25/2013 WHO Classification of Uterine Carcinoma The Cancer Genome Atlas Classification of Uterine Cancer Endometrioid adenocarcinoma � Serous carcinoma � Clear cell carcinoma � Transitional cell carcinoma � Mucinous carcinoma � Small cell carcinoma � Squamous cell carcinoma � Undifferentiated carcinoma � Carcinosarcoma � Mixed type (each type must be > 10% overall tumor) � Outline of Talk Practical Approach to Classifying Uterine Carcinoma Practical issues: Evaluate in order : � Problematic variations: A pattern-based approach � Clinical context: Menopausal status / age � Immunostain pearls and pitfalls � Low magnification: Architecture � Newer non-WHO definition of undifferentiated uterine carcinoma � High magnification: Cytology � Adjacent tissue : Precursor lesion � If needed: Immunohistochemistry 4
5/25/2013 Practical Approach to Classifying Uterine Carcinoma Pre- Precursor IHC menopause lesion Endometrioid,g1,2 yes Atypical hyperplasia ER, PTEN loss Proteus: the “shape shifter” Endometrioid,g3 uncommon Atypical hyperplasia ER, p16, p53 Serous uncommon Serous EIC p53, p16 Clear cell uncommon ? HNF Undifferentiated uncommon ? EMA/Keratin loss Problematic Patterns of Uterine Cancer Problematic Patterns of Uterine Cancer Pure glandular Pure glandular Grade 1 endometrioid carcinoma Pseudo-glandular serous carcinoma Papillary Papillary Papillary endometrioid carcinoma Serous carcinoma Villoglandular endocervical adenocarcinoma Solid, with high grade nuclei Solid, with high grade nuclei Solid serous carcinoma Grade 3 endometrioid carcinoma Undifferentiated carcinoma Neuroendocrine carcinoma Spindled Spindled Endometrioid carcinoma with spindle cells Endometrioid carcinoma with corded and hyalinized pattern Endometrioid carcinoma arising in APA Carcinosarcoma Clear cell-rich Clear cell-rich Endometrioid carcinoma with clear cells Serous carcinoma with clear cells Clear cell carcinoma Mucin-rich Mucin-rich Endometrioid carcinoma with mucinous cells Endocervical carcinoma Necrosis, desmoplasia in a biopsy with low grade architecture Necrosis, desmoplasia in a biopsy with low grade architecture Myoinvasive g 1 endometrioid carcinoma or serous carcinoma Under-sampled dedifferentiated carcinoma / g3 endometrioid 5
5/25/2013 Problematic Patterns of Uterine Cancer Pure Glandular Pattern Uterine Cancer @ low magnification: � Pure glandular Simple gland shape � Papillary Columnar cells � Solid, with high grade nuclei Spindled � Complex Atypical Hyperplasia Clear cell-rich Hobnail , papillary, clear cell � Grade 1 Endometrioid Carcinoma Mucinous � Pseudoglandular Serous Carcinoma (grade 3) Necrosis, desmoplasia in a biopsy with low grade architecture Pseudoglandular Serous Carcinoma Pseudoglandular Serous Carcinoma 6
5/25/2013 Pseudoglandular Serous Carcinoma Pseudoglandular Serous Carcinoma Pseudoglandular Serous Carcinoma Pseudoglandular Serous Carcinoma in a polyp 7
5/25/2013 Pure Glandular Pattern Uterine Cancer Endometrioid carcinoma Nucleoli Serous carcinoma (upper end of size) irregular, large, cherry-red Grade 1 Pseudoglandular Endometrioid Serous Architectural Grade Low Low Nuclear Low High Grade Discordant architecture versus nuclear grade Pleomorphic nuclei � Cherry-red macronucleoli � Smudge cells � Atypical mitoses � Pseudoglandular Serous Carcinoma: Pseudoglandular Serous Carcinoma: Smudged chromatin Atypical mitoses Normal N/C ratio 8
5/25/2013 Look for Precursor Lesion Pure Glandular Pattern Uterine Cancer “Early serous carcinoma” Adenomyosis Myoinvasion by Pseudoglandular “Serous EIC” Serous cancer Architectural Grade Low Low Atrophy Nuclear Low High Grade Serous Discordant architecture Carcinoma versus nuclear grade Pleomorphic nuclei � Cherry-red macronucleoli � Smudge cells � Atypical mitoses � Pseudoglandular Serous Carcinoma Pseudoglandular Serous Carcinoma: Myoinvasion “Gaping” glands 9
5/25/2013 Pseudoglandular Serous Carcinoma: Myoinvasion Pseudoglandular Serous Carcinoma: Myoinvasion mimics adenomyosis mimics adenomyosis LVI in Serous Carcinoma may occur without myoinvasion Glandular Pattern of Endometrial Cancer Grade 1 Pseudoglandular Endometrioid Serous Architectural Grade Low Low Nuclear Low High Grade p16, p53 Wild type Aberrant ER Diffuse, strong Variable 10
5/25/2013 p53 IHC Interpretation in GYN Serous Carcinoma p53 IHC Interpretation in GYN Serous Carcinoma Pattern of p53 IHC staining p53 gene mutation Pattern of p53 IHC staining Stain Interpretation Meaning Strong/diffuse (>60% cells) 90 % Strong/diffuse (>60% cells) Aberrant p53 Favor serous carcinoma Completely negative 88 % Completely negative Weak/patchy (rare to 50%) 20 % Weak/patchy (rare to 50%) Wild type p53 (normal) Not serous carcinoma Yemenelyanova 2011 Mod Pathol p53 interpretation in GYN Serous Carcinoma Diffuse / strong p16 Patchy p16 Favor serous carcinoma Not in favor of serous carcinoma Aberrant p53 Aberrant p53 Wild type p53 Favor serous carcinoma Favor serous carcinoma Not serous carcinoma Check for internal control 11
5/25/2013 Pseudoglandular serous carcinoma Endometrioid Adenocarcinoma, grades 1 & 2 p53 p16 p53 p16 Diffuse, strong Diffuse, strong Wild type Patchy Pseudoglandular serous carcinoma Mixed pseudoglandular serous carcinoma plus grade 1 endometrioid cancer p53 p16 12
5/25/2013 Mixed pseudoglandular serous carcinoma plus grade 1 endometrioid cancer Mixed pseudoglandular serous carcinoma plus grade 1 endometrioid cancer p53 p16 Mixed pseudoglandular serous carcinoma plus grade 1 endometrioid cancer PTEN Mutation Estrogen Receptor Common in endometrioid carcinoma Uncommon in non-endometrioid carcinoma Matias-Guiu & Prat 2013 Histopathology 13
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