Toronto Notes [36 ed.] 9781927363607

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TORONTO NOTES 2020

Comprehensive medical reference and review for the Medical Council of Canada Qualifying Exam (MCCQE) Part I and the United States Medical Licensing Exam (USMLE) Step II

36th Edition Editors-in-Chief: Sara Mirali and Ayesh Seneviratne

Wherever the art of medicine is loved, there is also a love of humanity. – Hippocrates

Toronto Notes for Medical Students, Inc. Toronto, Ontario, Canada

Thirty-sixth Edition Copyright © 2020 – Toronto Notes for Medical Students, Inc. Toronto, Ontario, Canada. Typeset and production by Type & Graphics Inc. ISBN 978-1-927363-60-7 (36th ed.) All rights reserved. Printed in Toronto, Ontario, Canada. Toronto Notes 2020 is provided for the sole use of the purchaser. It is made available on the condition that the information contained herein will not be sold or photocopied. No part of this publication may be used or reproduced in any form or by any means without prior written permission from the publisher. Every effort has been made to obtain permission for all copyrighted material contained herein. Previous editions copyright © 1985 to 2020. Cover illustration: Julia Devorak and Farah Hamade Illustrations: Biomedical Communications, University of Toronto Notice: THIS PUBLICATION HAS NOT BEEN AUTHORED, REVIEWED, OR OTHERWISE SUPPORTED BY THE MEDICAL COUNCIL OF CANADA NOR DOES IT RECEIVE ENDORSEMENT BY THE MEDICAL COUNCIL AS REVIEW MATERIAL FOR THE MCCQE PART I. THIS PUBLICATION HAS NOT BEEN AUTHORED, REVIEWED, OR OTHERWISE SUPPORTED BY THE NATIONAL BOARD OF MEDICAL EXAMINERS U.S.A. NOR DOES IT RECEIVE ENDORSEMENT BY THE NATIONAL BOARD AS REVIEW MATERIAL FOR THE USMLE. The editors of this edition have taken every effort to ensure that the information contained herein is accurate and conforms to the standards accepted at the time of publication. However, due to the constantly changing nature of the medical sciences and the possibility of human error, the reader is encouraged to exercise individual clinical judgement and consult with other sources of information that may become available with continuing research. The authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this textbook, atlas, or software and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. In particular, the reader is advised to check the manufacturer’s insert of all pharmacologic products before administration.

FEEDBACK AND ERRATA We are constantly trying to improve the Toronto Notes and welcome your feedback. If you have found an error in this edition please do not hesitate to contact us. As well, we look forward to receiving any comments regarding any component of the Toronto Notes package and website. Please send your feedback to: [email protected] Alternatively, send mail to:

Toronto Notes for Medical Students Editors-in-Chief c/o The Medical Society 1 King’s College Circle, Room 2260 Toronto, Ontario M5S 1A8 Canada email: [email protected] Tel: 1-416-946-3047 Fax: 1-416-978-8730

Library of Congress Cataloging-in-Publication Data is available upon request

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Toronto Notes 2020

Dedicated to all past and present contributors and supporters of Toronto Notes who have made the production of the 2020 edition possible!

The Toronto Notes for Medical Students is dedicated to helping fund many charitable endeavours and medical student initiatives at the University of Toronto’s Faculty of Medicine and beyond. Programs that have received Toronto Notes for Medical Students funding include: Community Affairs Projects • Saturday Program for Inner City High School and Grade 8 students • St. Felix Mentorship Program for Inner City children • Parkdale Mentorship Program for Grade 10-12 students • WoodGreen Community Centre • Let’s Talk Science • Growing Up Healthy

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Note: Many of you have wondered about the Toronto Notes logo, which is based on the rod of Asclepius, the Greek god of medicine. The rod of Asclepius consists of a single serpent entwined around a staff. This icon symbolizes both rebirth, by way of a snake shedding its skin, and also authority, by way of the staff. In ancient Greek mythology, Asclepius was the son of Apollo and a skilled practitioner of medicine who learned the medical arts from the centaur Chiron. Asclepius’ healing abilities were so great that he was said to be able to bring back people from the dead. These powers displeased the gods, who punished Asclepius by placing him in the sky as the constellation Orphiuchus. The rod of Asclepius is at times confused with the caduceus, or wand, of Hermes, a staff entwined with two serpents and often depicted with wings. The caduceus is often used as a symbol of medicine or medical professionals, but there is little historical basis for this symbolism. As you may have guessed, our logo uses the rod of Asclepius that is modified to also resemble the CN Tower – our way of recognizing the university and community in which we have been privileged to learn the art and science of medicine. Thomas O’Brien, MD Class of 2009, M.D. Program, University of Toronto

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Toronto Notes 2020

Preface – From the Editors Dear Readers, As the Editors-in-Chief of Toronto Notes 2020, we are proud to present this updated edition. Toronto Notes began humbly in 1985 from a set of student notes circulated among medical students at the University of Toronto. Over time, Toronto Notes has grown into one of the premier study resources for generations of medical trainees. This rich history solidified our commitment to publish a comprehensive study resource for medical students engaged in clinical rotations and studying for both the Canadian MCCQE Part 1 and the USMLE Step 2. For the past 36 years, we have remained committed to our original vision. The 2020 edition of Toronto Notes contains significant improvements including: 1. For the first time, Toronto Notes is offered as a 3 book set. We hope this makes our premier study resource more portable for our readers. 2. An improved interactive e-book with high-quality colour images. 3. The clinical handbook is now combined with STAT notes, making it the perfect resource for all of your clinical rotations. The updated handbook also contains a new quick-reference pharmacology table that provides a succinct overview of common drugs, routes of administration, and usage information. 4. Our updated website has been redesigned to complement your studies. Visit us online for our newly updated Colour Atlas, our Radiology Imaging Database, practice review questions, and more. Toronto Notes 2020 is produced by Toronto Notes for Medical Students Inc., which is a non-profit organization supporting various charity organizations in Toronto and beyond. This year, Toronto Notes for Medical Students has supported organizations including medical school clubs, community outreach groups, student bursaries and scholarships, and the Canadian Cancer Society. We would like to thank you for supporting these initiatives through your purchase of Toronto Notes 2020. 4

We want to highlight the exceptional work of our team, composed of over 150 medical students, medical illustrators, and faculty members at the University of Toronto Faculty of Medicine. Without the tireless effort expended by these individuals, the production of Toronto Notes 2020 would not have been possible. In particular, we would like to highlight the amazing work of our executive team, all of whom made personal sacrifices in balancing their clinical and academic duties with the responsibilities asked of them: our production managers, Megan Drupals and Matthaeus Ware, our associate editors, Vanessa Sheng, Jia Tanwani, Calvin Diep, Jagan Sivakumaran, Danielle Jeong, and Nivethan Vela, our EBM editors, Melissa Allwood, Milica Milakovic, Michael Elfassy, Kimia Sheikholeslami, Khizar Karim, and Ryan Wang, our clinical handbook editors, Priya Dhir, Helen Genis, and Meghan Kerr, and our communication managers, Courtney Francis and Shane Natalwalla. Lastly, we would like to thank our partners at Type & Graphics Inc., particularly Enrica Aguilera, for their assistance during the production of Toronto Notes 2020. We hope that Toronto Notes 2020 enhances your medical knowledge and allows you to perform better on both your clinical rotations and licensing exams. On behalf of the Toronto Notes 2020 team, we wish you success in your studies and academic endeavours. Sincerely, Sara Mirali, BSc (Hons), MD/PhD Candidate and Ayesh Seneviratne, MSc, MD/PhD Candidate Editors-in-Chief, Toronto Notes 2020 MD Program, University of Toronto

Toronto Notes 2020

Acknowledgements We would like to acknowledge the exceptional work of all previous Toronto Notes (formerly MCCQE Notes) Editors-in-Chief and their editorial teams. The 36th edition of this text was made possible with their contributions. 2019 (35th ed.): Taraneh (Tara) Tofighi and Mark Shafarenko 2018 (34th ed.): Tina Binesh Marvasti and Sydney McQueen 2017 (33rd ed.): Jieun Kim and Ilya Mukovozov 2016 (32nd ed.): Zamir Merali and Justin D. Woodfine 2015 (31th ed.): Justin Hall and Azra Premji 2014 (30th ed.): Miliana Vojvodic and Ann Young 2013 (29th ed.): Curtis Woodford and Christopher Yao 2012 (28th ed.): Jesse M. Klostranec and David L. Kolin 2011 (27th ed.): Yingming Amy Chen and Christopher Tran 2010 (26th ed.): Simon Baxter and Gordon McSheffrey 2009 (25th ed.): Sagar Dugani and Danica Lam 2008 (24th ed.): Rebecca Colman and Ron Somogyi 2007 (23rd ed.): Marilyn Heng and Joseph Ari Greenwald 2006 (22nd ed.): Carolyn Jane Shiau and Andrew Jonathan Toren 2005 (21st ed.): Blair John Normand Leonard and Jonathan Chi-Wai Yeung 2004 (20th ed.): Andrea Molckovsky and Kashif S. Pirzada 2003 (19th ed.): Prateek Lala and Andrea Waddell 2002 (18th ed.): Neety Panu and Sunny Wong 2001 (17th ed.): Jason Yue and Gagan Ahuja 2000 (16th ed.): Marcus Law and Brian Rotenberg 1999 (15th ed.): Sofia Ahmed and Matthew Cheung 1998 (14th ed.): Marilyn Abraham and M Appleby 1997 (13th ed.): William Harris and Paul Kurdyak 1996 (12th ed.): Michael B. Chang and Laura J. Macnow 1995 (11th ed.): Ann L. Mai and Brian J. Murray 1994 (10th ed.): Kenneth Pace and Peter Ferguson 1993 (9th ed.): Joan Cheng and Russell Goldman 1992 (8th ed.): Gideon Cohen-Nehemia and Shanthi Vasudevan All former Chief Editors from 1991 (7th ed.) to 1985 (1st ed.)

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Student Contributors Editors-in-Chief Sara Mirali Ayesh Seneviratne

Production Managers Megan Drupals Matthaeus Ware

PRIMARY

Clinical Handbook Editors Helen Genis Priya Dhir Meghan Kerr

Website Managers/ Atlas Editors Sylvie Bowden Emily Chen Sandra Fiset Amrit Sampalli

MEDICINE

Associate Editors Vanessa Sheng Jia Tanwani

EBM Editors Melissa Allwood Milica Milakovic

Chapter Editors Ethical, Legal, and Organizational Medicine Anna Kurdina David Wiercigroch Anesthesia and Perioperative Medicine Kosalan Akilan Nicole Falzone John Mikhaeil Clinical Pharmacology Felix Chan Arman Zereshkian

Medical Genetics Sivakami Mylvaganam Medical Imaging Mana Modares Taryn Rohringer Daniel Schlam

Dermatology Josh Fletcher Khalad Maliyar Arunima Sivanand

Pediatrics Vinyas Harish Alexandra Kilian Linlei Ye Kimberly Young

Emergency Medicine Abirami Kirubarajan Marissa Lu Aidan McParland Jason Park

Psychiatry Maria Berseneva Brigida Bruno Daniel Kapustin Ronak Saluja Public Health and Preventive Medicine Harpreet Chahal Ben Shachar Vishalini Sivarajah

Copy Editors

Associate Editors Calvin Diep Jagan Sivakumaran

EBM Editors Michael Elfassy Kimia Sheikholeslami

Cardiology and Cardiac Surgery Armin Abadeh David Bobrowski Irakli Dzneladze Kimberley Lau Endocrinology Ayesha Tasneem Yifan Yang Wid Yaseen Gastroenterology Arshia Javidan Jocelyn Jia Sechiv Jugnundan Geriatric Medicine Laavanya Dharmakulaseelan Fizza Manzoor Hannah Tateishi

Medical Genetics Janis Chang Medical Imaging Yasser Salama Rachel Trister Pediatrics Marina Atalla Kristen Dietrich Brian Earl Stephanie Hosang Kristen Munro Psychiatry Taaha Muhammad Serena Kay Amita Mall Public Health and Preventive Medicine Krish Bilimoria

Nephrology Savar Kaul Nishwa Shah

General Surgery and Thoracic Surgery Kimberley Lam-TinCheung Darby Little Andreea Matei Sonieya Nagarajah

Neurology Megan Hird Eshita Kapoor Cathy Meng Fei Li

Gynecology Sarah Freeman Vanessa Rojas Luengas Ryan Ramos

Respirology Samuel Gurupatham Aneesh Thakore

Neurosurgery Connor Brenna Karanbir Brar Karim Mithani

Rheumatology Daniel Pau Hilary Pang

Hematology Sze Wah Samuel Chan RuiQi (Richard) Chen Kathryn Corbett

Cardiology and Cardiac Surgery Klaudiusz Stoklosa Siobhan Wong Endocrinology Orly Bogler Grace Zhao Gastroenterology Lauren Beck Geriatric Medicine Emily Bellicoso Hematology Lauren Clarfield Isabella Fan

Associate Editors Danielle Jeong Nivethan Vela

EBM Editors Khizar Karim Ryan Wang

Chapter Editors Infectious Diseases Monica Shah Donald Wang

Obstetrics Michelle Anderson Sophia Duong Emily Li Ophthalmology Shicheng (Tony) Jin Prem Nichani Daniel Sei Joon Park Austin Pereira

Copy Editors

Ethical, Legal, and Organizational Medicine Monisha Basu Anesthesia and Perioperative Medicine Dong An Fadi Gorgi Kirusanthy Kaneshwaran Clinical Pharmacology Isabelle Laksono Dermatology Airiss Chan Matthew Ladda Sheida Naderi-Azad Emergency Medicine Anuja Bhalerao Kiran Grant Family Medicine Isabelle MacLean Casey Rosen Jackie Tsang

BMC Production Editors Julia Devorak Farah Hamade

SURGERY

Chapter Editors Family Medicine Kate Dillon Tiffany Got Healey Shulman Alexandra Silberberg

Communications Managers Courtney Francis Shane Natalwalla

Orthopedics Akshdeep Singh Bhatia Anthony Giuliano Sam Keshen Otolaryngology Amirpouyan (Pouyan) Namavarian Gianluca Sampieri Eunice You Plastic Surgery George Ho Shawn Khan Janakan Somasundaram Urology Adam Bobrowski Jethro Kwong Min Joon Lee Vascular Surgery Kennedy Ayoo Brianna Barsanti-Innes

Copy Editors Infectious Diseases Meera Mahendiran Elliot Smith Nephrology Joel George Seiwon Park Neurology Ortenc Hoxha Valerie Kim Respirology Erica Brant Rina Huo Rheumatology Lindsay Cho Vibeeshan Jegatheeswaran

General Surgery and Thoracic Surgery Isha Narula Sung Hoon (Peter) Song Gynecology Andrew Butti Xin Xu Neurosurgery Sara Ahmed Hetshree Joshi Obstetrics Ye Rin (Yenah) Seo Eliya Zhao Ophthalmology Ruben Kalaichandran Abdul Sidiqi

Orthopedics Anser Daud Emmanuel Igbokwe Otolaryngology Emily DeHaas Bryan Wong Plastic Surgery Shawn Khan Mithila Somasundaram Urology Susan Dong Julia Hollingsworth Vascular Surgery Frozan Safi

BMC ILLUSTRATORS Taeah Kim

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Mona Li

Chloe Ng

Kim Nipp

Lesia Szyca

Emily Taylor

Rachael Whitehead

Alexander Young

Toronto Notes 2020

Faculty Contributors, University of Toronto All contributing professors have been appointed at the University of Toronto. PRIMARY Ethical, Legal, and Organizational Medicine Ruby Shanker, MBBS, MHSc University Health Network, Dalla Lana School of Public Health, University of Toronto Anesthesia and Perioperative Medicine Ahtsham Niazi, MBBS, FCARCSI, FRCPC Department of Anesthesia and Pain Management, University Health Network Jeff Wassermann, MD, FRCPC Department of Anesthesia, St. Michael’s Hospital Clinical Pharmacology David Juurlink, BPhm, MD, PhD, FRCPC Division of Clinical Pharmacology and Toxicology, Departments of Medicine and Pediatrics, Sunnybrook Health Sciences Centre Dermatology David Adam, MD, FRCPC Division of Dermatology, Department of Medicine, St. Michael’s Hospital Marissa Joseph, MD, FRCPC Division of Dermatology, Department of Medicine, Women’s College Hospital and The Hospital for Sick Children Jensen Yeung, MD, FRCPC Division of Dermatology, Department of Medicine, Women’s College Hospital Emergency Medicine Mark Freedman, MD, FRCPC Department of Emergency Medicine, Sunnybrook Health Sciences Centre Fernando Teixeira, MD, FRCPC Department of Emergency Medicine, St. Michael’s Hospital Family Medicine Ruby Alvi, MD, CCFP, MHSc Department of Family and Community Medicine, University of Toronto Azadeh (Azi) Moaveni, MD, CCFP Department of Family and Community Medicine, University Health Network, Toronto Western Hospital Dr. Sherylan Young, MD, CCFP, FCFP Department of Family and Community Medicine, Sunnybrook Health Sciences Centre Medical Genetics Hanna Faghfoury, MDCM, FRCPC, FCCMG The Fred A Litwin Family Centre in Genetic Medicine, Department of Medicine, Mount Sinai Hospital and University Health Network

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Joyce So, MD, PhD, FRCPC, FCCMG The Fred A Litwin Family Centre in Genetic Medicine, Department of Medicine, Mount Sinai Hospital and University Health Network Medical Imaging Nasir Jaffer, MD, FRCPC Division of Abdominal Imaging, Department of Medical Imaging, Mount Sinai Hospital and University Health Network Joint Department of Medical Imaging, University of Toronto John Kavanagh, MD, FRCPC Division of Cardiothoracic Imaging, Department of Medical Imaging, Joint Department of Medical Imaging, University of Toronto Eugene Yu, MD, FRCPC Division of Neuroradiology, Department of Medical Imaging, University Health Network Pediatrics Julie Johnstone, MD (FRCPC), MScCH Division of Pediatric Medicine, Department of Pediatrics, The Hospital for Sick Children Laila Premji, MD, FRCPC Division of Paediatric Medicine, Department of Paediatrics, The Hospital for Sick Children Janaki Vallipuram, MD, FRCPC Department of Pediatrics, The Hospital for Sick Children Psychiatry Benoit Mulsant, MD, MS, FRCPC Department of Psychiatry, Centre for Addiction and Mental Health Dr. Mary Preisman, MD, FRCPC Department of Psychiatry, Mount Sinai Hospital Dr. Amit Rotem, MD Department of Psychiatry, Centre for Addiction and Mental Health Dr. Ilana Heather Shawn, MD, FRCPC Department of Psychiatry, St. Michael’s Hospital Public Health and Preventive Medicine Barry Pakes, BSc, MD, MPH, CCFP, DTMH, FRCPC, PhD Dalla Lana School of Public Health, University of Toronto Nav Persaud, MD, MSc, BA, BSc Department of Family and Community Medicine, St. Michael’s Hospital Department of Family and Community Medicine, University of Toronto

