2016 Current Issues in Surgical Pathology Syllabus • Summary provided Appendiceal GCC and LAMN • Complete presentation Navigating the Alphabet Soup in the Appendix sanjay.kakar@ucsf.edu Sanjay Kakar, MD University of California, San Francisco Appendiceal tumors Ludwig Wittgenstein Low grade appendiceal mucinous neoplasm • Austrian born philosopher • Peritoneal spread, chemotherapy • Famous treatise Tractatus • 5-year survival 50-60% • Logical structure and • But not called ‘adenocarcinoma’ limitations of language Goblet cell carcinoid • Meaning of words as used in a language • Not a neuroendocrine tumor • Staged and treated like adenocarcinoma • But called ‘carcinoid’ 1
Outline LAMN • Appendiceal LAMN WHO 2010: Low grade carcinoma • Peritoneal involvement by mucinous neoplasms • Low grade • Goblet cell carcinoid • ‘Pushing invasion’ -Terminology -Grading and staging -Important elements for reporting Appendiceal adenoma: intact LAMN vs. adenoma muscularis mucosa LAMN Appendiceal adenoma Low grade cytologic atypia Low grade cytologic atypia At minimum, muscularis Muscularis mucosa is mucosa is obliterated intact Can extend through the Confined to lumen wall 2
LAMN: Pushing invasion, obliteration of m mucosa LAMN vs. adenoma • Intactness of muscularis mucosa • No mucin (cellular or acellular) in the appendiceal wall • In borderline cases, go with LAMN Complex growth pattern LAMN vs adenocarcinoma LAMN Mucinous adenocarcinoma Low grade High grade Pushing invasion Destructive invasion -No desmoplasia or -Complex growth pattern destructive invasion -Angulated infiltrative glands or single cells -Desmoplasia -Tumor cells floating in mucin WHO 2010 Davison, Mod Pathol 2014 Carr, AJSP 2016 3
Complex growth pattern Angulated infiltrative glands, desmoplasia Few floating cells common in LAMN Tumor cells in extracellular mucin 4
Few floating cells common in LAMN Implications of diagnosis LAMN Mucinous adenocarcinoma LN metastasis Rare Common Hematogenous Rare Can occur spread Peritoneal Common Common metastasis Treatment Follow-up -Rt hemicolectomy imaging -Systemic chemo if needed High grade appendiceal Grade mucinous neoplasm (HAMN) • By definition, LAMN is low grade • HAMN is not part of WHO 2010 • Focal or diffuse high grade changes classification in tumors which architecturally • Included: AJCC 8 th edition resemble LAMN CAP protocol (2017 version) -No destructive invasion or desmoplasia Carr, AJSP 2016: Peritoneal Surface Oncology Group International (PSOGI) 5
High grade features: cribriform growth pattern HAMN: rare tumor • Architecture like LAMN, no destructive invasion or desmoplasia • Focal or diffuse high grade cytologic atypia HAMN: high grade features, no destructive invasion LAMN: staging • WHO 2010: Low grade carcinoma • AJCC and CAP: LAMN should be staged 6
LAMN: depth of invasion and recurrence LAMN: staging challenges Confined Acellular Cellular LAMN Study to MP mucin beyond • Erroneous interpretation as mucinous beyond MP MP adenocarcinoma Umetsu/Kakar 0/21 0/5 4/7 2016 • T category is difficult to apply Higa 1973 0/7 4/7 Depth of cellular or acellular mucin Misdraji 2003 0/27 * 20/31 Correlation of depth with outcome Pai 2009 0/16 1/14 21/27 Yantiss 2009 - 1/44** 2/10 Total 0/64 2/70 (3%) 51/82 (62%) LAMN: Acellular mucin on serosal surface LAMN staging: AJCC 8 th edition Category Change/update Tis (LAMN) LAMN extending into muscularis propria, but not beyond it T1, T2 Not applicable to LAMN T3 Cellular LAMN into subserosa ?Acellular mucin into subserosa T4a Involvement of serosal surface Cellular LAMN or acellular mucin 7
LAMN: Acellular mucin as T4a LAMN Elements in pathology reporting • Based on limited data • Submit the entire appendix • Entire appendix was not submitted • Extent of disease: both cellular and • Risk of overtreatment acellular mucin (T category) • Pathology report: • Margin assessment “ Acellular mucin on serosal surface has a low • Absence of high risk features: risk of recurrence, and categorization of this finding as T4a is based on limited data. Treatment No high grade cytology or complex growth options should be evaluated in light of this No destructive invasion or desmoplasia information.” LAMN HAMN Elements in pathology reporting Do not use obsolete terms • Extent of high grade changes • Mucocele • Use mucinous adenocarcinoma staging • Mucinous cystadenoma scheme -Outcome may be similar to mucinous AC AJCC, 8 th Edition Misdraji, AJSP 2003 8