MEDICINE Cardiology Chi-Ming Chow, MD, CM, MSc, FRCPC Division of Cardiology, Department of Medicine, St. Michael’s Hospital Paul Dorian, MD, MSc, FRCPC Division of Cardiology, St. Michael’s Hospital Anna Woo, MD CM, SM, DABIM, FRCPC Division of Cardiology Department of Medicine University Health Network Toronto General Hospital Endocrinology Julie Gilmour, MBCHB, FRCPC, MSC Department of Endocrinology, St. Michael’s Hospital Karen Gomez-Hernandez, MD, MSc Department of Endocrinology, University Health Network Mount Sinai Hospital Phillip Segal, MD, FRCPC Division of Endocrinology, University Health Network Gastroenterology Maria Cino, BSc(Hon), MSc, MD, FRCPC Division of Gastroenterology, University Health Network, Toronto Western Hospital Gabor Kandel, MD, FRCPC Division of Gastroenterology, Department of Medicine, St. Michael’s Hospital Piero Tartaro, MD, MSc, FRCPC Division of Gastroenterology, Department of Medicine, Sunnybrook Health Sciences Centre Geriatric Medicine Vicky Chau, MD, MScCH, FRCPC Division of Geriatric Medicine, Department of Medicine, University Health Network Karen D’Silva, MD, MS, FRCPC Division of Geriatrics, St Michael’s Hospital Dan Liberman, MD, MScCH, FRCPC Division of Geriatric Medicine, Department of Medicine, University Health Network Hematology Gloria Lim, MD, MSc, FRCPC Division of Hematology, Department of Medicine, St. Michael’s Hospital

Toronto Notes 2020

Faculty Contributors, University of Toronto Martina Trinkaus, MD, FRCPC Division of Hematology, Department of Medicine, St. Michael’s Hospital Richard Wells, MD, D.Phil, FRCPC Division of Medical Oncology and Hematology, Department of Medicine, Sunnybrook Health Sciences Centre Infectious Diseases Ari Bitnun, MD, MSc, FRCPC Division of Infectious Diseases, Department of Medicine, The Hospital for Sick Children Paul Bunce, BSc, MA, MD, FRCPC Division of Infectious Diseases, Department of Medicine, University Health Network Susan M. Poutanen, MD, MPH, FRCPC Department of Microbiology, University Health Network Mount Sinai Hospital Nephrology Zahirieh Alireza, MD, FRCPC Division of Nephrology, Sunnybrook Health Sciences Centre Istvan Mucsi, MD, PhD, FRCPC Multi-Organ Transplant Program and Division of Nephrology, University Health Network Gemini Tanna, MD, FRCPC Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre Neurology Esther Bui, MD, FRCPC Division of Neurology, Department of Medicine, University Health Network Xavier Montalban, MD, PhD Division of Neurology, Department of Medicine, St. Michael’s Hospital Respirology Anju Anand, MD, FRCPC Divison of Respirology, Department of Medicine, St. Michael’s Hospital Meyer Balter, MD, FRCPC, FACP, FCCP Division of Respiratory Medicine, Mount Sinai Hospital Rheumatology Simon Carette, MD, FRCPC Division of Rheumatology, Department of Medicine, Mount Sinai Hospital Arthur Bookman, MD, FRCPC Division of Rheumatology, University Health Network

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SURGERY General Surgery and Thoracic Surgery Abdollah Behzadi, MD, MBA, FRCSC, FACS Department of General Surgery, Trillium Health Partners Michael Ko, MD, PhD, FRCSC Department of General Surgery, St Joseph’s Health Care

Joshua Teichman, MD, FRCSC Department of Ophthalmology, Trillium Health Partners Orthopedics Jeremy Hall, MD, FRCSC Dvision of Orthopedic Surgery, Department of Surgery, St. Michael’s Hospital

Jesse Pasternak, MD, MPH, FRCSC Department of General Surgery, University Health Network

Herb von Schroeder, MD, MSc, FRCSC Divisions of Orthopedic Surgery and Plastic Surgery, Department of Surgery, University Health Network

Fayez Quereshy, MD, MBA, FRCSC Department of General Surgery, University Health Network, Toronto Western Hospital

Sarah Ward, MD, MLA, MSc , FRCSC Divisions of Orthopedic Surgery, Department of Surgery, St. Michael’s Hospital

Gynecology Sari Kives, MD, FRCSC Department of Obstetrics and Gynecology, St. Michael’s Hospital and The Hospital for Sick Children Danielle Vicus, MD, FRCSC, MSc Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre Fay Weisberg, MD, FRCSC Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Toronto Neurosurgery Todd Mainprize, MD, FRCSC Department of Neurosurgery, Sunnybrook Health Sciences Centre Eric Massicotte, MD, MSc, FRCSC Department of Neurosurgery, University Health Network, Toronto Western Hospital Obstetrics Rohan D’Souza, MD, MSc, FRCOG, PhD (C) Department of Obstetrics and Gynecology, Mount Sinai Hospital Richard Pittini, MD, MEd, FRCSC, FACOG Department of Obstetrics and Gynecology, University of Toronto, Sunnybrook Health Sciences Centre Amanda Selk, MD, FRCSC Department of Obstetrics and Gynecology, Mount Sinai Hospital Ophthalmology Asim Ali, MD, FRCSC Department of Opthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto Wai-Ching Lam, MD, FRCSC Department of Ophthalmology and Vision Science, University Health Network, Toronto Western Hospital

Dr. David Wasserstein, MD, FRCSC, MSc, MPH(c) Division of Orthopaedic Surgery, Sunnybrook Health Sciences Centre Otolaryngology Jonathan Irish, MD, MSc, FRCSC Department of Otolaryngology Head and Neck Surgery, University Health Network Evan Propst, MD, MSc, FRCSC Department of Otolaryngology Head and Neck Surgery, The Hospital for Sick Children Plastic Surgery Siba Haykal, MD, PhD, FRCSC Division of Plastic and Reconstructive Surgery, Department of Surgery, University Health Network Melinda Musgrave, MD, PhD, FRCSC Division of Plastic and Reconstructive Surgery, Department of Surgery, St. Michael’s Hospital Urology Sender Herschorn, MDCM, FRCSC Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre and Women’s College Hospital Jason Lee, MD, MHPE, FRCSC Division of Urology, Department of Surgery, University Health Network, Toronto General Hospital Vascular Surgery Elisa Greco, BSc, MBChB, MD, FRCS Division of Vascular Surgery, Department of Surgery, St. Michael’s Hospital George Oreopoulos, MD, MSc, FRCSC Division of Vascular Surgery, Department of Surgery, University Health Network

Marisa Sit, MD, FRCSC Department of Opthalmology and Vision Sciences, University Health Network, Toronto Western Hospital

Toronto Notes 2020

Table of Contents Index Abbreviations Common Unit Conversions Commonly Measured Laboratory Values Ethical, Legal, and Organizational Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ELOM Anesthesia and Perioperative Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A Cardiology and Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CP Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D Emergency Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ER Endocrinology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E Family Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FM Gastroenterology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G General Surgery and Thoracic Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GS Geriatric Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GM Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GY Hematology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ID Medical Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MG Medical Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MI Nephrology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NP Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N Neurosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NS Obstetrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OB Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OP Orthopedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OR Otolaryngology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OT Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P Plastic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PL Psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PS Public Health and Preventive Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PH Respirology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R Rheumatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RH Urology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U Vascular Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VS Index

9

Toronto Notes 2020

How to Use This Book This book has been designed to remain as one book or to be taken apart into smaller booklets. Identify the beginning and end of a particular section, then carefully bend the pages along the perforated line next to the spine of the book. Then tear the pages out along the perforation. The layout of Toronto Notes allows easy identification of important information. These items are indicated by icons interspersed throughout the text:

Icon Icon Name

Significance

Key Objectives

This icon is found next to headings in the text. It identifies key objectives and conditions as determined by the Medical Council of Canada or the National Board of Medical Examiners in the USA. If it appears beside a dark title bar, all subsequent subheadings should be considered key topics.

Clinical Pearl

This icon is found in sidebars of the text. It identifies concise, important information which will aid in the diagnosis or management of conditions discussed in the accompanying text.

Memory Aid

This icon is found in sidebars of the text. It identifies helpful mnemonic devices and other memory aids.

Clinical Flag

This icon is found in sidebars of the text. It indicates information or findings that require urgent management or specialist referral.

Evidence Based Medicine

This icon is found in sidebars of the text. It identifies key research studies for evidence-based clinical decision making related to topics discussed in the accompanying text.

Colour Photo Atlas

This icon is found next to headings in the text. It indicates topics that correspond with images found in the Colour Photo Atlas available online (www.torontonotes.ca).

Radiology Atlas

This icon is found next to headings in the text. It indicates topics that correspond to images found in the Radiology Atlas available online (www.torontonotes.ca).

Online Resources

This icon is found next to headings in the text. It indicates topics that correspond with electronic resources such as Functional Neuroanatomy or ECGs Made Simple, available online (www.torontonotes.ca).

Chapter Divisions To aid in studying and finding relevant material quickly, each chapter is organized in the following general framework: Basic Anatomy/Physiology Review • features the high-yield, salient background information students are often assumed to have remembered from their early medical school education Common Differential Diagnoses • aims to outline a clinically useful framework to tackle the common presentations and problems faced in the area of expertise Diagnoses • the bulk of the book • etiology, epidemiology, pathophysiology, clinical features, investigations, management, complications, and prognosis Common Medications • a quick reference section for review of medications commonly prescribed

10

Toronto Notes 2020

Common Unit Conversions To convert from the conventional unit to the SI unit, multiply by conversion factor To convert from the SI unit to the conventional unit, divide by conversion factor Conventional Unit

Conversion Factor

SI Unit

ACTH

pg/mL

0.22

pmol/L

Albumin

g/dL

10

g/L

Bilirubin

mg/dL

17.1

µmol/L

Calcium

mg/dL

0.25

mmol/L

Cholesterol

mg/dL

0.0259

mmol/L

Cortisol

µg/dL

27.59

nmol/L

Creatinine

mg/dL

88.4

µmol/L

Creatinine clearance

mL/min

0.0167

mL/s

Ethanol

mg/dL

0.217

mmol/L

Ferritin

ng/mL

2.247

pmol/L

Glucose

mg/dL

0.0555

mmol/L

HbA1c

%

0.01

proportion of 1.0

Hemaglobin

g/dL

10

g/L

HDL cholesterol

mg/dL

0.0259

mmol/L

Iron, total

µg/dL

0.179

µmol/L

Lactate (lactic acid)

mg/dL

0.111

mmol/L

LDL cholesterol

mg/dL

0.0259

mmol/L

1

x 109 cells/L

103

cells/mm3

Leukocytes

x

Magnesium

mg/dL

0.411

mmol/L

MCV

µm3

1

fL

1

x 109 cells/L

Platelets

x

103

cells/mm3

Reticulocytes

% of RBCs

0.01

proportion of 1.0

Salicylate

mg/L

0.00724

mmol/L

Testosterone

ng/dL

0.0347

nmol/L

Thyroxine (T4)

ng/dL

12.87

pmol/L

Total Iron Binding Capacity

µg/dL

0.179

µmol/L

Triiodothyronine (T3)

pg/dL

0.0154

pmol/L

Triglycerides

mg/dL

0.0113

mmol/L

Urea nitrogen

mg/dL

0.357

mmol/L

Uric acid

mg/dL

59.48

µmol/L

Celsius  Fahrenheit

F = (C x 1.8) + 32

Fahrenheit  Celsius

C = (F – 32) x 0.5555

Kilograms  Pounds

1 kg = 2.2 lbs

Pounds  Ounces

1 lb = 16 oz

Ounces  Grams

1 oz = 28.3 g

Inches  Centimetres

1 in = 2.54 cm

11

Toronto Notes 2020

Commonly Measured Laboratory Values Test

Conventional Units

SI Units

Arterial Blood Gases pH PCO2 PO2

7.35-7.45 35-45 mmHg 80-105 mmHg

7.35-7.45 4.7-6.0 kPa 10.6-14 kPa

Serum Electrolytes Bicarbonate Calcium Chloride Magnesium Phosphate Potassium Sodium

22-28 mEq/L 8.4-10.2 mg/dL 95-106 mEq/L 1.3-2.1 mEq/L 2.7-4.5 mg/dL 3.5-5.0 mEq/L 136-145 mEq/L

22-28 mmol/L 2.1-2.5 mmol/L 95-106 mmol/L 0.65-1.05 mmol/L 0.87-1.45 mmol/L 3.5-5.0 mmol/L 136-145 mmol/L

Serum Nonelectrolytes Albumin ALP ALT Amylase AST Bilirubin (direct) Bilirubin (total) BUN Cholesterol Creatinine (female) Creatinine (male) Creatine Kinase – MB fraction Ferritin (female) Ferritin (male) Glucose (fasting) HbA1c LDH Osmolality

3.5-5.0 g/dL 35-100 U/L 8-20 U/L 25-125 U/L 8-20 U/L 0-0.3 mg/dL 0.1-1.0 mg/dL 7-18 mg/dL 40 ◆ risk factors for or history of endometrial cancer ◆ failure of medical treatment ◆ significant intermenstrual bleeding ◆ consider in women with infrequent menses suggesting anovulatory cycles

Hysterectomy Indications • uterine fibroids • endometriosis, adenomyosis • uterine prolapse • pelvic pain • AUB • cancer (endometrium, ovaries, fallopian tubes, cervix) Complications • general anesthetic • bleeding • infection • injury to other organs (ureter, bladder, rectum) • loss of ovarian function (if ovaries removed, iatrogenic menopause) Approaches 1. Open (abdominal approach): uterus removed via transverse (Pfannenstiel) or midline laparotomy 2. Minimally invasive approaches ■ vaginal hysterectomy: entire procedure performed through the vagina. No abdominal incisions ■ laparoscopic-assisted vaginal hysterectomy: vascular pedicles are divided by a combination of laparoscopic and vaginal approaches ■ total laparoscopic hysterectomy: all vascular pedicles including the colpotomy approached laparoscopically and removed through the vagina ■ robotic: a type of laparoscopic approach. May be advantageous in high BMI patients. More costly

No. 377 – Hysterectomy for Benign Gynaecological Indications J Obstet Gynaecol Can 2019;41(4):543-557 Summary: 1. Hysterectomy should be approached by either vaginal, laparoscopic, or open routes 2. Correction of preoperative anemia (hemoglobin 6 mo or 3 cycles after documented menarche

GY9 Gynecology

Disorders of Menstruation

Toronto Notes 2020

Table 4. Management of Amenorrhea (continued) Etiology

Management

2º amenorrhea is pregnancy until proven otherwise

2º AMENORRHEA HP-axis dysfunction

Identify modifiable underlying cause Combined OCP to decrease risk of osteoporosis, maintain normal vaginal and breast development (NOT proven to work)

Hyperprolactinemia

MRI/CT head to rule out lesion If no demonstrable lesions by MRI Bromocriptine, cabergoline if fertility desired Combined OCPs if no fertility desired Demonstrable lesions by MRI: surgical management

Polycystic ovarian syndrome Premature ovarian failure

See Polycystic Ovarian Syndrome, GY23 Screen for DM, hypothyroidism, hypoparathyroidism, hypocorticolism Hormonal therapy with estrogen + progestin to decrease risk of osteoporosis; can use OCP after induction of puberty

Uterine defect Asherman’s syndrome

Evaluation with hysterosalpingography or sonohysterography Hysteroscopy: excision of synechiae

Abnormal Uterine Bleeding Abnormal Uterine Bleeding (AUB)

Regular (predictable cycle)

Irregular (unpredictable cycle)

Heavy

Intermenstrual Bleeding

AUB-A AUB-LSM AUB-C AUB-E

AUB-P

AUB and/or unpredictable AUB

AUB-O AUB-M

Figure 7. Diagnostic approach to abnormal uterine bleeding

Approach • menstrual bleeding should be evaluated by ascertaining: frequency/regularity of menses, duration, volume of flow, impact on quality of life, and timing (inter or premenstrual or breakthrough) • is it regular? ■ regular: cycle to cycle variability of 40 yr with AUB, for women 6 mo – ulipristal acetate • surgical ■ endometrial ablation ◆ if finished childbearing ◆ repeat procedure may be required if symptom recur, especially if 6 mo: include add-back progestin or estrogen to prevent decreased BMD, reduce vasomotor side-effects ◆ danazol (Danocrine®): weak androgen – side effects: weight gain, fluid retention, acne, hirsutism, voice change • surgical ■ conservative laparoscopy using laser, electrocautery ± laparotomy ◆ ablation/resection of implants, lysis of adhesions, ovarian cystectomy of endometriomas ■ definitive: bilateral salpingo-oophorectomy ± hysterectomy ■ best time to become pregnant is immediately after conservative surgery ■ if patient is not planning to become pregnant post-op, suppress ovulation medically to prevent recurrence

Adenomyosis • synonym: “endometriosis interna” (uterine wall may be diffusely involved) Epidemiology • 15% of females >35 yr old; found in 20-40% of hysterectomy specimens • mean age at presentation: 40-50 yr old (older age group than seen in endometriosis) • adenomyosis is a common histologic finding in asymptomatic patients

Adenomyosis Extension of areas of endometrial glands and stroma into the myometrium

Clinical Features • often asymptomatic • heavy menstrual bleeding, secondary dysmenorrhea, pelvic discomfort • dyspareunia, dyschezia • uterus symmetrically bulky, usually 35 yr • more common in African Americans, where they are also larger and occur at earlier age • common indication for major surgery in females • minimal malignant potential (1:1000) • typically regress after menopause Pathogenesis • estrogen stimulates monoclonal smooth muscle proliferation • progesterone stimulates production of proteins that inhibit apoptosis • degenerative changes (occur when tumour outgrows blood supply) ■ fibroids can degenerate, become calcified, develop sarcomatous component, or obtain parasitic blood supply

Leiomyomata/Fibroids Benign smooth muscle tumour of the uterus (most common gynecological tumour)

Submucosal leiomyomata are most symptomatic (bleeding, infertility)

The effect of pregnancy on fibroid size is variable

GY14 Gynecology

Toronto Notes 2020

Fibroids

Clinical Features • majority asymptomatic (60%), often discovered as incidental finding on pelvic exam or U/S • abnormal uterine bleeding (30%): dysmenorrhea, heavy menstrual bleeding • pressure/bulk symptoms (20-50%) ■ pelvic pressure/heaviness ■ increased abdominal girth ■ urinary frequency and urgency ■ constipation, bloating (rare) ■ acute urinary retention (extremely rare, but surgical emergency!) • acute pelvic pain ■ fibroid degeneration ■ fibroid torsion (if pedunculated subserosal) • infertility, recurrent pregnancy loss • pregnancy complications (potential enlargement and increased pain, obstructed labour, difficult C-section) Investigations • bimanual exam: uterus asymmetrically enlarged, usually mobile • CBC: anemia • U/S: to confirm diagnosis and assess location of fibroids • sonohysterogram: useful for differentiating endometrial polyps from submucosal fibroids, or for assessing intracavitary growth • endometrial biopsy to rule out uterine cancer for abnormal uterine bleeding (especially if age >40 yr) • occasionally MRI is used for pre-operative planning (e.g. before myomectomy) Treatment • only if symptomatic (heavy menstrual bleeding, menometrorrhagia, bulk symptoms), rapidly enlarging or intracavitary • treat anemia if present • conservative approach (watch and wait) if: ■ symptoms absent or minimal ■ fibroids 99% with perfect use) • may be less effective in women >90 kg • may not be covered by drug plans Contraceptive Ring (Nuva Ring®) • thin flexible plastic ring; releases etonogestrel 120 µg/d and estradiol 15 µg/d • works for 3 wk then removed for 1 wk to allow for menstruation • as effective as OCP in preventing pregnancy (98%) • side effects: vaginal infections/irritation, vaginal discharge • may have better cycle control; i.e. decreased breakthrough bleeding

Counselling the Adolescent about Contraception More than 90% of adolescent pregnancies are unintended, and ~50% of all pregnancies occur within the first 6 mo of initiating sexual activity; in addition, 85% of sexually active women become pregnant within 1 yr if no contraception is used and even some of the least effective contraceptive methods markedly decrease the risk of pregnancy

New Oral Contraceptive Preparations and the Risk of Venous Thromboembolism vs. Second Generation Drugs BMJ 2015;350:h2135 Summary: Risks of thromboembolism associated with combined OCPs were higher for drug preparations with newer progesterone types than for second generation drugs (levonorgestrel and noresthisterone) and norgestimate. Methods: Two nested case-control studies were performed on UK population through two large databases containing total of 1340 practices. Women aged 15-49 years with a first diagnosis of VTE in 2001-13 were matched with five controls by age, practice, and calendar year. OR for VTE incidence and use of combined OCPs were adjusted for smoking status, alcohol consumption, ethnic group, BMI, comorbidities, and other contraceptive drugs. Results: Current exposure to OCP was associated with adjusted OR of 2.97 (95% CI 2.783.17) compared to no exposure in previous year. Risks associated with current exposure to new progesterone drug preparations (desogestrel, gestodene, drospirenone, cyproterone) were significantly higher than those for second generation contraceptives (levonorgestrel, noresthisterone) and norgestimate.

GY16 Gynecology

Toronto Notes 2020

Contraception

Starting Hormonal Contraceptives • thorough history and physical exam, including blood pressure and breast exam • can start at any time during cycle but ideal if within 5 d of LMP • follow-up visit 6 wk after hormonal contraceptives prescribed • pelvic exam not required as STI screening can be done by urine and pap smear screening does not start until >21 yr Table 8. Combined Estrogen and Progestin Contraceptive Methods Advantages

Side Effects

Contraindications

Highly effective Reversible Cycle regulation Decreased dysmenorrhea and heavy menstrual bleeding (less anemia) Decreased benign breast disease and ovarian cyst development Decreased risk of ovarian and endometrial cancer Increased cervical mucus which may lower risk of STIs Decreased PMS symptoms Improved acne Osteoporosis protection (possibly)

Estrogen-related Nausea Breast changes (tenderness, enlargement) Fluid retention/bloating/edema Weight gain (rare) Migraine, headaches Thromboembolic events Liver adenoma (rare) Breakthrough bleeding (low estradiol levels)

Absolute Known/suspected pregnancy Undiagnosed abnormal vaginal bleeding Prior thromboembolic events, thromboembolic disorders (Factor V Leiden mutation; protein C or S, or antithrombin III deficiency), active thrombophlebitis Cerebrovascular or coronary artery disease Estrogen-dependent tumours (breast, uterus) Impaired liver function associated with acute liver disease Congenital hypertriglyceridemia Smoker age >35 yr Migraines with focal neurological symptoms (excluding aura) Uncontrolled HTN

Progestin-related Amenorrhea/breakthrough bleeding Headaches Breast tenderness Increased appetite Decreased libido Mood changes HTN Acne/oily skin* Hirsutism* * Androgenic side effects may be minimized by prescribing formulations containing desogestrel, norgestimate, drospirenone, or cyproterone acetate

Relative Migraines (non-focal with aura 3 wk in a row (unlike monophasic formulation)

Yasmin® and Yaz®

Yasmin®: 30 µg ethinyl estradiol + 3 mg drospirenone (a new progestin) Yaz®: 20 µg ethinyl estradiol + 3 mg drospirenone – 24/4-d pill (4 d pill free interval) Drospirenone has antimineralocorticoid activity and antiandrogenic effects

Decreased perception of cyclic weight gain/bloating Fewer PMS symptoms Improved acne

Hyperkalemia (rare, contraindicated in renal and adrenal insufficiency) Check potassium if patient also on ACEI, ARB, K+-sparing diuretic, heparin Continue use of spironolactone

Alesse

®

PROGESTIN-ONLY METHOD Table 10. Progestin Only Contraceptive Methods Indications

Mechanism of Action

Side Effects

Contraindications

Suitable for postpartum women (does not affect breast milk supply) Women with contraindications to combined OCP (e.g. thromboembolic or myocardial disease) Women intolerant of estrogenic side effects of combined OCPs

Progestin prevents LH surge Thickening of cervical mucus Decrease tubal motility Endometrial decidualization Ovulation suppression – oral progestins (not IM) do not consistently suppress compared to combined OCPs

Irregular menstrual bleeding Weight gain Headache Breast tenderness Mood changes Functional ovarian cysts Acne/oily skin Hirsutism

Absolute None

Irregular breakthrough bleeding often occurs in the first few months after starting OCP; usually resolves after three cycles Progestin only contraceptives must be taken at the same time every day

Missed Combined OCPs Miss 1 pill in 3 h Use back-up contraceptive method for at least 48 h; continue to take remainder of pills as prescribed Missed Depo-Provera • If last injection given 13-14 wk prior: give next injection immediately • If >14 wk prior, do β-hCG – If β-hCG is positive, give EPC and no injection – If β-hCG is negative, give next injection right away and: • Intercourse occurred in last 5 d: give EPC, use back-up contraception for 7 d ; repeat β-hCG in 3 wk • Intercourse occurred >5 d ago but within the last 14 d: use back-up contraception for 7 d; repeat β-hCG in 3 wk • Intercourse occurred >14 d ago: use backup contraception for 7 d – No evidence of fetal abnormalities if conceived on DMPA SOGC Committee Opinion on Missed Hormonal Contraceptives: New Recommendations. JOGC 2008;30:1050-62. http://www.sogc.org/guidelines/ documents/gui219ECO0811.pdf

Intrauterine Device Table 11. IUS/IUD Contraceptive Methods Mechanism of Action

Side Effects

Contraindications

Copper-Containing IUD (Nova-T®): mild foreign body reaction in endometrium; toxic to sperm and alters sperm motility

Both Copper and Progesterone IUD Breakthrough bleeding Expulsion (5% in the 1st yr, greatest in 1st mo and in nulliparous women) Uterine wall perforation (1/1000) on insertion If pregnancy occurs with an IUD, increased risk of ectopic Increased risk of PID (within first 10 d of insertion only)

Absolute Both Copper and Progesterone IUD Known or suspected pregnancy Undiagnosed genital tract bleeding Acute or chronic PID Lifestyle risk for STIs*

Progesterone-Releasing IUS (MirenaV, Kyleena®, Jaydess®): decidualization of endometrium and thickening of cervical mucus; minimal effect on ovulation Highly effective (95-99%); failure rate 0-1.2% Contraceptive effects last 5 yr Reversible, private, convenient May be used in women with contraindications to OCPs or wanting long-term contraception

Copper IUD: increased blood loss and duration of menses, dysmenorrhea Progesterone IUD: bloating, headache

*Cervical swabs for gonorrhea and chlamydia should be done prior to insertion

Copper IUD Known allergy to copper Wilson’s disease Relative Both Copper and Progesterone IUD Valvular heart disease Past history of PID or ectopic pregnancy Presence of prosthesis Abnormalities of uterine cavity, intracavitary fibroids Cervical stenosis Immunosuppressed individuals (e.g. HIV) Copper IUD Severe dysmenorrhea or heavy menstrual bleeding

Continuous or Extended Cycle vs. Cyclic Use of Combined Hormonal Contraceptives for Contraception Cochrane DB Syst Rev 2014:7 Purpose: Systematic review of RCTs assessing the efficacy and side effects of cyclic administration vs. extended use (longer periods of active pills and/ or shorter periods placebo) or continuous use (uninterrupted active pill administration) of combination oral contraceptives (COC). Results: The initial review published in 2012 identified 12 RCTs that ultimately showed no difference between groups with regards to efficacy (pregnancy rates), safety, and compliance rates. Continuous or extended CHCs were shown to reduce menstrual symptoms (headaches, tiredness, bloating, and menstrual pain). In addition, 11 of 12 studies reported similar or improved bleeding patterns with continuous or extended cycles. Conclusions: This recently published updated systematic review identified a further 4 RCTs, however, results did not change.

Committee Opinion No. 602: Depot Medroxyprogresterone Acetate and Bone Effects Obstet Gynecol 2014(6):1298-402 • The effect of DMPA on BMD should neither prevent practitioners from prescribing DMPA nor limit its use to 2 consecutive yr. • BMD loss due to DMPA appears to be substantially or fully reversible. • Contraceptive implants and intrauterine devices that do not affect BMD should be considered as first-line for adolescents. • Inform patients about benefits and the potential risks of DMPA, and encourage daily exercise, calcium and vitamin D intake. • Routine BMD monitoring is not recommended for DMPA users.

GY18 Gynecology

Toronto Notes 2020

Termination of Pregnancy

Emergency Postcoital Contraception Table 12. Emergency Contraceptive Methods Method

Mechanism of Action

Side Effects

Contraindications

HORMONAL Yuzpe Method Used within 72 h of unprotected intercourse; limited evidence of benefit up to 5 d Ovral® 2 tablets then repeat in 12 h (ethinyl estradiol 100 µg/ levonorgestrel 500 µg) Can substitute with any OCP as long as same dose of estrogen used 2% overall risk of pregnancy Efficacy decreased with time (e.g. less effective at 72 h than 24 h)

Nausea (due to estrogen; Unknown; theories include: treat with Gravol®) Suppresses ovulation or causes Irregular spotting deficient luteal phase Alters endometrium to prevent implantation Affects sperm/ova transport

Same as above “Plan B” Consists of levonorgestrel 750 µg q12h for 2 doses (can also take 2 doses together); taken within 72 h of intercourse. Can be taken up to 5 d Greater efficacy (75-95% if used within 24 h) and better side effect profile than Yuzpe method but efficacy decreases with time; 1st line if >24 h No estrogen thus very few contraindications/side effects (less nausea) Less effective in overweight individuals (>75 kg less effective, >80 kg not recommended) Ulipristal 30 mg PO within 5 d

Pre-existing pregnancy (although not teratogenic) Caution in women with contraindications to OCP (although NO absolute contraindications)

Same as above

Same as above but no caution in women with contraindications to OCP

Selective Progesterone Receptor Modulator (SPERM) with primarily antiprogestin activity: may delay ovulation by up to 5 d

Headache, hot flashes, constipation, vertigo, endometrial thickening

Same as above but no caution in women with contraindications to OCP

See Table 11

See Table 11

See Table 11

NON-HORMONAL Postcoital IUD (Copper) Insert up to 7 d postcoitus Prevents implantation 1% failure rate Can use for short duration in higher risk individuals Mirena® IUS cannot be used as EPC

Follow-up • 3-4 wk post treatment to confirm efficacy (confirmed by spontaneous menses or pregnancy test) • contraception counselling

Termination of Pregnancy Indications • patient desires an end to pregnancy • may be for medical reasons (mother or fetus unhealthy) or social reasons, including patient request Legal Issues • no current law in Canada concerning abortion therefore considered legal at any gestational age • CPSO: a physician must refer for abortion services regardless of personal beliefs, but not compelled to perform procedure Rates • 13.1 abortions/1000 women aged 15-44 in Canada (2017 CIHI data) • worldwide: 42 million induced abortions per year; half are unsafe (WHO data) • maternal mortality almost zero where induced abortion is safe and legal; rises to 100 maternal deaths/100,000 live births in sub-Saharan Africa and other countries where abortion is illegal and unsafe • in Canada, 91% of induced abortions occur fimbrial (11%) > ovarian (3%) > interstitial (2%) > abdominal (1%)

Epidemiology • 1/100 pregnancies • fourth leading cause of maternal mortality, leading cause of maternal death in first trimester • increase in incidence over the last 3 decades • three commonest locations for ectopic pregnancy: ampullary (70%), isthmic (12%), fimbrial (11%) Etiology • 50% due to damage of fallopian tube cilia following PID • intrinsic abnormality of the fertilized ovum • conception late in cycle • transmigration of fertilized ovum to contralateral tube

© Andrea Gauthier 2012

Sites of ectopic pregnancy and blood supply to the uterus, ovary, and fallopian tube

Cervix

Embryonic demise can be diagnosed by ultrasound based on an intrauterine gestational sac, embryonic crown-rump length ≥7 mm, and no cardiac activity

GY21 Gynecology

Toronto Notes 2020

Ectopic Pregnancy

Suspected Ectopic Pregnancy

1. Positive urine β-hCG; 2. Abdominal pain; 3. Vaginal bleeding

Hemodynamically unstable or suspicion of impending/ongoing ruptured ectopic

Hemodynamically stable Transvaginal U/S Serum β-hCG

Intrauterine pregnancy

Surgery

β-hCG level low and declining, AND no fetal heartbeat or extrauterine sac suspicious for ectopic pregnancy, AND patient is reliable for follow-up

20%) • obstruction (~15%) • cryptorchidism (~8%) • immunologic (~3%) Investigations • semen analysis and culture • postcoital (Huhner) test: rarely done

Polycystic Ovarian Syndrome • also called chronic ovarian androgenism Etiology Insulin estrogen peripheral conversion to estrogen

FSH secretion +

LH secretion

ovarian secretion of androgens

Obesity

Figure 12. Pathophysiology of polycystic ovarian syndrome

Hirsutism

Anovulation Oligomenorrhea Infertility

Polycystic Ovarian Syndrome – HAIR-AN Hirsutism, HyperAndrogenism, Infertility, Insulin Resistance, Acanthosis Nigricans

GY24 Gynecology

Polycystic Ovarian Syndrome

Diagnosis • Rotterdam diagnostic criteria: 2 of 3 required ■ oligomenorrhea/irregular menses for 6 mo ■ hyperandrogenism ◆ clinical evidence - hirsutism or acne ◆ biochemical evidence - raised free testosterone ■ polycystic ovaries on U/S (not appropriate in adolescents) Clinical Features • average age 15-35 yr at presentation • in adolescents, wait at least 1-2 yr to make diagnosis as adolescence resembles PCOS • abnormal/irregular uterine bleeding, hirsutism, infertility, obesity, virilization • acanthosis nigricans: browning of skin folds in intertriginous zones (indicative of insulin resistance) • insulin resistance occurs in both lean and obese patients • family history of DM Investigations • goal: identify hyperandrogenism or chronic anovulation and rule out specific pituitary or adrenal disease as the cause • laboratory ■ prolactin, 17-hydroxyprogesterone, free testosterone, DHEA-S, TSH, free T4, androstenedione, SHBG ■ LH:FSH >2:1; LH is chronically high with FSH mid-range or low (low sensitivity and specificity) ■ increased DHEA-S, androstenedione and free testosterone (most sensitive), decreased SHBG • transvaginal or transabdominal U/S: polycystic-appearing ovaries (“string of pearls” – 12 or more small follicles 2-9 mm, or increased ovarian volume) • tests for insulin resistance or glucose tolerance ■ fasting glucose:insulin ratio 6 recurrences per yr or recurrence every 2 mo ■ acyclovir 400 mg PO bid or valacyclovir 500 mg PO OD or valacyclovir 1 g PO OD or famciclovir 250 mg PO bid • severe disease: IV acyclovir 5-10 mg/kg IV q8h x 2-7 d or until clinical improvement observed followed by oral antiviral therapy to complete 10 d of therapy total • education regarding transmission: avoid sexual contact from onset of prodrome until lesions have cleared, use barrier contraception SYPHILIS Etiology • Treponema pallidum Classifications • primary syphilis ■ 3-4 wk after exposure ■ painless chancre on vulva, vagina, or cervix ■ painless inguinal lymphadenopathy ■ serological tests usually negative, local infection only • secondary syphilis (can resolve spontaneously) ■ 2-6 mo after initial infection ■ nonspecific symptoms: malaise, anorexia, headache, diffuse lymphadenopathy ■ generalized maculopapular rash: palms, soles, trunk, limbs ■ condylomata lata: anogenital, broad-based, fleshy, grey lesions ■ serological tests usually positive • latent syphilis ■ no clinical manifestations; detected by serology only • tertiary syphilis ■ may involve any organ system ■ neurological: tabes dorsalis, general paresis ■ cardiovascular: aortic aneurysm, dilated aortic root ■ vulvar gumma: nodules that enlarge, ulcerate, and become necrotic (rare) • congenital syphilis ■ may cause fetal anomalies, stillbirths, or neonatal death Investigations • aspiration of ulcer serum or node • darkfield microscopy (most sensitive and specific diagnostic test for syphilis): look for spirochetes • non-treponemal screening tests (VDRL, RPR); non-reactive after treatment, can be positive with other conditions • specific anti-treponemal antibody tests (FTA-ABS, MHA-TP, TP-PA) ■ confirmatory tests; remain reactive for life (even after adequate treatment) Treatment • reportable disease, partners should be referred for treatment • treatment of primary, secondary, latent syphilis of 1 yr duration ■ benzathine penicillin G 2.4 million units IM q1wk x 3 wk • treatment of neurosyphilis ■ IV aqueous penicillin G 3-4 million units IM q4h x 10-14 d • screening ■ high-risk groups ■ in pregnancy (see Obstetrics, Infections During Pregnancy, OB29) Complications • if untreated, 1/3 will experience late complications HIV • see Infectious Diseases, ID25

Epidemiology of Genital Ulcers HSV 70-80% 1º Syphilis 5% Chancroid 38°C • Mucopurulent cervical discharge • Positive culture for N. gonorrhoeae, C. trachomatis, E. coli, or other vaginal flora • Cul-de-sac fluid, pelvic abscess or inflammatory mass on U/S or bimanual • Leukocytosis • Elevated ESR or CRP (not commonly used)

GY31 Gynecology

Toronto Notes 2020

Gynecological Infections

Treatment • must treat with polymicrobial coverage Table 16. Inpatient and Outpatient Management Options for Pelvic Inflammatory Disease Inpatient

Outpatient

Indications

Moderate to severe illness Atypical infection Adnexal mass, tubo-ovarian mass, or pelvic abscess Unable to tolerate oral antibiotics or failed oral therapy Immunocompromised Pregnant Adolescent (first episode) Surgical emergency cannot be excluded (e.g. ovarian torsion) PID is secondary to instrumentation