Peritoneal involvement Pseudomyxoma peritonei • Terminology • Mucinous ascites • Grading • Omental cake • Treatment • Mucin accumulation in peritoneum due to involvement by mucinous neoplasm Peritoneal involvement Peritoneal involvement Pseudomyxoma peritonei Appendix shows LAMN Low grade Low grade High grade • LAMN with peritoneal LAMN with peritoneal LAMN with peritoneal Mucinous adenocarcinoma, involvement involvement involvement, or high grade with peritoneal • Include synonyms in a Mucinous adenocarcinoma, low Mucinous adenocarcinoma, low involvement comment grade with peritoneal grade with peritoneal involvement involvement Appendix: no LAMN or Mucinous carcinoma peritonei, Mucinous carcinoma peritonei, Mucinous carcinoma peritonei, not known low grade low grade high grade • Mucinous carcinoma Disseminated peritoneal peritonei, low grade Disseminated peritoneal Peritoneal mucinous adenomucinosis (DPAM) • Mucinous adenocarcinoma, adenomucinosis (DPAM) adenocarcinoma (PMAC) low grade 9
Grading of peritoneal disease Peritoneal involvement WHO 2010 Primary sites High grade • Appendix 2-tier scheme Mucinous adenocarcinoma, • Colorectum high grade with peritoneal -Low grade • Ovary involvement -High grade • Pancreas Mucinous carcinoma peritonei, high grade Criteria Peritoneal mucinous -Cytologic atypia adenocarcinoma (PMAC) -Architecture Grading of peritoneal disease High grade AJCC 7 th edition/CAP WHO 2010 -Complex growth 2-tier scheme 3-tier scheme -Stratification -Low grade -Well-differentiated (G1) -Loss of polarity -High grade -Moderately differentiated (G2) -Prominent nucleoli -Poorly differentiated (G3) -Frequent mitoses Criteria No defined criteria -Signet ring cells -Cytologic atypia -Extent of gland formation not -Architecture applicable to mucinous tumors 10
# of 5-year Study Grading scheme cases survival DPAM 75% Ronnett PMCA-I/D 50% Gestalt grading scheme 109 (2001) PMCA 14% DPAM 75% Smeenk 103 PMCA-I 42% • Looks good: G1 (2007) PMCA 0% DPAM 80% • Looks bad: G3 Guo PMCA-I/D 67% 92 (2012) PMCA 50% • All others: G2 PMP1 86% Shetty 211 PMP2 63% (2013) PMP3 32% G1 91% Davison 151 G2 61% (2014) G3 23% Well differentiated 57% NCDB database 3105 Moderately differentiated 32% Poorly differentiated 11% AJCC 8 th edition/CAP Challenges in grading (modified Davison scheme) G1 -Low grade cytologic atypia (similar to LAMN) • Invasive implants -Includes acellular mucin -Cellularity <20% • Small or borderline G2 -No destructive invasion of implants component G2 -Mix of low and high grade cytologic atypia, or • Discrepant grading in appendix diffuse high grade cytologic atypia -Architectural complexity and peritoneum -Destructive invasion of implants • Signet ring cells -Cellularity >20% G3 -Signet ring cells infiltrating the stroma -Poorly differentiated adenocarcinoma component Davison, Mod Pathol 2014 11
LAMN: Noninvasive ovarian implant Challenges in grading Invasive implants • Mucinous tumors on visceral organs like liver, colon etc. not sufficient • Destructive invasion and desmoplasia LAMN: Noninvasive ovarian implant Challenges in grading Small or borderline G2 component • Significance unclear • Descriptive report stating that there is a minor G2 component 12
LAMN, T4a Challenges in grading Discrepant grade in appendix and peritoneum • Uncommon • Higher grade peritoneal disease generally drives prognosis Peritoneum: signet ring cell carcinoma Pseudo-signet ring cells 13
AJCC 8 th : M categories Challenges in grading Category Definition M1a Acellular mucin with disseminated peritoneal Signet ring cell component involvement • >10% cutoff has been suggested for G3 M1b Peritoneal mucinous depositis containing tumor cells designation (not specified in AJCC) M1c Metastasis to sites other than peritoneum • Disregard cells in mucin resembling signet ring cells Stage Definition • Consider only if infiltrating signet ring IVa Any T or N, M1a (acellular mucin) Any T or N, M1b (G1) cells in stroma IVb Any T or N, M1b (G2, G3) IVc Any T or N, M1c (Any G) Sirintrapun, Hum Pathol 2014 Davison, Mod Pathol 2014 HIPEC: Hot chemotherapy Grade: impact on treatment leads to hot debate Stage IVa Stage IVb M1a: acellular mucin M1b: G2, G3 tumors Debate at ASCO meeting M1b : G1 tumors • ‘Heating drugs makes them more Combined peritoneal Role of surgery and effective’ surgery (tumor debulking) HIPEC controversial • ‘Precious little data that heated with HIPEC (hyperthermic intraperitoneal chemotherapy does anything’ chemotherapy) Systemic chemotherapy Systemic chemotherapy not useful 14
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