Typical findings Mild to moderate illness Oral antibiotics tolerated Compliance ensured Follow-up within 48-72 h (to ensure symptoms not worsening)

Antibiotic Regimen

Cefoxitin 2 g IV q6h + doxycycline 100 mg PO/IV q12h or Clindamycin 900 mg IV q8h + gentamycin 2 mg/kg IV/IM loading dose then gentamycin 1.5 mg/kg q8h maintenance dose Continue IV antibiotics for 24 h after symptoms have improved then doxycycline 100 mg PO bid to complete 14 d Percutaneous drainage of abscess under U/S guidance When no response to treatment, laparoscopic drainage If failure, treatment is surgical (salpingectomy, TAH/BSO)

1st line: ceftriaxone 250 mg IM x 1 + doxycycline 100 mg PO bid x 14 d or cefoxitin 2 g IM x 1 + probenecid 1 g PO + doxycycline 100 mg PO bid ± metronidazole 500 mg PO bid x 14 d 2nd line: ofloxacin 400 mg PO bid x14 d or levofloxacin 500 mg PO OD x 14 d ± metronidazole 500 mg PO bid x 14 d Consider removing IUD after a minimum of 24 h of treatment Reportable disease Treat partners Consider re-testing for C. trachomatis and N. gonorrhoeae 4-6 wk after treatment if documented infection

Complications of Untreated PID • chronic pelvic pain • abscess, peritonitis • adhesion formation • ectopic pregnancy • infertility ■ 1 episode of PID: 13% infertility ■ 2 episodes of PID: 36% infertility • bacteremia • septic arthritis, endocarditis Pelvic Pain

Acute

Gynecological

Non-gynecological

GI GU Appendicitis UTI (e.g. cystitis, Mesenteric adenitis pyelonephritis) Diverticulitis Renal colic IBD

Adnexal Uterine Mittelschmerz Fibroid Ruptured degeneration ovarian cyst Torsion of Ruptured ectopic pedunculated pregnancy fibroid Hemorrhage into Pyometra/ cyst/neoplasm hematometra Ovarian/tubal torsion

Figure 15. Approach to pelvic pain

Infectious Acute PID Endometritis

Chronic

Pregnancyrelated Labour Ectopic pregnancy Spontaneous abortion Placental abruption

Gynecological Non-gynecological Chronic PID Referred pain Endometriosis Urinary retention Adenomyosis Urethral syndrome Adhesions Interstitial cystitis Dysmenorrhea GI neoplasm Ovarian cyst IBS Pelvic congestion IBD syndrome Constipation Ovarian remnant Partial bowel syndrome obstruction Fibroid (rare) Diverticulitis Uterine prolapse Hernia formation (rare) Nerve entrapment Sexual/physical/ psychological abuse Depression Anxiety Somatization

GY32 Gynecology

Sexual Abuse

Toronto Notes 2020

Toxic Shock Syndrome • see Infectious Diseases, ID21 Risk Factors • tampon use • diaphragm, cervical cap, or sponge use (prolonged use, i.e. >24 h) • wound infections • post-partum infections • early recognition and treatment of syndrome is imperative as incorrect diagnosis can be fatal Clinical Feature • sudden high fever • sore throat, headache, diarrhea • erythroderma • signs of multisystem organ failure • refractory hypotension • exfoliation of palmar and plantar surfaces of the hands and feet 1-2 wk after onset of illness Treatment • remove potential sources of infection (foreign objects and wound debris) • debride necrotic tissues • adequate hydration • penicillinase-resistant antibiotics (e.g. cloxacillin) • steroid use controversial, but, if started within 72 h, may reduce severity of symptoms and duration of fever

Surgical Infections Post-Operative Infections in Gynecological Surgery • pelvic cellulitis ■ common post hysterectomy, affects vaginal vault ■ erythema, induration, tenderness, discharge involving vaginal cuff ■ treat if fever and leukocytosis with broad-spectrum antibiotics (i.e. clindamycin and gentamicin) ■ drain if excessive purulence or large mass ■ can result in intra-abdominal and pelvic abscess • see General Surgery, Post-Operative Fever, GS7

Sexual Abuse • see Family Medicine, FM26, Emergency Medicine, ER27

Sexuality and Sexual Dysfunction SEXUAL RESPONSE 1. desire: energy that allows an individual to initiate or respond to sexual stimulation 2. arousal: physical and emotional stimulation leading to breast and genital vasodilation and clitoral engorgement 3. orgasm: physical and emotional stimulation is maximized, allowing the individual to relinquish their sense of control 4. resolution: most of the congestion and tension resolves within seconds, complete resolution may take up to 60 min SEXUAL DYSFUNCTION Etiology • psychological or emotional: depression, abuse • hormonal: menopause • neurologic dysfunction: spinal cord injury • vascular insufficiency: DM • drug side effects: β-blockers • trauma: episiotomy Classification • lack of desire (60-70% of women) • lack of arousal • anorgasmia (5-10%) ■ primary anorgasmia: never before achieved orgasm under any circumstances ■ secondary anorgasmia: was able to achieve orgasms before but now unable to

Toxic Shock Syndrome Multiple organ system failure due to S. aureus exotoxin (rare condition)

GY33 Gynecology

Toronto Notes 2020

Menopause

• dyspareunia (3-6%): painful intercourse, superficial or deep ■ vaginismus (15%) ■ vulvodynia ■ vaginal atrophy ■ vulvar vestibulitis: associated with history of frequent yeast infections ■ PID Dyspareunia

Dyspareunia Cycle

Introital

Midvaginal

Deep

Inadequate lubrication Vaginismus Rigid/intact hymen Bartholin’s or Skene’s gland infection Lichen sclerosis Vulvovaginitis: atrophic (hypoestrogen), chemical, infectious (chlamydia, trichomoniasis)

Urethritis Short vagina Trigonitis Congenital abnormality of the vagina (e.g. vaginal septum)

Endometriosis Adenomyosis Leiomyomata/fibroids PID (acute vs. chronic) Hydrosalpinx Tubo-ovarian abscess Uterine retroversion Ovarian cyst

Painful intercourse (initially due to organic etiology) 2o vaginismus

Fear of pain with intercourse

Anxiety with or without sexual response

Figure 17. Dyspareunia cycle

Figure 16. Approach to dyspareunia

Treatment • lack of desire: assess factors, rule out organic causes, relationship therapy, sensate focus exercises • anorgasmia: self-exploration/pleasuring, relationship therapy if needed, bridging techniques (different sexual positions, clitoral stimulation during intercourse) • dyspareunia ■ Kegel and reverse Kegel exercises ■ dilator treatment ■ comfort with self-exam ■ psychotherapy, other behavioural techniques ■ female on top position: allows for control of speed and duration ■ vestibulitis: remove local irritants, change in contraceptive methods, dietary changes (increased citrate, decreased oxalate), and vestibulectomy (rare) ■ vulvodynia: local moisturization, cold compresses, systemic nerve-blocking therapy (amitriptyline, gabapentin) orally or topically, topical anesthetics, estrogen cream ■ pain clinic ■ removal of environmental factors: bubble baths, soaps, perfumes, sanitary pads with plastic lining

Kegel Exercises Regular contraction and relaxation to strengthen pelvic floor muscles Reverse Kegel Exercises 1 s contraction then 5 s of relaxation

Menopause • see Family Medicine, FM40 Definitions • lack of menses for 1 yr • types of menopause ■ physiological; average age 51 yr (follicular atresia) ■ primary ovarian insufficiency; before age 40 (autoimmune disorder, infection, Turner’s syndrome) ■ iatrogenic (surgical/radiation/chemotherapy) Clinical Features • associated with estrogen deficiency ■ vasomotor instability (tends to dissipate with time) ◆ hot flushes/flashes, night sweats, sleep disturbances, formication, nausea, palpitations ■ urogenital atrophy involving vagina, urethra, bladder ◆ dyspareunia, pruritus, vaginal dryness, bleeding, post-coital bleeding, urinary frequency, urgency, incontinence ◆ inspection may reveal: thinning of tissues, erythema, petechiae, bleeding points, dryness on speculum exam ■ skeletal ◆ osteoporosis, joint and muscle pain, back pain ■ skin and soft tissue ◆ decreased breast size, skin thinning/loss of elasticity ■ psychological ◆ increased anxiety, depression, irritability, fatigue, decreased libido, memory loss Investigations • increased levels of FSH (>35 IU/L) on day 3 of cycle (if still cycling) and LH (FSH>LH) • FSH level not always predictive due to monthly variation; use absence of menses for 1 yr to diagnose • decreased levels of estradiol (later)

Menopause Occurrence of last spontaneous menstrual period, resulting from loss of ovarian function (loss of oocyte response to gonadotropins) “Being in menopause” Lack of menses for 1 yr Perimenopause Period of time surrounding menopause (2-8 yr preceding + 1 yr after last menses) characterized by fluctuating hormone levels, irregular menstrual cycles, and symptom onset

• 85% of women experience hot flashes • 20-30% seek medical attention • 10% are unable to work

GY34 Gynecology

Toronto Notes 2020

Menopause

Treatment

Menopause Pathophysiology

Table 17. Treatment of Menopause

Degenerating theca cells fail to react to endogenous gonadotropins (FSH, LH)

Goal is for individual symptom management Vasomotor Instability

Vaginal Atrophy

Urogenital Health

Osteoporosis

Decreased Libido

CVD*

HRT (first line) SSRI venlafaxine gabapentin propranaolol clonidine acupuncture

Local estrogen: cream (Premarin®), vaginal suppository (VagiFem®), ring (Estring®), lubricants (Replens®), oral or transdermal hormone replacement therapy, intravaginal laser

Lifestyle changes (weight loss, bladder re-training), local estrogen replacement, surgery

1000-1500 mg calcium OD, 800-1000 IU vitamin D, weightbearing exercise, smoking cessation, bisphosphonates (e.g. alendronate), selective estrogen receptor modifiers (SERMs) (e.g.raloxifene [Evista®]), HRT (second-line treatment)

Vaginal Manage lubrications, CVD risk counselling, factors androgenreplacement testoterone cream or the oral form (Andriol®)

Mood And Memory

Less estrogen is produced

Antidepressants (first line), HRT (augments effect)

Decreased negative feedback on hypothalamic-pituitary-adrenal axis Increased FSH and LH Stromal cells continue to produce androgens as a result of increased LH stimulation

Figure 18. Menopause pathophysiology

*CVD (cardiovascular disease)

• Osteoporosis is the single most important health hazard associated with menopause • Cardiovascular disease is the leading cause of death post-menopause

Hormone Replacement Therapy • see Family Medicine, FM40 • primary indication is treatment of menopausal symptoms (vasomotor instability) • keep doses low (e.g. 0.3 mg Premarin®) and duration of treatment short (70 yr and for women who start HRT >10 yr post-menopause Breast Cancer: 8 additional cases with combined HRT (WHI); risk only increased after >5 yr of combined HRT use; no increased risk for estrogen alone Dementia and Mild Cognitive Impairment: 50% greater risk of developing dementia in women taking estrogen alone after age 65; risk is greater for women taking combined HRT; risk of developing dementia was reduced for women taking HRT before age 65

Toronto Notes 2020

Absolute Contraindications to HRT ABCD Acute liver disease Undiagnosed vaginal Bleeding Cancer (breast/uterine), Cardiovascular disease DVT (thromboembolic disease)

Long-Term Hormone Therapy for Perimenopausal and Postmenopausal Women Cochrane DB Syst Rev 2012;7:CD004143 Purpose: To determine the effect of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and QOL in perimenopausal and postmenopausal women, during HRT use, and after cessation of HRT. Results: 23 studies with 42,380 women included. 70% of the data from the WHI (1998) and HERS (1998). None of the studies focused on perimenopausal women. Combined continuous HRT: increased risk of coronary event after 1 yr (absolute risk 18/1000, 95% CI 3-7), venous thromboembolism after 1 yr (AR 7/1000, 95% CI 4-11), stroke after 3 yr (AR 18/1000, 95% CI 14-23), breast cancer after 5.6 yr (AR 23/1000, 95% CI 1929), gallbladder disease after 5.6 yr (AR 27/1000, 95% CI 21-34), and death from lung cancer after 5.6 yr use (AR 9/1000, 95% CI 6-13). Estrogen only HRT: increased risk of venous thromboembolism after 1-2 yr use (AR 5/1000, 95% CI 2-10; after 7 yr AR 21/1000, 95% CI 16-28), stroke after 7 yr (AR 32/1000, 95% CI 25-40), and gallbladder disease after 7 yr use (AR 45/1000, 95% CI 36-57) and did not significantly affect the risk of breast cancer. Women >65 yr of age taking combined HRT had a statistically significant increase in the incidence of dementia after 4 yr use (AR 18/1000, 95% CI 11-30). Women taking HRT had a decreased risk of fractures with combined HRT after 5.6 yr (AR 86/1000, 95% CI 79-84) and 7.1 yr of estrogen only HRT (AR 102/1000, 95% CI 91-112). Conclusions: HRT is not indicated for primary or secondary prevention of cardiovascular disease or dementia. Although HRT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk, for whom non-estrogen therapies are unsuitable.

GY36 Gynecology

Toronto Notes 2020

Urogynecology

Sacrum

© Lori Waters 2008

Urogynecology Small intestine

Utero-sacral ligaments Uterus Rectum

Rectocele

Bladder Vaginal Canal Urethra

Cystocele

Uterine Prolapse

Enterocele

Figure 19. Pelvic anatomy

Prolapse Etiology • relaxation, weakness, or defect in the cardinal and uterosacral ligaments which normally maintain the uterus in an anteflexed position and prevent it from descending through the urogenital diaphragm (i.e. levator ani muscles) • related to: ■ vaginal childbirth ■ aging ■ decreased estrogen (post-menopause) ■ following pelvic surgery ■ increased intra-abdominal pressure (obesity, chronic cough, constipation, ascites, heavy lifting) ■ congenital (rarely) ■ ethnicity (Caucasian women > Asian or African women) ■ collagen disorders GENERAL CONSERVATIVE TREATMENT (for pelvic relaxation/prolapse and urinary incontinence) • Kegel exercises • local vaginal estrogen therapy • vaginal pessary (intravaginal suspension disc)

Grading of Pelvic Organ Prolapse • 0 = no descent during straining • 1 = distal portion of prolapse >1 cm above level of hymen • 2 = distal portion of prolapse ≤1 cm above or below level of hymen • 3 = distal portion of prolapse >1 cm below level of hymen but without complete vaginal eversion • 4 = complete eversion of total length of lower genital tract • Procidentia: failure of genital supports and complete protrusion of uterus through the vagina

Pelvic Relaxation/Prolapse Protrusion of pelvic organs into or out of the vagina

GY37 Gynecology

Urogynecology

Toronto Notes 2020

Table 20. Pelvic Prolapse Type Cystocele (protrusion of bladder into the anterior vaginal wall) Enterocele (prolapse of small bowel in upper posterior vaginal wall) Rectocele (protrusion of rectum into posterior vaginal wall) Uterine Prolapse (protrusion of cervix and uterus into vagina)

Clinical Features Frequency, urgency, nocturia Stress incontinence Incomplete bladder emptying ± associated increased incidence of UTIs (may lead to renal impairment)

Straining/digitation to evacuate stool Constipation

Groin/back pain (stretching of uterosacral ligaments) Feeling of heaviness/pressure in the pelvis Worse with standing, lifting Worse at the end of the day Relieved by lying down Ulceration/bleeding (particularly if hypoestrogenic) ± urinary incontinence

Vault Prolapse (protrusion of apex of vaginal vault into vagina, posthysterectomy)

Treatment See above Anterior colporrhaphy (“anterior repair”) Consider additional/alternative surgical procedure if documented urinary stress incontinence Similar to hernia repair Contents reduced, neck of peritoneal sac ligated, uterosacral ligaments, and levator ani muscles approximated See above Also laxatives and stool softeners Posterior colporrhaphy (“posterior repair”), plication of endopelvic fascia and perineal muscles approximated in midline to support rectum and perineum (can result in dyspareunia) See above Vaginal hysterectomy ± surgical prevention of vault prolapse Consider additional surgical procedures if urinary incontinence, cystocele, rectocele, and/or enterocele are present

The only true hernia of the pelvis is an ENTEROCELE because peritoneum herniates with the small bowel

See above Sacralcolpopexy (vaginal vault suspension), sacrospinous fixation, or uterosacral ligament suspension

Urinary Incontinence • see Urology, U6 STRESS INCONTINENCE Definition • involuntary loss of urine with increased intra-abdominal pressure (cough, laugh, sneeze, walk, run) RISK FACTORS FOR STRESS INCONTINENCE IN WOMEN • age • obesity • parity • vaginal delivery • pelvic prolapse • pelvic surgery • hypoestrogenic state (post-menopause) • smoking • neurological/pulmonary disease Treatment • see Prolapse, GY36 • surgical ■ tension-free vaginal tape (TVT), tension-free obturator tape (TOT), prosthetic/fascial slings or retropubic bladder suspension (Burch or Marshall-Marchetti-Krantz procedures) URGE INCONTINENCE Definition • urine loss associated with an abrupt, sudden urge to void • “overactive bladder” • diagnosed based on symptoms Etiology • idiopathic (90%) • detrusor muscle overactivity (“detrusor instability”) Associated Symptoms • frequency, urgency, nocturia, leakage Treatment • behaviour modification (reduce caffeine/liquid, smoking cessation, regular voiding schedule) • Kegel exercises • medications ■ anticholinergics: oxybutinin (Ditropan®), tolterodine (Detrol®), solifenacin (VESIcare®) ■ tricyclic antidepressants: imipramine

Urge Incontinence Urine loss associated with an abrupt, sudden urge to void

Rule Out Neurological Causes of Urge Incontinence • MS • Herniated disc • DM

GY38 Gynecology

Toronto Notes 2020

Gynecological Oncology

Gynecological Oncology Pelvic Mass Pelvic Mass

Ovarian

Functional Cysts (always benign) Corpus luteum cyst Follicular cyst Theca lutein cyst Hemorrhagic cyst

Neoplasm

Benign Dermoid cyst (most common) Endometrioma Malignant Epithelial cell (most common in >40 yr) Germ cell (most common in ovary > cervix > vulva > vagina > fallopian tube

Risk Factors for Endometrial Cancer

Type I

Type II

Description (Both types related to estrogen, but Type II to a lesser degree)

Characterized as estrogen-related (i.e. excess/unopposed estrogen): Endometrioid Includes well-differentiated endometrioid adenocarcinoma

Characterized as non-estrogen related: Non-endometrioid Includes serous, clear cell, grade 4 endometrioid and undifferentiated carcinomas, as well as carcinosarcoma More aggressive histologic subtypes; prognosis typically worse than type I, with a poorer 5 yr survival

COLD NUT Cancer (ovarian, breast, colon) Obesity Late menopause Diabetes mellitus Nulliparity Unopposed estrogen: PCOS, anovulation, HRT Tamoxifen: chronic use

Risk Factors (Increasing age and family history are risk factors for both types)

PCOS Diabetes mellitus Unbalanced HRT (balanced HRT is protective) Nulliparity Late menopause (>55 yr), early menarche Estrogen-producing ovarian tumours (e.g. granulosa cell tumours) HNPCC (hereditary non-polyposis colorectal cancer)/Lynch II syndrome Tamoxifen

Parous women Increasing age of menarche and number of children not significantly associated with reduced risk in clear-cell endometrial carcinoma Has been associated with p53 mutations

Postmenopausal bleeding = endometrial cancer until proven otherwise (95% present with vaginal bleeding)

~80% of cases Postmenopausal bleeding in majority Abnormal uterine bleeding in majority of affected pre-menopausal women (menorrhagia, intermenstrual bleeding)

~15% of cases Post-menstrual bleeding Abnormal uterine bleeding

An endometrial thickness of 5 mm or more is considered abnormal in a postmenopausal woman with vaginal bleeding

Clinical Features

GY39 Gynecology

Screening • no known benefit for mass screening • annual endometrial sampling starting at age 30-35 only for women at high risk (HNPCC [Hereditary Non-Polyposis Colorectal Cancer]/ Lynch II syndrome) • routine pelvic ultrasound should not be used as screening test (high false positives) Investigations • endometrial sampling ■ office endometrial biopsy ■ D&C ± hysteroscopy • ± pelvic ultrasound (in women where adequate endometrial sampling not feasible without invasive methods) ■ not acceptable as alternative to pelvic exam or endometrial sampling to rule out cancer Table 22. FIGO Staging of Endometrial Cancer (2009) Description

Stage

Description

I

Confined to corpus uteri including endocervical glandular involvement No or less than half myometrial invasion Invades through ≥½ of myometrium Tumour invades cervical stroma, but does not extend beyond uterus* Tumour involving serosa, adnexa, vagina, or parametrium Invasion of serosa ± adnexae Vaginal ± parametrial involvement

IIIC IIIC1 IIIC2 IV

Metastasis to pelvic ± para-aortic LNs Positive pelvic LN Positive para-aortic LN ± positive pelvic LNs Invasion of bladder ± bowel mucosa ± distant metastases (note: omental disease is stage IV) Invasion of bladder ± bowel mucosa Distant mets, including intra-abdominal and intraperitoneal mets ± inguinal LNs

III IIIA IIIB

FIGO: International Federation of Gynecology and Obstetrics Stage II)

IVA IVB

Prognostic Factors Most important is FIGO stage Other Prognostic Factors: • Age • Grade • Histologic subtype • Depth of myometrial invasion • Presence of lymphovascular space involvement (LVSI)

Complications of Therapy

Stage

IA IB II

Toronto Notes 2020

Gynecological Oncology

*Note: endocervical glandular involvement is now considered as Stage I (previously

Treatment • surgical: hysterectomy/bilateral salpingo-oophorectomy (BSO) and pelvic washings ± pelvic and paraaortic node dissection ± omentectomy ■ goals: diagnosis, staging, treatment, defining optimal adjuvant treatment ■ laparoscopic approach associated with improved quality of life (optimal for most patients) • adjuvant radiotherapy (for improved local control in patients at risk for local recurrence) and adjuvant chemotherapy (in patients at risk for distant recurrence or with metastatic disease): based on presence of poor prognostic factors in definitive pathology • chemotherapy: often used for recurrent disease (if high grade or aggressive histology) • hormonal therapy: progestins can be used for recurrent disease (especially if low-grade) UTERINE SARCOMA • rare; 3-9% of all uterine malignancies • arise from stromal components (endometrial stroma, mesenchymal or myometrial tissues) • behave more aggressively and are associated with worse prognosis than endometrial carcinoma; 5 yr survival is 35% • vaginal bleeding is most common presenting symptom

Surgical Complications • Surgical site infection • Lymphedema Radiation Complications • Radiation fibrosis • Cystitis • Proctois

Uterine Sarcoma – Symptoms BAD-P Bleeding Abdominal distention Foul-smelling vaginal Discharge Pelvic pressure

A rapidly enlarging uterus, especially in a postmenopausal woman, should prompt consideration of leiomyosarcoma. Nevertheless, all postmenopausal patients with an enlarging uterus should have an endometrial biopsy

Table 23. Summary of Uterine Sarcoma Subtypes and Features Type

Epidemiology

Features

Diagnosis

Treatment

1. Leiomyosarcoma

Most common type of uterine sarcoma Average age of presentation is 55 yr, but may present in pre-menopausal women Often coexists with benign leiomyomata (fibroids)

Histologic distinction from leiomyoma 1. Increased mitotic count (>10 mitoses/10 high-power fields) 2. Tumour necrosis 3. Cellular atypia Rapidly enlarging fibroids in a pre-menopausal woman Enlarging fibroids in a postmenopausal woman

Often post-operatively after uterus removed for presumed fibroids Stage using FIGO 2009 staging for leiomyosarcomas and ECC

Hysterectomy/BSO usually No routine pelvic lymphadenectomy Chemotherapy is used in cases of metastatic disease Radiation therapy does not improve local control or survival Poor outcomes overall, even for early-stage disease

2. Endometrial Stromal Sarcoma (ESS)

Usually presents in perimenopausal or postmenopausal women with abnormal uterine bleeding

Abnormal uterine bleeding Good prognosis

Diagnosed by histology of endometrial biopsy or D&C Stage using FIGO 2009 staging for leiomyosarcomas and ECC

Hysterectomy & BSO (remove ovaries as ovarian hormones may stimulate growth) No routine pelvic lymphadenectomy Adjuvant therapy based on stage and histologic features (hormones and/or radiation) Hormonal therapy (progestins) may be used for metastatic disease

3. Undifferentiated Sarcoma

Rare; less common than Severe nuclear pleomorphism, high mitotic activity, leiomyosarcoma, endometrial stromal tumour cell necrosis, and lack smooth muscle or sarcoma endometrial stromal differentiation Poor prognosis

Often found incidentally post-operatively for abnormal bleeding

Treatment primarily surgical Radiation and/or chemotherapy for advanced diseased or unresectable disease

The rarest of the uterine sarcoma Mixed tumour of low malignancy potential

Treatment is surgical with hysterectomy and BSO Mixture of benign epithelium with malignant low-grade sarcoma Often found incidentally at time of hysterectomy for PMB Stage using FIGO 2009 staging for adenosarcoma

PURE TYPE

MIXED TYPE 4. Adenosarcoma

Present with abnormal vaginal bleeding Polypoid mass in uterine cavity

GY40 Gynecology

Toronto Notes 2020

Gynecological Oncology

Table 24. FIGO Staging of Uterine Sarcoma (2009) Stage

Description

Stage

Description

I IA IB

Tumour limited to uterus 5 cm

III IIIA IIIB IIIC

Tumour invades abdominal tissues, one site Metastasis to pelvic and/or para-aortic lymph nodes Tumour invades bladder and/or rectum

II IIA IIB

Tumour extends beyond uterus To the pelvis, adnexal involvement To extra-uterine pelvic tissue

IV IVA IVB

Tumour invades bladder and/or rectum Distant metastasis

Ovary BENIGN OVARIAN TUMOURS • see Table 25 • many are asymptomatic • usually enlarge slowly, if at all • may rupture or undergo torsion, causing pain ■ pain associated with torsion of an adnexal mass usually originates in the iliac fossa and radiates to the flank • peritoneal irritation may result from an infarcted tumour (rare) MALIGNANT OVARIAN TUMOURS • see Table 25 Epidemiology • lifetime risk 1.4% • in women >50 yr, more than 50% of ovarian tumours are malignant • causes more deaths in North America than all other gynecologic malignancies combined • 4th leading cause of cancer death in women • 85% epithelial; 15% non-epithelial • 10-15% of epithelial ovarian cancers are related to hereditary predisposition Risk Factors (for epithelial ovarian cancers) • early menarche and/or late menopause • personal history of breast, colon, endometrial cancer • family history of breast, colon, endometrial, ovarian cancer • Lynch syndrome and BRCA mutations • use of fertility drugs Protective Factors (for epithelial ovarian cancers) • OCP: likely due to ovulation suppression (significant reduction in risk even after 1 yr of use) • pregnancy/breastfeeding Prophylactic Measures • salpingectomy (prophylactic) • BSO (prophylactic hysterectomy or tubal ligation performed for this reason in high-risk women [i.e. BRCA mutation carriers]) Screening • no effective method of mass screening • routine CA-125 level measurements or U/S not recommended ■ high false positive rates • controversial in high-risk groups: transvaginal U/S and CA-125, starting age 30 (no consensus on interval) ■ familial ovarian cancer (>1 first degree relative affected, BRCA-1 mutation) ■ other cancers (e.g. endometrial, breast, colon) ■ BRCA-1 or BRCA-2 mutation: recommendation is prophylactic bilateral oophorectomy after age 35 or when childbearing is completed Clinical Features • most women with epithelial ovarian cancer present with advanced stage disease as patients often asymptomatic until disseminated (symptoms with early-stage disease are vague and non-specific) • when present, symptoms may include: ■ abdominal symptoms (nausea, bloating, pain, dyspepsia, anorexia, early satiety) ■ symptoms of mass effect ◆ increased abdominal girth (from ascites or tumour itself) ◆ urinary urgency and frequency ◆ constipation

Ovaries are like GEMS Germ-cell Epithelial Metastatic Sex cord stromal

Most (70%) epithelial ovarian cancers present at stage III disease

Ovarian Tumour Markers • Epithelial cell: CA-125 • Stromal • Granulosa cell: inhibin • Sertoli-Leydig: androgens • Germ cell • Dysgerminoma: LDH • Yolk sac: AFP • Choriocarcinoma: β-hCG • Immature teratoma: none • Embryonal cell: AFP + β-hCG

Diagnosis of ovarian tumours requires surgical pathology

Any adnexal mass in postmenopausal women should be considered malignant until proven otherwise

Omental Cake: a term for ascites plus a fixed upper abdominal and pelvic mass; almost always signifies ovarian cancer

Malignant Ovarian Tumour Prognosis 5 Year Survival Stage I 75-95% Stage II 60-75% Stage III 23-41% Stage IV 11%

Screening for Ovarian Cancer Updated Evidence Report and Systematic Review for the US Preventive Services Task Force JAMA 2018; 319(6):595-606 Objective: To systematically review evidence on benefits and harms of ovarian cancer screening among average-risk, asymptomatic women. Methods: Systematic review of RCTs of ovarian cancer screening in average-risk women that reported mortality or quality-of-life outcomes. Interventions included transvaginal ultrasound and/or CA-125 testing. Comparators were usual care or no screening. Results: Four trials (N = 293 587) were included. No trial found a significant difference in ovarian cancer mortality with screening. In 2 trials, screening led to surgery for suspected ovarian cancer in 1% of women without cancer and in 3% for transvaginal ultrasound with or without CA-125 screening, with major complications occurring in 3% to 15% of surgeries. Evidence of psychological harms was found in cases of repeat follow-up scans and tests. Conclusions: Ovarian cancer mortality did not significantly differ between screened women and those with no screening or in usual care.

GY41 Gynecology

Toronto Notes 2020

Gynecological Oncology

Low Malignant Potential (also called “Borderline”) Tumours • a subcategory of epithelial ovarian cancer (~15% of all epithelial ovarian tumours) • pregnancy, OCP, and breastfeeding are protective factors • tumour cells with histologically malignant characteristics arise from the ovarian surface, but do not invade ovarian stroma • able to metastasize, but not commonly • treated primarily with surgery (BSO/omental biopsy ± hysterectomy) ■ chemotherapy has limited benefit: can be treated with hormonal manipulation (letrozole) • generally slow growing, excellent prognosis ■ 5 yr survival >99% ■ recurrences tend to occur late, may be associated with low-grade serous carcinoma Table 25. Ovarian Tumours Type Description FUNCTIONAL TUMOURS (all benign) Follicular Cyst Follicle fails to rupture during ovulation

Presentation

Ultrasound/Cytology

Usually asymptomatic 4-8 cm mass, unilocular, May rupture, bleed, tort, infarct causing lined with granulosa cells pain ± signs of peritoneal irritation

More likely to cause pain than follicular Larger (10-15 cm) and cyst firmer than follicular cysts May delay onset of next period Theca-Lutein Cyst Due to atretic follicles stimulated by abnormal Associated with molar pregnancy, β-hCG levels ovulation induction with clomiphene Endometrioma See Endometriosis, GY11 Polycystic Ovaries See Polycystic Ovarian Syndrome, GY23 BENIGN GERM-CELL TUMOURS Benign Cystic Single most common ovarian germ cell May rupture, twist, infarct Smooth-walled, mobile, Teratoma (dermoid) neoplasm 20% bilateral unilocular Elements of all 3 cell lines; contains dermal 20% occur outside of reproductive yr Ultrasound may show appendages (sweat and calcification which is sebaceous glands, hair follicles, teeth) pathognomonic MALIGNANT GERM-CELL TUMOURS General Information Rapidly growing, 2-3% of all ovarian cancers Usually children and young women (200: gynecologic oncology referral is recommended

GY43 Gynecology

Toronto Notes 2020

Gynecological Oncology

Fallopian Tube

Treatment • as for malignant epithelial ovarian tumours

Cervix BENIGN CERVICAL LESIONS • Nabothian cyst/inclusion cyst: no treatment required • endocervical polyps: treatment is polypectomy (office procedure) MALIGNANT CERVICAL LESIONS Epidemiology • majority are SCC (95%); adenocarcinomas increasing (5%); rare subtypes include small cell, adenosquamous • 8000 deaths annually in North America • annual Pap test reduces a woman’s chance of dying from cervical cancer from 0.4% to 0.05% • average age at presentation: 52 yr old

Cervical Cancer Screening Guidelines (Pap Test) • see Family Medicine, FM5

Gland opening

sfo

n

Risk Factors • HPV infection ■ see Sexually Transmitted Infections, GY26 ■ high risk of neoplasia associated with types 16, 18 ■ low risk of neoplasia associated with types 6, 11 ■ >99% of cervical cancers contain one of the high risk HPV types • high-risk behaviours (risk factors for HPV infection) ■ multiple partners ■ other STIs (HSV, trichomonas) ■ early age at first intercourse ■ high-risk male partner • smoking • poor screening uptake is the most important risk factor for cervical cancer in Canada • at-risk groups include: ■ immigrant Canadians ■ First Nations Canadians ■ geographically-isolated Canadians ■ sex-trade workers ■ low socioeconomic status Canadians

Original squamous epithelium Squamous metaplasia Columnar epithelium

Tra

Etiology • at birth, vagina is lined with squamous epithelium; columnar epithelium lines only the endocervix and the central area of the ectocervix (original squamocolumnar junction) • during puberty, estrogen stimulates eversion of a single columnar layer (ectopy), thus exposing it to the acidic pH of the vagina, leading to metaplasia (change of exposed epithelium from columnar to squamous) ■ a new squamocolumnar junction forms as a result • the transformation zone (TZ) is the area located between the original and the current squamocolumnar junction • the majority of dysplasias and cancers arise in the TZ of the cervix • must have active metaplasia in presence of inducing agent (HPV) to get dysplasia • dysplasia progresses to carcinoma in situ (CIS), which further progresses to invasion • slow process (~10 yr on average) • growth is by local extension • metastasis occurs late

Causes of Elevated CA-125 • Age influences reliability of test as a tumour marker • 50% sensitivity in early-stage ovarian cancer (poor), therefore not good for screening Malignant • Gyne: ovary, uterus • Non-Gyne: pancreas, stomach, colon, rectum Non-Malignant • Gyne: benign ovarian neoplasm, endometriosis, pregnancy, fibroids, PID • Non-Gyne: cirrhosis, pancreatitis, renal failure

r m ati o n z

External os

New squamocolumnar junction Original squamocolumnar junction

© Ayalah Hutchins

Clinical Features • classic triad present in minority of cases, but very specific ■ watery discharge (most specific): “hydrops tubae profluens” ■ vaginal bleeding or discharge in 50% of patients ■ crampy lower abdominal/pelvic pain ■ most patients present with a pelvic mass (see Ovarian Tumours, GY41 for guidelines regarding diagnosis/investigation)

Effectiveness, Safety, and Cost-Effectiveness of Primary Cytoreductive Surgery Cochrane Database Syst Rev 2011;(8):CD007565 Summary: During primary surgery for stage III or IV epithelial ovarian cancer, all attempts should be made to achieve complete cytoreduction. When this is not achievable, optimal (1cm) was compared with optimal (2 cm and 7 mm wide Clinically visible lesion confined to cervix, or microscopic lesion >IA Clinically visible lesion ≤4 mm in greatest dimension Clinically visible lesion >4 mm in greatest dimension

II IIA IIA1 IIA2 IIB

Beyond uterus but not to the pelvic wall or lower 1/3 of vagina No obvious parametrial involvement Clinically visible lesion ≤4 mm in greatest dimension Clinically visible lesion >4 mm in greatest dimension Obvious parametrial involvement

III IIIA IIIB

Extends to pelvic wall, and/or involves lower 1/3 of vagina and/or causes hydronephrosis or non-functioning kidney Involves lower 1/3 vagina but no extension into pelvic side wall Extension into pelvic side wall and/or hydronephrosis or non-functioning kidney

IV IVA IVB

Carcinoma has extended beyond true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum Spread of the growth to adjacent organs (bladder or rectum) Distant metastases

Treatment: Prevention and Management Prevention: HPV Vaccine • two vaccines currently approved (Gardasil®, Cervarix®)

Causes of Elevated CA-125 • Age influences reliability of test as a tumour marker • 50% sensitivity in early stage ovarian cancer (poor) – therefore not good for screening Malignant • Gyne: ovary, uterus • Non-Gyne: pancreas, stomach, colon, rectum Non-Malignant • Gyne: benign ovarian neoplasm, endometriosis, pregnancy, fibroids, PID • Non-Gyne: cirrhosis, pancreatitis, renal failure

Cervical Cancer Prognosis 5 yr Survival Stage 0 99% Stage I 75% Stage II 55% Stage III 30% Stage IV 7% Overall 50-60%

Table 28. Comparison of Two Vaccines against Human Papillomavirus (HPV) Gardasil®*

Cervarix®

Viral Strains Covered

6, 11, 16, 18

16, 18

Route of Administration

IM

IM

Schedule of Dosing

0, 2, 6 mo

0, 1, 6 mo

Side Effects

Local: redness, pain, swelling General: headache, low grade fever, GI upset

Local: redness, pain, swelling General: headache, low grade fever, GI upset

Approved Age

Females age 9-45, males age 9-26

Females age 10-25

Pregnant women and women who are nursing (limited data) *Gardasil-9 also covers types 31, 33, 45, 52, and 58; also used to prevent genital wards Contraindications

• should be administered before onset of sexual activity (i.e. before exposure to virus) for optimal benefit of vaccination • may be given at the same time as hepatitis B or other vaccines using a different injection site • not for treatment of active infections • most women will not be infected with all four types of the virus at the same time, therefore vaccine is still indicated for sexually active females or those with a history of previous HPV infection or HPVrelated disease • conception should be avoided until 30 d after last dose of vaccination

Efficacy of Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Vaccine Against Cervical Infection and Precancer Caused by Oncogenic HPV Types (PATRICIA): Final Analysis of a Double-Blind, Randomized Study in Young Women Lancet 2009;374:301-14 Study: Phase III double-blind, controlled RCT. Patients: 18,644 women aged 15-25. Selected Outcomes: Development of HPV-16/18 associated CIN II+ was the primary outcome. Secondary to this were persistence of infections with HPV-16, HPV-18, or other oncogenic HPV types. Selected Results: Efficacy against development of HPV-16/18 associated CIN II+ was 98.1% (p4 cm associated with poorer prognosis • overall 5 yr survival rate: 79% Treatment • T1 lesions (tumour confined to vulva; no extension to adjacent perineal structures): radical local excision • T2 lesions (tumour of any size with extension to adjacent perineal structures): modified radical vulvectomy • T3 lesions (extension to any of: proximal 2/3 of urethra, proximal 2/3 of the vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone): chemoradiation followed by selective resection of residual primary • node positive disease: adjuvant chemoradiation or radiation therapy

Any suspicious lesion of the vulva should be biopsied

GY48 Gynecology

Gynecological Oncology

Vagina BENIGN VAGINAL LESIONS • inclusion cysts ■ cysts form at site of abnormal healing of laceration (e.g. episiotomy) ■ no treatment required • endometriosis ■ dark lesions that tend to bleed at time of menses ■ treatment: excision • Gartner’s duct cysts ■ remnants of Wolffian duct, seen along side of cervix ■ treatment: conservative unless symptomatic • urethral diverticulum ■ can lead to recurrent urethral infection, dyspareunia ■ treatment: surgical correction if symptomatic MALIGNANT VAGINAL LESIONS Epidemiology • primary carcinomas of the vagina represent 2-3% of malignant neoplasms of the female genital tract • 80-90% are SCC • more than 50% diagnosed between 70-90 yr old Risk Factors • associated with HPV infection (analogous to cervical cancer) • increased incidence in patients with prior history of cervical and vulvar cancer Investigations • cytology ■ significant false negative rate for existing malignancy (i.e. if gross lesion present, biopsy) • colposcopy • Schiller test (normal squamous epithelium takes up Lugol’s iodine) • biopsy, partial vaginectomy (wide local excision for diagnosis) • rule out disease on cervix, vulva, or anus (most vaginal cancers are metastatic from one of these sites) • staging Clinical Features Table 30. Clinical Features of Malignant Vaginal Lesions Type

Clinical Features

Vaginal Intra-Epithelial Neoplasia (VAIN)

Grades: analogous to cervical dysplasia

Squamous Cell Carcinoma (SCC)

Most common site is upper 1/3 of posterior wall of vagina Asymptomatic Painless discharge and bleeding Vaginal discharge (often foul-smelling) Vaginal bleeding especially during/post-coitus Urinary and/or rectal symptom 2° to compression

Adenocarcinoma

Most are metastatic, usually from cervix, endometrium, ovary, or colon Most primaries are clear-cell adenocarcinomas 2 types: non-DES and DES syndrome

Treatment • Stage I ■ radiation therapy: for tumours >2 cm diameter or tumour involvement of the mid- to low-grade vagina ■ surgical excision: radical hysterectomy, upper vaginectomy, and bilateral pelvic lymphadenectomy • Stage II-IV: chemoradiation

Toronto Notes 2020

GY49 Gynecology

Gynecological Oncology

Toronto Notes 2020

Gestational Trophoblastic Disease/Neoplasia • refers to a spectrum of proliferative abnormalities of the trophoblast Epidemiology • 1/1000 pregnancies • marked geographic variation (as high as 1/125 in Taiwan) • 80% benign, 15% locally invasive, 5% metastatic • cure rate >95% HYDATIDIFORM MOLE (Benign GTD) Complete Mole • most common type of hydatidiform mole • diffuse trophoblastic hyperplasia, hydropic swelling of chorionic villi, no fetal tissues or membranes present • 46XX or 46XY, chromosomes completely of paternal origin (90%) • 2 sperm fertilize empty egg or 1 sperm with reduplication • 15-20% risk of progression to malignant sequelae • risk factors ■ geographic (South East Asia most common) ■ others (maternal age >40 yr, β-carotene deficiency, vitamin A deficiency not proven) • clinical features often present during apparent pregnancy with abnormal symptoms/findings ■ vaginal bleeding (97%) ■ hyperemesis gravidarum (26%) ■ excessive uterine size for LMP (51%) ■ hyperthyroidism (7%) ■ theca-lutein cysts >6 cm (50%) ■ β-hCG >100,000 IU/L ■ preeclampsia (27%) ■ no fetal heartbeat detected Partial (or Incomplete) Mole • focal trophoblastic hyperplasia and hydropic villi are associated with fetus or fetal parts • often triploid (XXY, XYY, XXX) with chromosome complement from both parents ■ usually related to single ovum fertilized by two sperm • low risk of progression to malignant sequelae (100,000 IU/L ■ excessive uterine size ■ prominent theca-lutein cysts Treatment • suction D&C with sharp curettage and oxytocin • Rhogam® if Rh negative • prophylactic chemotherapy of no proven benefit • chemotherapy for GTN if develops after evacuation Follow-up • contraception required to avoid pregnancy during entire follow-up period • serial β-hCGs (as tumour marker) every week until negative x 3 (usually takes several wk), then monthly for 6-12 mo prior to trying to conceive again • increase or plateau of β-hCG indicates GTN: patient needs chemotherapy GTN (MALIGNANT GTD) Invasive Mole or Persistent GTN • diagnosis made by rising or plateau in β-hCG, development of metastases following treatment of documented molar pregnancy • histology: molar tissue from D&C • metastases are rare (4%)

With development of hypertension early in pregnancy (i.e. 4 mo from antecedent pregnancy) – high pre-treatment β-hCG titre: >100,000 IU/24 h urine or >40,000 IU/L of blood – brain or liver metastases – prior chemotherapy – metastatic disease following term pregnancy ◆ good prognosis characterized by the absence of each of these features Investigations (for Staging) • blood work: CBC, electrolytes, creatinine, β-hCG, TSH, LFTs • imaging: CXR, U/S pelvis only • if CXR shows lung metastasis then CT abdo/pelvis, MRI brain • if suspect brain metastasis but CT brain negative, consider lumbar puncture for CSF β-hCG • ratio of plasma β-hCG:CSF β-hCG 40

40

Antecedent Pregnancy

Mole

Abortion

Term

Interval (End of Antecedent Pregnancy to Chemotherapy in Months)

13

HCG IU/1

105

Number of Metastases

0

1-4

5-8

>8

Site of Metastases

Lung

Spleen, kidney

GI tract

Brain, liver

3-5 cm

>5 cm

Largest Tumour Mass

2

4

Single drug

Prior Chemotherapy

Two drug

Follow-up (for GTN) • contraception for all stages to avoid pregnancy during entire follow-up period • stage I, II, III ■ weekly β-hCG until 3 consecutive normal results ■ then monthly x 12 mo • stage IV ■ weekly β-hCG until 3 consecutive normal results ■ then monthly x 24 mo GTN Diagnosis • β-hCG plateau: 20% in any two values over two wk or longer (e.g. measure at days 1, 7, 14) OR • β-hCG persistently elevated >6 mo OR • metastases on work-up

Common Medications Table 33. Common Medications Drug Name (Brand Name)

Action

Dosing Schedule

Indications

Side Effects (S/E), Contraindications (C/I), Drug Interactions (D/I)

acyclovir (Zovirax®)

Antiviral; inhibits DNA synthesis and viral replication

First Episode: 400 mg PO tid x 7-10 d Recurrence: 400 mg PO tid x 5 d

Genital herpes

S/E: headache, GI upset D/I: zidovudine, probenecid

bromocriptine (Parlodel®)

Dopaminomimetic, agonist at D2R and antagonist at D1R; acts directly on anterior pituitary cells to inhibit synthesis and release of prolactin

Initial: 1.25-2.5 mg PO qhs with food Then: increase by 2.5 mg every 2-7 d as needed until optimal therapeutic response Usual Range: 1.5-15 mg OD

Galactorrhea + amenorrhea 2° to hyperprolactinemia Prolactin-dependent menstrual disorders and infertility Prolactin-secreting adenomas (microadenomas, prior to surgery of macroadenomas) IVF

S/E: N/V, headache, postural hypotension, somnolence C/I: uncontrolled HTN, pregnancy-induced HTN, CAD, breastfeeding D/I: domperidone, macrolides, octreotide

clomiphene citrate (Clomid®)

Increases output of pituitary gonadotropins to induce ovulation

50 mg OD x 5 d Try 100 mg or 160 mg OD If ineffective 3 courses: adequate trial

Patients with persistent ovulatory dysfunction (e.g. amenorrhea, PCOS) who desire pregnancy

S/E: Common: hot flashes, abdominal discomfort, exaggerated cyclic ovarian enlargement, accentuation of Mittelschmerz Rare: ovarian hyperstimulation syndrome, multiple pregnancy, visual blurring, birth defects C/I: pregnancy, liver disease, hormone-dependent tumours, ovarian cyst, undiagnosed vaginal bleeding

clotrimazole (Canesten®)

Antifungal; disrupt fungal cell membrane

Tablet: 100 mg/d intravaginally x 7 d or 200 mg/d x 3 d or 500 mg x 1 dose Cream (1 or 2%): 1 applicator intravaginally qhs x 3-7 d Topical: apply bid x 7 d

Vulvovaginal candidiasis

S/E: vulvar/vaginal burning

danazol (Cyclomen® [CAN]) (Danocrine® [US])

Synthetic steroid: inhibits pituitary gonadotropin output and ovarian steroid synthesis Has mild androgenic properties

200-800 mg in 2-3 divided doses Use for 3-6 mo Biannual hepatic U/S required if >6 mo use

Endometriosis 1° menorrhagia/DUB

S/E: weight gain, acne, mild hirsutism, hepatic dysfunction C/I: pregnancy, undiagnosed vaginal bleeding, breastfeeding, severely impaired renal/hepatic/cardiac function, porphyria, genital neoplasia, thromboembolic disease D/I: warfarin, carbamazepine, cyclosporine, tacrolimus, anti-hypertensives

For IVF: Initial: 1.25 mg/d PO between days 4-6 of follicular phase Then: 2.5 mg/d until 3 d after onset menstruation

GY52 Gynecology

Toronto Notes 2020

Common Medications

Table 33. Common Medications (continued) Drug Name (Brand Name)

Action

Dosing Schedule

Indications

Side Effects (S/E), Contraindications (C/I), Drug Interactions (D/I)

doxycycline

Tetracycline derivative; inhibit protein synthesis

100 mg PO bid x ≥7 d

Chlamydia, gonococcal infection, syphilis

S/E: GI upset, hepatotoxicity C/I: pregnancy, severe hepatic dysfunction D/I: warfarin, digoxin

fluconazole (Diflucan®)

Antifungal; disrupt fungal cell membrane

150 mg PO x 1 dose

Vulvovaginal candidiasis unresponsive to clotrimazole

S/E: headache, rash, N/V, abdominal pain, diarrhea D/I: terfenadine, cisapride, astemizole, hydrochlorothiazide, phenytoin, warfarin, rifampin

leuprolide (Lupron®)

Synthetic GnRH analog; induces reversible hypoestrogenic state

3.75 mg IM q1mo or 11.25 mg IM q3mo Usually ≤6 mo, check bone density if >6 mo Retreatment with Lupron® alone not recommended because of effects on bone density

Endometriosis Leiomyomata DUB Precocious puberty

S/E: hot flashes, sweats, headache, vaginitis, reduction in bone density, acne, GI upset C/I: pregnancy, undiagnosed vaginal bleeding, breastfeeding

menotropin (Pergonal®)

Human gonadotropin with FSH and LH effects; induce ovulation and stimulate ovarian follicle development

75-150 U of FSH and LH IM OD x 7-12 d, then 10,000 U HCG 1 d after last dose

Infertility

S/E: bloating, irritation at injection site, abdominal/pelvic pain, headache, N/V, multiple pregnancy C/I: primary ovarian failure, intracranial lesion (e.g. pituitary tumour), uncontrolled thyroid/adrenal dysfunction, ovarian cyst (not PCOS), pregnancy, undiagnosed uterine bleeding

metronidazole (Flagyl®)

Bactericidal; forms toxic metabolites which damage bacterial DNA

2 g PO x 1 dose or 500 mg PO bid x 7 d

Bacterial vaginosis, trichomonas vaginitis

S/E: headache, dizziness, N/V, diarrhea, disulfiram-like reaction (flushing, tachycardia, N/V) C/I: pregnancy (1st trimester) D/I: cisapride, warfarin, cimetidine, lithium, alcohol, amiodarone, milk thistle, carbamazepine

oxybutinin (Ditropan®)

Anticholinergic; relaxes bladder smooth muscle, inhibits involuntary detrusor contraction

5 or 10 mg/d PO May increase doses by 5 mg weekly to a max of 30 mg/d

Overactive bladder (urge incontinence)

S/E: dry mouth/eyes, constipation, palpitations, urinary retention, dizziness, headache C/I: glaucoma, GI ileus, severe colitis, obstructive uropathy, use with caution if impaired hepatic/renal function

tolterodine (Detrol®)

Anticholinergic

1-2 mg PO bid

Overactive bladder (urge incontinence)

S/E: anaphylaxis, psychosis, tachycardia, dry mouth/ eyes, headache, constipation, urinary retention, chest pain, abdominal pain C/I: glaucoma, gastric/urinary retention, use with caution if impaired hepatic/renal function

tranexamic acid (Cyklokapron®)

Anti-fibrinolytic; reversibly inhibits plasminogen activation

1-1.5 g tid-qid for first 4 d of cycle Max 4 g/d Ophthalmic check if used for several wk

Menorrhagia

S/E: N/V, diarrhea, dizziness, rare cases of thrombosis, abdominal pain, MSK pain C/I: thromboembolic disease, acquired disturbances of colour vision, subarachnoid hemorrhage, age 400 x 109/L • primary thrombocytosis (uncommon): due to myeloproliferative neoplasms (e.g. CML, polycythemia vera, primary myelofibrosis, and essential thrombocytosis; rarely associated with MDS) • reactive/secondary thrombocytosis (common): acute phase reactant (e.g. surgery, inflammation, infection, trauma, bleeding, iron deficiency, neoplasms, and ischemic injury) Clinical Features • history: trauma, surgery, splenectomy, infection, inflammation, bleeding, iron deficiency, prior diagnosis of chronic hematologic disorder, and constitutional symptoms (malignancy) • vasomotor symptoms: headache, visual disturbances, lightheadedness, atypical chest pain, acral dysesthesia, erythromelalgia, livedo reticularis, and aquagenic pruritus • clotting risk, bleeding risk (rare) • physical exam: splenomegaly can be seen in myeloproliferative neoplasms (MPNs) Investigations • CBC, peripheral blood film, serum ferritin concentration • non-specific markers of infection or inflammation (e.g. CRP, ESR, ferritin) • if reactive process has been ruled out, bone marrow biopsy may be required to rule out MPN/MDS Treatment • primary: ASA ± cytoreductive agents (e.g. hydroxyurea, anagrelide, interferon-α) • secondary: treat underlying cause

Pancytopenia Definition • a decrease in all hematopoietic cell lines Clinical Features • anemia: fatigue (see Anemia, H6) • leukopenia: recurrent infections (see Neutropenia, H9) • thrombocytopenia: mucocutaneous bleeding (see Thrombocytopenia, H7) Investigations • CBC, peripheral blood film, serum ferritin concentration, B12, folate • non-specific markers of infection or inflammation (e.g. CRP, ESR, ferritin) • workup as per Figure 4 and presenting symptoms/physical exam • if reactive process has been ruled out, bone marrow biopsy may be required

References APS: see Hematology, H34 Aplastic Anemia: see Hematology, H17 B12/Folate Deficiency: see Hematology, H24,H25 DIC: see Hematology, H32 HIT: see Hematology, H29 HIV: see Infectious Diseases, ID25 ITP: see Hematology, H27 Myelodysplasia: see Hematology, H39 Preeclampsia: see Obstetrics, OB24 SLE: see Rheumatology, RH11

H9 Hematology

Common Presenting Problems

Toronto Notes 2020

Pancytopenia

Hypocellular BM

• Acquired aplastic anemia • Inherited aplastic anemia • Some myelodysplastic syndromes • Myelofibrosis • Overwhelming infections (e.g. bacteria/viral) • Toxic depression of BM • Anorexia nervosa • PNH

Cellular BM

1º BM disease • Myelodysplasia • Lymphoma • Leukemia • Myeloma

BM = bone marrow; PNH = paroxysmal nocturnal hemoglobinuria

2º to systemic disease • SLE • Hypersplenism • Vit B12/folate deficiency • Alcoholism • TB • Sarcoidosis • HIV • Myelofibrosis

Figure 4. Approach to pancytopenia

Neutrophilia Definition • variable definition, but generally an absolute neutrophil count (ANC) >7.7 x 109/L (WHO definition) Etiology • primary neutrophilia ■ chronic myeloid leukemia (CML) ■ other myeloproliferative disorders: PV, ET, myelofibrosis ■ hereditary neutrophilia (autosomal dominant) ■ chronic idiopathic neutrophilia in otherwise healthy patients ■ leukocyte adhesion deficiency • secondary neutrophilia ■ stress/exercise/epinephrine: movement of neutrophils from marginated pool into circulating pool ■ obesity ■ infection: leukocytosis with left shift ± toxic granulation, Döhle bodies (intra-cytoplasmic structures composed of agglutinated ribosomes) ■ inflammation: e.g. rheumatoid arthritis (RA), IBD, chronic hepatitis, MI, PE, and burns ■ malignancy: hematologic (i.e. marrow invasion by tumour) and non-hematologic (especially large cell lung cancer) ■ medications: glucocorticoids, β-agonists, lithium, G-CSF Clinical Features • look for signs and symptoms of fever, inflammation, malignancy to determine appropriate further investigations ■ including lymphadenopathy and organomegaly • examine oral cavity, teeth, peri-rectal area, genitals, and skin for signs of infection Investigations • CBC and differential: mature neutrophils or bands >20% of total WBC suggests infection/inflammation • blood film: Döhle bodies, toxic granulation, and cytoplasmic vacuoles in infection • may require bone marrow biopsy if MPN suspected Treatment • directed at underlying cause

Neutropenia Definition • mild: ANC 1.0-1.5 x 109/L • moderate: ANC 0.5-1.0 x 109/L (risk of infection starts to increase) • severe: ANC 3 mo; consider flow cytometry of peripheral blood

H11 Hematology

Common Presenting Problems

Toronto Notes 2020

Lymphopenia Definition • absolute lymphocyte count 0.5 x 109/L Etiology • primary: due to clonal bone marrow disorder ■ if no primary etiology identified, classified as hypereosinophilic syndrome ◆ 6 mo of eosinophilia (count >1.5 x 109/L) with no other detectable causes and end organ damage ◆ can involve heart, bone marrow, and CNS • secondary ■ most common causes are parasitic (usually helminth) infections and allergic reactions ■ less common causes ◆ collagen vascular diseases (e.g. RA, polyarteritis nodosa, see Rheumatology, RH20) ◆ respiratory causes (asthma, eosinophilic pneumonia, and Churg-Strauss) ◆ cholesterol emboli ◆ hematologic malignancy: see Chronic Myeloid Leukemia, H40 and Hodgkin Lymphoma, H45 ◆ adrenal insufficiency, see Endocrinology, E36 ◆ medications (penicillins) ◆ atopic dermatitis Treatment • treat underlying cause • ensure strongyloides serology is collected to rule out infection before initiating steroids for patients at risk

Agranulocytosis Definition • absolute neutrophil count is 50 x 109/L, marked left shift (myelocytes, metamyelocytes, and bands in peripheral blood smear)

Approach to Lymphadenopathy History • constitutional/B-symptoms: seen in TB, lymphoma, other malignancies • growth pattern: acute vs. chronic • exposures: cats (cat scratch – Bartonella henselae), ticks (Lyme disease – Borrelia burgdorferi), and high risk behaviours (HIV) • joint pain/swelling, rashes (connective tissue disorder) • pruritus (seen in Hodgkin lymphoma) • medications (can cause serum sickness → lymphadenopathy) Clinical Features • determine if lymphadenopathy is localized or generalized • localized: typically reactive or neoplastic ■ cervical (bacterial/mycobacterial infections, ENT malignancies, and metastatic cancer) ■ supraclavicular ◆ right (mediastinal, bronchogenic, esophageal cancer) ◆ left (gastric, gall bladder, pancreas, renal, and testicular/ovarian cancer) ■ axillary (cat scratch fever, breast cancer, and metastatic cancer) ■ epitrochlear (infections, sarcoidosis, and lymphoma) ■ check for splenomegaly, constitutional symptoms Investigations • CBC and differential, blood film • if generalized, consider tuberculin test, HIV RNA, VDRL, Monospot®/EBV serology, ANA, and imaging • if localized and no symptoms suggestive of malignancy, can observe 3-4 wk (if no resolution → biopsy) • excisional biopsy is preferred as it preserves node architecture (essential for diagnosing lymphoma) • in areas difficult to access (retroperitoneal, mediastinal/hilar) multiple core biopsies may be more practical/feasible • FNA should NOT be used for diagnostic purposes in lymphoproliferative disease (excisional biopsy is the gold standard) ■ FNA is helpful for recurrence of solid tumour malignancy ■ imaging such as U/S or CT can provide more info, but generally adds little to diagnosis Table 7. Inflammatory vs. Neoplastic Lymph Nodes Feature

Inflammatory

Neoplastic

Consistency

Fluctuant/soft

Firm/hard

Mobility

Mobile

Matted/immobile

Tenderness

Tender

Non-tender

Size

2 cm

*Note: these classifications are not absolute; lymphoma and CLL nodes can feel rubbery and are frequently mobile, non-tender

Table 8. Differential Diagnosis of Generalized Lymphadenopathy Reactive

Inflammatory

Neoplastic

Bacterial (TB, Lyme, brucellosis, cat scratch disease, and syphilis)

Collagen disease (RA, dermatomyositis, SLE, vasculitis, and Sjögren’s)

Lymphoproliferative disorder/ lymphoma

Viral (EBV, CMV, HIV)

Drug hypersensitivity

Metastatic cancer

Parasitic (toxoplasmosis)

Sarcoidosis, amyloidosis

Histiocytosis X

Fungal (histoplasmosis)

Serum sickness

Constitutional/B-Symptoms • Unexplained temperature >38°C • Unexplained weight loss (>10% of body weight in 6 mo) • Night sweats

Drugs that can cause Lymphadenopathy • Allopurinol • Atenolol • Captopril • Carbamazepine • Cephalosporins • Gold • Hydralazine • Penicillin • Phenytoin • Primidone • Pyrimethamine • Quinidine • Sulfonamides • Sulindac

H13 Hematology

Approach to Splenomegaly

Toronto Notes 2020

Approach to Splenomegaly Table 9. Differential Diagnosis of Splenomegaly Increased Demand for Splenic Function Hematological Nutritional anemias Hemoglobinopathies Hemolysis Spherocytosis Sequestration crisis Elliptocytosis

Infectious Viral e.g. EBV, HIV/ AIDS, CMV Bacterial e.g. Bacterial endocarditis, TB Parasitic e.g. Malaria, Histoplasmosis, Leishmaniasis Fungal

Inflammatory SLE Sarcoidosis Felty syndrome Still’s disease

Congestive

Infiltrative

Cirrhosis Portal HTN Portal vein obstruction (including right heart failure) Splenic vein thrombosis

Non-Malignant Benign metaplasia Cysts Amyloidosis, Sarcoidosis Hamartomas Vascular abnormalities Lysosomal storage diseases (Gaucher’s, Niemann-Pick) Glycogen storage diseases Malignant Leukemia (CML, CLL) Lymphoproliferative disease Hodgkin lymphoma Myeloproliferative disorders Metastatic tumour

Causes of Splenomegaly CHINA Cirrhosis/Congestion (portal HTN) Hematological Infectious Neoplasm (malignant, non-malignant) Autoimmunue

The underlined conditions cause massive splenomegaly (spleen crosses midline or reaches pelvis)

History • constitutional symptoms, feeling of fullness in LUQ, and early satiety • signs or symptoms of infection (e.g. mononucleosis) or malignancy • history of liver disease, hemolytic anemia, or high-risk exposures Clinical Features • jaundice, petechiae • signs of chronic liver disease • percussion (Castell’s sign, Traube’s space, and Nixon’s method) and palpation • associated lymphadenopathy or hepatomegaly • signs of CHF Investigations • CBC and differential, blood film • as indicated: liver enzymes (AST, ALT, ALP, and GGT) and/or LFTs (platelet, INR, albumin, and bilirubin), reticulocyte count, Monospot®/EBV, haptoglobin, LDH, infectious, and autoimmune workup • imaging ■ ultrasound of abdomen/liver to assess for cirrhosis and portal vein thrombosis (if positive, refer to hepatology) ■ echo for cardiac function ■ CT to rule out lymphoma and assess splenic lesions

Microcytic Anemia • MCV 15)

Hypochromic, microcytic

Anemia of Chronic Disease

N/





N

N

Normocytic/microcytic

Sideroblastic Anemia

N/



N

N/



Dual population Basophilic stippling

Thalassemia

N/

N/

N

N/

N/

Hypochromic, microcytic Basophilic stippling Poikilocytosis

Iron Metabolism Iron Intake (Dietary) • average North American adult diet = 10-20 mg iron (Fe) daily • steady state absorption is 5-10% (0.5-2 mg/d); enhanced by citric acid, ascorbic acid (vitamin C) and reduced by polyphenols (e.g. in tea), phytate (e.g. in bran), dietary calcium, and soy protein • males more likely to have positive Fe balance; up to 20% of menstruating females have negative Fe balance

Causes of Microcytic Anemia TAILS Thalassemia Anemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anemia

H14 Hematology

Toronto Notes 2020

Microcytic Anemia

Iron Absorption and Transport • dietary iron is absorbed in the duodenum (e.g. absorption impaired in IBD and Celiac disease) • in circulation the majority of non-heme iron is bound to transferrin which transfers iron from enterocytes and storage pool sites (macrophages of the reticuloendothelial system and hepatocytes) to RBC precursors in the bone marrow Iron Levels • hepcidin is a hormone produced by hepatocytes that regulates systemic iron levels ■ binds to iron exporter ferroportin (on duodenal enterocytes and reticuloendothelial cells) and induces its degradation, thereby inhibiting iron export into circulation (diminished absorption of iron and iron trapping in reticuloendothelial system cells) ■ hepcidin production is: ◆ increased in states of iron overload (inhibiting additional iron absorption) and inflammation (mediating anemia of chronic inflammation through iron trapping) ◆ decreased in states where erythropoiesis is increased (e.g. hemolysis) or oxygen tension is low Iron Storage • ferritin ■ ferric iron (Fe3+) complexed to a protein called apoferritin (liver, spleen, and bone marrow are main ferritin storage sites) ■ small quantities are present in plasma in equilibrium with intracellular ferritin ■ also an acute phase reactant – can be spuriously elevated despite low Fe stores in response to a stressor • hemosiderin ■ aggregates or crystals of ferritin with the apoferritin partially removed ■ macrophage-monocyte system is main source of hemosiderin storage Dietary Fe3+ in GI lumen Fe3+

LEGEND

Fe2+

Ferritin

Hemosiderin

Hepcidin

Transferrin

Fe3+

Erythropoiesis Oxygen

Enterocytes of proximal duodenum

Fe3+ Fe2+

Hepatocyte Macrophage

Fe 3+ -Hb

_

RBC

Hepcidin Fe2+

Plasma

Fe3+ Fe

3+

Iron Absorption and Transport

+ Fe3+ RBC precursors in bone marrow

Iron Homeostasis

Body iron stores Inflammation/infection

© Cassandra Cetlin 2015, after Julie Man 2011

Fe3+

Fe

2+

Figure 5. Iron metabolism

Iron Indices • bone marrow aspirate: gold standard test for assessment of iron stores (rarely done) • serum ferritin: most important blood test for iron stores ■ decreased in iron deficiency anemia ■ elevated in infection, inflammation, malignancy, liver disease, hyperthyroidism, and iron overload • serum iron: measure of all non-heme iron present in blood ■ varies significantly daily • total iron binding capacity (TIBC): indirect measure of total amount of transferrin present in blood ■ normally, one third of TIBC is saturated with iron ■ increased TIBC has high specificity for decreased iron, low sensitivity • saturation ■ serum Fe divided by TIBC, expressed as a proportion or a percentage • soluble transferrin receptor (sTfR) ■ reflects the availability of iron at the tissue level ■ the transferrin receptor is expressed on the surface of erythroblasts and is responsible for iron uptake – some are cleaved off and are present in circulation as sTfR ■ in iron deficient states more transferrin receptors are expressed on erythroblasts leading to an increase in sTfR ■ low in reduced erythropoiesis and iron overload ■ useful in determining iron deficiency in the setting of chronic inflammatory disorders (see Iron Deficiency Anemia, H15)

H15 Hematology

Toronto Notes 2020

Microcytic Anemia

Iron Deficiency Anemia • see Pediatrics, P43 • most common cause of anemia in North America Etiology • increased demand ■ increased physiological need for iron in the body (e.g. pregnancy) • decreased supply: dietary deficiencies (rarely the only etiology in the developed world) ■ cow’s milk (infant diet), “tea and toast” diet (elderly), absorption imbalances, post-gastrectomy, malabsorption (IBD of duodenum, celiac disease, autoimmune atrophic gastritis, and H.pylori infection) • increased losses ■ hemorrhage ◆ obvious causes: menorrhagia, abnormal uterine bleeding, and frank GI bleed ◆ occult: peptic ulcer disease, GI cancer ■ hemolysis ◆ chronic intravascular hemolysis (e.g. PNH, cardiac valve RBC fragmentation) Clinical Features • iron deficiency may cause fatigue before clinical anemia develops • signs/symptoms of anemia: see Anemia, H6 • brittle hair, nail changes (brittle, koilonychia) • pica (appetite for non-food substances e.g. ice, paint, and dirt) • restless leg syndrome

Plummer-Vinson Syndrome • Dysphagia (esophageal) • Glossitis • Iron deficiency anemia • Stomatitis

Investigations • iron indices, including soluble transferrin receptor ■ low ferritin (M (3:1)

History of Recent Infection

Common

Rare

Onset of Bleed

Abrupt

Insidious

Duration

Usually wk

Mo to yr

Spontaneous Remissions

80% or more

Uncommon

Terminology of ITP • also known as immune thrombocytopenia • primary: isolated thrombocytopenia (platelet count 12 mo • refractory: post-splenectomy Pathophysiology • primary or secondary ITP • an acquired immune-mediated disorder (pathophysiology incompletely understood) ■ anti-platelet antibodies bind to platelet surface → increased splenic clearance ■ impaired platelet production ■ helper T-cell and cytotoxic T-cell activation also implicated in platelet destruction Clinical Feature • variable presentation: asymptomatic, fatigue, minimal bruising, mucocutaneous bleed (e.g. purpura, ecchymoses, petechiae, continuous epistaxis, menorrhagia), and intracranial bleed • assess for symptoms/signs suggesting a secondary cause Investigations • CBC and reticulocyte count: thrombocytopenia • PT and aPTT: normal • peripheral blood film: decreased platelets, giant platelets (rule out platelet clumping) • HIV, HCV, H. pylori serology • vitamin B12, ANA, C3, C4, depending on clinical symptoms • bone marrow aspirate and biopsy: increased number of megakaryocytes ■ recommended in patients >60 yr of age, pre-splenectomy or have failed traditional ITP therapy, those with systemic symptoms, an abnormal blood film ■ bone marrow aspirate and biopsy should be considered if there is any suspicion of diminished bone marrow function (e.g. myelodysplasia, infiltration) Treatment • rarely indicated if platelets >30 x 109/L unless active bleeding, trauma, or surgery • emergency treatment (active bleeding [CNS, GI, or GU] or in need of emergency surgery) ■ general measures: stop drugs that reduce platelet function, control blood pressure, minimize trauma ■ corticosteroids: prednisone (1 mg/kg/d) or dexamethasone (40 mg PO/d x 4 d) ■ antifibrinolytic: tranexamic acid (1 g PO tid or 1 g IV q6h) if mucosal bleeding ■ IVIg 1 g/kg/d x 2 doses (raises platelet count faster than corticosteroids) ■ platelet transfusion: for refractory, major bleeding or need for urgent surgery (expect that platelet recovery will be diminished) ■ emergency splenectomy: may be considered, vaccinations prior if possible (pneumococcus, meningococcus, H. influenzae b) ■ management of intracranial bleeding: IV steroids, IVIg, platelets • non-urgent treatment (platelet count 100 • partial response: platelet 30-100 • no response: platelet 50% AND platelet nadir ≥20 x 109/L

Platelet count fall 30-50% OR platelet nadir 10-19 x 109/L

Platelet count fall 5% of normal factor level), moderate (1-5%), severe (1.5 or aPTT >38 ◆ 10 units of cryoprecipitate if fibrinogen 2.0 for 2 consecutive days ■ direct oral anticoagulants (DOACs) ◆ apixaban or rivaroxaban; with no laboratory monitoring required, patients with CrCl >25 ml/ min (apixaban) or 30 ml/min (rivaroxaban) ◆ dabigatran (factor IIa inhibitor): LMWH or IV heparin for at least 5-10 d before initiating dabigatran, patients with CrCl >30 mL/min ◆ important drug interactions to consider for DOACs (no relevant food interactions however) ■ cancer patients: LMWH more effective than warfarin at preventing recurrence of venous thrombosis in cancer patients; increasing evidence to support DOACs in cancer-associated thrombosis • duration of anticoagulant treatment ■ provoked VTE with transient risk factor: 3 mo ■ provoked VTE with ongoing risk factor: consider indefinite therapy with annual reassessment ■ first unprovoked VTE: at least 3 mo, subsequent reassessment ■ unprovoked proximal DVT or PE: consider indefinite therapy with annual reassessment ■ second unprovoked VTE: consider indefinite therapy ■ cancer-associated DVT: at least 3 mo, longer if continued evidence of cancer • IVC filters ■ temporary filter indicated only if acute DVT (30 min High Risk Surgical Patients >40 yr, surgery for malignancy or lower extremity orthopedic surgery lasting >30 min, inhibitor deficiency, or other risk factor High Risk Medical Patients Heart failure, severe respiratory disease, ischemic stroke and lower limb paralysis, confined to bed and have >1 additional risk factor (e.g. active cancer, previous VTE, sepsis, acute neurologic disease, IBD)

H37 Hematology

Hematologic Malignancies and Related Disoders

■ surgery: avoid elective surgery in the first 3 mo after a venous thromboembolic event ◆ pre-operatively: IV heparin may be used up to 4-6 h pre-operatively ◆ perioperatively: warfarin or DOACs discontinued for at least 3-5 d pre-operatively (consider mechanism of drug clearance) ◆ post-operatively: IV heparin, LMWH, DOAC can be used for anticoagulation (consult with surgeon prior to re-initiation) ◆ for patients at high risk for thromboembolism (VTE 60 yr

Leukemia: malignant cells arise in bone marrow that may spread elsewhere (including blood, lymph nodes, and lymphoid tissue) Lymphoma: malignant cells arise in lymph nodes and lymphoid tissues that may spread elsewhere (including blood and bone marrow) BUT the location where the malignant cells are found does not solely define the type of hematologic malignancy – classified based on the characteristics of the cell (histology, histochemistry, immunophenotyping, cytogenetics, molecular changes)

Treatment of Pulmonary Embolism • see Respirology, R19

Hematologic Malignancies and Related Disoders MATURATION OF CELLS

Acute Lymphocytic Leukemia (ALL)

Chronic Lymphocytic Leukemia (CLL)

Multiple Myeloma (MM)

Lymphomas

Naïve

Germination

B-lymphocytes Hematopoietic stem cell

Lymphoid progenitor

Acute Leukemia Definition (WHO): presence of 20% blast cells or greater in the peripheral blood or bone marrow at presentation Classification: divided into myeloid (AML) and lymphoid (ALL) depending on whether blasts are myeloblasts or lymphoblasts, respectively

Plasma cell T-lymphocytes

MATURATION OF CELLS

Acute Myelogenous Leukemia (AML)

Auer rods are pathognomonic for AML

Myeloproliferative Disorders Neutrophils Eosinophils

Granulocytes Chronic Myelogenous Leukemia (CML)

Basophils Hematopoietic stem cell

Myeloid progenitor

Monocytes

Chronic Myelomonocytic Leukemia (CMML)

Platelets

Essential Thrombocytosis

Erthrocytes

Figure 15. Hematopoietic derivation of hematologic disorders

Polycythemia Vera

Basic initial workup for all hematological malignancies: 1. ALL CHILDBEARING WOMEN must have a b-HCG pre initiation of treatment of any cancer diagnosis 2. ALL PATIENTS MUST HAVE HBsAb, HBsAg, HBcAb collected irrespective of cancer diagnosis and must be treated to avoid reactivation 3. All aggressive lymphoma patients must be screened for HIV 4. All patients must be screened for TB risk factors

H38 Hematology

Toronto Notes 2020

Myeloid Malignancies

Hematological Malignancies and Related Disorders

Lymphoid Disorders

Leukemia • ALL • CLL

Lymphomas • Hodgkin • Non-Hodgkin • B Cell • T Cell • Other cell origin (e.g. NK)

Myeloid Disorders

Plasma Cell Dyscrasias • Multiple myeloma • MGUS • Waldenstrom’s macroglobulinemia

Leukemia • AML

MPNs • PV • ET • CML • IMF

MDS

ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; ET = essential thrombocythemia; IMF = idiopathic myelofibrosis; MDS = myelodysplastic syndromes; MGUS = monoclonal gammopathy of unknown significance; MPN = myeloproliferative neoplasms; PV = polycythemia vera

Figure 16. Overview of hematologic malignancies and related disorders

Myeloid Malignancies Acute Myeloid Leukemia Definition • rapidly progressive malignancy characterized by failure of myeloid cells to differentiate beyond blast stage Epidemiology • incidence increases with age; median age of onset is 65 yr old; 80% of acute adult leukemias • accounts for 10-15% of childhood leukemias Risk Factors • male, older age, smoking, obesity, myelodysplastic syndromes (MDS), benzene, radiation, Down Syndrome, alkylating agents and radiation therapy as treatment for previous malignancy Pathophysiology • etiology subdivided into: ■ primary: de novo ■ secondary: hematologic malignancies (e.g. myeloproliferative disorders and MDS) or previous chemotherapeutic agents (e.g. alkylating agents) • uncontrolled growth of blasts in marrow leads to: ■ suppression of normal hematopoietic cells ■ appearance of blasts in peripheral blood – risk of leukostasis ■ accumulation of blasts in other sites (e.g. skin, gums) ■ metabolic consequences; tumour lysis syndrome Clinical Features • signs and symptoms develop over a period of weeks • manifestations of bone marrow failure ■ anemia, thrombocytopenia (associated with DIC in promyelocytic leukemia), neutropenia (even with normal WBC), leads to infections, and fever • accumulation of blast cells in marrow ■ skeletal pain, bony tenderness (especially sternum) • organ infiltration ■ gingival hypertrophy (particularly myelomonocytic leukemia) – may present to dentist first ■ extramedullary involvement ■ hepatosplenomegaly (in ALL) ■ lymphadenopathy (not marked in ALL) ■ gonads (in ALL) ■ skin: leukemia cutis or myeloid sarcoma ■ eyes: hemorrhages and/or whitish plaques, Roth spots, cotton wool spots, and vision changes (uncommon) • leukostasis/hyperleukocytosis syndrome (medical emergency) ■ large numbers of blasts interfere with circulation and lead to hypoxia and hemorrhage – can cause diffuse pulmonary infiltrates, CNS bleeding, respiratory distress, altered mental status, and priapism ■ associated with AML more than ALL • metabolic effects; aggravated by treatment ■ increased uric acid → nephropathy, gout ■ release of phosphate → decreased Ca2+, decreased Mg2+ ■ release of procoagulants → DIC (higher risk in acute promyelocytic leukemia) • tumour lysis syndrome ■ hyperkalemia pre-treatment from blastic proliferation K+ after treatment (from lysed cells). Note – some forms of AML can present with hypokalemia due to secreted muraimdase that causes K+ wasting from renal tubules

H39 Hematology

Myeloid Malignancies

Toronto Notes 2020

Investigations • blood work ■ CBC: anemia, thrombocytopenia, variable WBC (most often cytopenias + blasts) ■ INR, aPTT, fibrin degradation products (FDP), fibrinogen (in case of DIC) ■ increased LDH, increased uric acid, increased PO43- (released by leukemic blasts), decreased Ca2+, in/decreased K+ ■ baseline renal and liver function tests ■ if considering treatment: screen for HepB, HepC, HIV, CMV • peripheral blood film – circulating blasts with Auer rods (azurophilic granules) are pathognomonic for AML • bone marrow aspirate for definitive diagnosis ■ blast count: AML >20% (normal is 49% in men or >48% in women, OR increased red cell mass (>25% above mean normal predicted value) 2. bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 3. presence of JAK2 V617F or JAK2 exon 12 mutation ■ Minor Criterion 1. serum erythropoietin level below reference range for normal (must have at least two major criteria if using erythropoietin level) Clinical Features • symptoms are secondary to high red cell mass and hyperviscosity (see Erythrocytosis, H6) • thrombotic complications: DVT, PE, Budd-Chiari (hepatic vein thrombosis), portal vein thrombosis, thrombophlebitis, increased incidence of stroke, and MI ■ due to increased blood viscosity, increased platelet number and/or activity ■ bleeding complications: epistaxis, gingival bleeding, ecchymoses, and GI bleeding ■ if high platelet counts: associated with acquired vWD • erythromelalgia (burning pain in hands and feet and erythema of the skin) ■ associated with platelets >400 x 109/L ■ pathognomonic microvascular thrombotic complication in PV and ET • pruritus, especially after warm bath or shower (40%) due to cutaneous mast cell degranulation and histamine release • epigastric distress, PUD ■ due to increased histamine from tissue basophils, alterations in gastric mucosal blood flow due to increased blood viscosity • gout (hyperuricemia), due to increased cell turnover • characteristic physical findings ■ plethora (ruddy complexion) of face (70%), palms ■ splenomegaly (70%), hepatomegaly (40%) Investigations (see Erythrocytosis, H6) • must rule out secondary polycythemia if high Epo level Treatment • phlebotomy to keep hematocrit 60%) • weight loss, fever, night sweats → secondary to hypermetabolic state • splenomegaly (90%) → secondary to extramedullary hematopoiesis; may cause early satiety • hepatomegaly (70%) → may get portal hypertension • bone and joint pain → secondary to osteosclerosis, gout • signs of extramedullary hematopoiesis (depends on organ involved)

Erythromelalgia is a pathognomonic microvascular thrombotic complication in PV and ET

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera NEJM 2013;368:22-33 Study: Prospective, RCT, mean follow-up of 28.9 mo. Blinding not described. Population: 365 patients with JAK2-positive polycythemia vera being treated with phlebotomy, hydroxyurea, or both. Intervention: Patients were randomized to a target hematocrit 65; hemoglobin 25,000/mm3; circulating blast cells ≥1% ■ based on the calculated score, a patient’s IMF is categorized as “low”, “intermediate 1”, “intermediate 2”, or “high” with a mean survival of 185, 78, 35, and 16 mo, respectively • risk of transformation to AML (8-10%)

Essential Thrombocythemia Definition • overproduction of platelets in the absence of recognizable stimulus • must rule out secondary thrombocythemia Epidemiology • increases with age; F:M = 2:1, but F=M at older age Diagnosis (2008 WHO Criteria Revised in 2016) requires meeting all four criteria 1. sustained platelet count >450 x 109/L 2. bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased number of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil granulopoiesis or erythropoiesis 3. not meeting WHO criteria for PV, primary myelofibrosis, bcr-abl CML, or myelodysplastic syndrome or other myeloid neoplasms 4. demonstration of JAK2 V617F, calreticulin or MPL mutation (or in its absence another clonal marker), no evidence for reactive thrombocytosis Clinical Features • often asymptomatic • vasomotor symptoms (40%) ■ headache (common), dizziness, syncope ■ erythromelalgia (burning pain of hands and feet, dusky colour, usually worse with heat, caused by platelet activation → microvascular thrombosis) • thrombosis (arterial and venous) • bleeding (often GI; associated with platelets >1000 x 109/L) • constitutional symptoms, splenomegaly • pregnancy complications; increased risk of spontaneous abortion • risk of transformation to AML (0.6-5%), myelofibrosis Investigations • CBC: increased platelets; may have abnormal platelet aggregation studies or vWD studies • JAK2 PCR assay; if negative, CALR PCR assay • bone marrow hypercellularity, megakaryocytic hyperplasia, giant megakaryocytes • increased K+, increased PO43- (2º to release of platelet cytoplasmic contents) • diagnosis: exclude other myeloproliferative disorders and reactive thrombocytosis Treatment • low dose ASA if previous history of thrombotic event, ≥1 cardiovascular risk factors, older, or symptomatic • cytoreductive therapy if thrombosis or thrombotic symptoms: hydroxyurea (HU) (1st-line therapy), anagrelide, interferon-α, or 32P (age >80 or lifespan 50 yr • association with Epstein-Barr virus in up to 50% of cases and causal role not determined Clinical Features • asymptomatic lymphadenopathy (70%) ■ non-tender, rubbery consistency ■ cervical/supraclavicular (60-80%), axillary (10-20%), inguinal (6-12%) • splenomegaly (50%) ± hepatomegaly • mediastinal mass ■ found on routine CXR, may be symptomatic (cough) ■ rarely may present with superior vena cava syndrome and pleural effusion • systemic symptoms ■ B symptoms (especially in widespread disease; fever in 30%, night sweats, weight loss) and pruritus • non-specific/paraneoplastic ■ alcohol-induced pain in nodes and nephrotic syndrome • starts at a single site in lymphatic system (node) and spreads first to adjacent nodes ■ disease progresses in contiguity with lymphatic system Investigations • CBC ■ anemia (chronic disease, rarely hemolytic), eosinophilia, lymphopenia, platelets normal or increased early disease, and decreased in advanced disease • biochemistry ■ HIV, HepB, HepC serologies ■ liver enzymes and/or LFTs (liver involvement) ■ renal function tests (prior to initiating chemotherapy) ■ ALP, Ca2+ (bone involvement) ■ ESR, LDH (monitor disease progression) • imaging ■ CXR, CT chest (lymph nodes, mediastinal mass), CT abdomen/pelvis (liver or spleen involvement), and PET scans

Hodgkin is distinguished from non-Hodgkin lymphoma by the presence of ReedSternberg cells

Hodgkin lymphoma classically presents as a painless, non-tender, firm, rubbery enlargement of superficial lymph nodes, most often in the cervical region

H46 Hematology

Lymphomas

Toronto Notes 2020

■ cardiac function assessment (MUGA scan or echocardiography): for patients at high risk of pre-treatment cardiac disease (age >60, history of HTN, CHF, PUD, CAD, MI, CVA, and malnourished), treatment can be cardiotoxic ■ PFTs: if history of lung disease (COPD, smoking, and previous radiation to lung) • excisional lymph node or core biopsy confirms diagnosis • bone marrow biopsy to assess marrow infiltration (only necessary if B-symptoms, PET positive marrow on imaging, or cytopenia) Treatment • stage I-II: chemotherapy (ABVD) followed by involved field or involved site radiotherapy (XRT) • stage III-IV: chemotherapy (ABVD) with XRT for bulky disease • relapse, resistant to therapy: high dose chemotherapy and autologous stem cell transplant ■ PET scan results essential in clarifying disease response

Treatment of HL depends on stage; treatment of NHL depends on histologic subtype

Complications of Treatment • cardiac disease: secondary to XRT, adriamycin is also cardiotoxic • pulmonary disease: secondary to bleomycin (interstitial pneumonitis) • infertility: recommend sperm banking • secondary malignancy in irradiated field ■ 8 yr after treatment ■ non-Hodgkin lymphoma • hypothyroidism: post XRT Prognosis • Hasenclever adverse prognostic factors: 1. serum albumin 4 nodal areas; elevated LDH; Lugano stage III-IV; hemoglobin 60; Ann Arbor stage (III-IV); performance status (ECOG/Zubrand 2-4); elevated LDH; >1 extranodal site ■ based on calculated risk, mean 5 yr survival ranges from 26-73% ■ ~40% rate of cure Table 35. Characteristics of Select Non-Hodgkin Lymphomas Follicular Lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL)

Burkitt Lymphoma

Mantle Cell Lymphoma

F Pathophysiology • accumulation of neoplastic lymphocytes in blood, bone marrow, lymph nodes, and spleen Clinical Features • 25% asymptomatic (incidental finding) • 5-10% present with B-symptoms (≥1 of: unintentional weight loss ≥10% of body weight within previous 6 mo, temperature >38ºC, or night sweats for ≥2 wk without evidence of infection, extreme fatigue) • lymphadenopathy (50-90%), splenomegaly (25-55%), hepatomegaly (15-25%) • immune dysregulation: autoimmune hemolytic anemia (DAT positive), ITP, hypogammaglobulinemia ± neutropenia • bone marrow failure: late, secondary to marrow involvement by CLL cells Investigations • CBC: clonal population of B lymphocytes >5 x 109/L • peripheral blood film ■ lymphocytes are small and mature ■ smudge cells characteristic flow cytometry of peripheral blood ■ CD5, CD20dim, CD23 • cytogenetics: FISH (dictates response to therapy and prognosis). imaging must be done post therapy to ensure post treatment remission v= • bone marrow aspirate ■ lymphocytes >30% of all nucleated cells ■ infiltration of marrow by lymphocytes in 4 patterns: nodular (10%), interstitial (30%), diffuse (35%, worse prognosis), or mixed (25%) Natural History and Treatment • natural history: indolent and incurable; most cases show slow progression • small minority present with aggressive disease; usually associated with chromosomal abnormalities (e.g. p53 deletion) • first line therapy is dictated by cytogenetic status and patient co-morbidities ■ observation if early, stable, asymptomatic ◆ treatment options vary by region; commonly fludarabine + cyclophosphamide + rituximab (FCR) in fit patients with normal CrCl; bendamustine + rituximab (BR) in less fit ◆ chlorambucil + anti-CD20 obinutuzumab in the elderly ◆ Ibrutinib (BTK inhibitor) in patients with IgVH mutation negativity and/ p53 positivity ■ corticosteroids, IVIg: especially for autoimmune phenomena ■ radiotherapy for isolated bulky nodes • molecular therapies ■ Idelalisib – PI3K inhibitor ■ Ibrutinib – BTK (Bruton’s tyrosine kinase) inhibitor ■ Venetoclax – BCL-2 inhibitor

Smudge cells are artifacts of damaged lymphocytes from slide preparation

H49 Hematology

Malignant Clonal Proliferations of Mature B-Cells

Toronto Notes 2020

Prognosis • 9 yr median survival, but varies greatly • prognosis predicted by Rai staging based on leukocytosis and cytogenetic status • low risk: lymphocytosis in blood and bone marrow only • intermediate risk: lymphocytosis with enlarged nodes in any site or splenomegaly, hepatomegaly • high risk: lymphocytosis with disease-related anemia (0.5 cm Calcium >2.80 mmol/L Renal failure (Cr >176 mmol/L) Anemia Bony lesions (lytic lesions or osteoporosis felt to be caused by myeloma)

Amyloid The general term for a variety of proteinaceous materials that have a similar structural organization and are abnormally deposited in tissues Found in a variety of clinical disorders and can cause systemic (e.g. MM [light chains]) or localized amyloidosis (e.g. Alzheimer disease [AB amyloid])

H50 Hematology

Malignant Clonal Proliferations of Mature B-Cells

Investigations • CBC ■ normocytic anemia, thrombocytopenia, and leukopenia ■ rouleaux formation on peripheral film • biochemistry ■ increased Ca2+, increased ESR, decreased anion gap, increased Cr, albumin, β2-microglobulin (as part of staging), and proteinuria (24 h urine collection) • monoclonal proteins ■ serum protein electrophoresis (SPEP): demonstrates monoclonal protein spike in serum in 80% (i.e. M protein) ■ urine protein electrophoresis (UPEP): demonstrates light chains in urine = Bence-Jones protein (15% secrete only light chains) ■ immunofixation: demonstrates M protein and identifies Ig type; also identifies light chains ■ serum free light chain quantification: kappa and lambda light chains, calculated ratio • bone marrow aspirate and biopsy ■ often focal abnormality, greater than 10% plasma cells, abnormal morphology, clonal plasma cells; send for fluorescence in situ hybridization (FISH) or cytogenetics (prognostic implications) • skeletal series (X-rays), MRI if symptoms of cord compression ■ presence of lytic lesions and areas at risk of pathologic fracture ■ bone scans are not useful since they detect osteoblast activity • β2-microglobulin, LDH, and CRP are poor prognosticators ■ HepBsAb, HepBsAg, HepBcAb

Toronto Notes 2020

Routine urinalysis will not detect light chains as dipstick detects albumin. Need sulfosalicylic acid or 24 h urine protein for immunofixation or electrophoresis

Light Chain Disease 15% of MM produce only light chains Renal failure is a major problem Kappa > lambda light chain has better prognosis

Diagnosis • International Myeloma Working Group Criteria (“SLiM CRAB”): ■ Sixty (60) percent or greater abnormal plasma cells on bone marrow examination ■ Light chain ratio (free, involved/uninvolved) of 100 or more in the blood (involved must be at least 100 mg/L) ■ MRI with more than one bone lesion (5 mm or greater) ■ CRAB – presence of end-organ damage related to plasma cell dyscrasia, such as: ◆ increased serum Ca2+ ◆ renal failure ◆ anemia ◆ lytic bone lesions Treatment • non-curative • treatment goals ■ improvement in quality of life (improve anemia, reverse renal failure, prevent fractures) ■ prevention of progression and complications ■ increase overall survival • autologous stem cell transplant if 65 yr old or transplant-ineligible ■ pending on patient co-morbidities can include a combination of: melphalan, prednisone, cyclophosphamide, PI (i.e. bortezomib), IMIDs, anti-CD38 agents (e.g. daratumumab) • dexamethasone and bortezomib if ARF; bortezomib ± dexamethasone in light chain amyloidosis • supportive management ■ bisphosphonates for those with osteopenia or lytic bone lesions (requires renal dosing) ■ local XRT for bone pain, spinal cord compression ■ kyphoplasty for vertebral fractures to improve pain relief and regain height ■ treat complications: hydration for hypercalcemia and renal failure, bisphosphonates for severe hypercalcemia, prophylactic antibiotics, erythropoietin for anemia, and DVT prophylaxis • all patients will relapse; choice of retreatment regimen depends on duration of remission, organ involvement, patient’s comorbidities, and preferences Prognosis • ISS - International Staging System (β2-microglobulin and albumin) used to stage and estimate prognosis • revised ISS for risk stratification: combination of original ISS, cytogenetic profile (i.e. p53 mutation associated with poor survival and resistance to chemotherapy), and LDH • median survival based on stage, usually 3-7 yr

Serum Free Light Chain Ratio is an Independent Risk Factor for Progression in MGUS Blood 2005;106:812-817 Purpose: To determine whether the presence of monoclonal free kappa or lambda immunoglobulin light chains in MGUS increases the risk of progression to malignancy. Methods: Retrospective study with median follow-up of 15 yr. Baseline serum samples obtained from 1383 MGUS patients seen at the Mayo clinic between 1960-1994. 1148 baseline samples were obtained within 30 d of diagnosis. Results: Malignant progression had occurred in 87 (7.6%) patients. In 379 (33%) patients, an abnormal serum free light chain (FLC) ratio was detected. There was a significantly higher risk of progression in patients with an abnormal FLC ratio relative to patients with a normal ratio (hazard ratio, 3.5; 95% Cl 2.3-5.5; p70 yr of age ■ asymptomatic Diagnosis • presence of a serum monoclonal protein (M protein) at a concentration 4 in fatty acid oxidation defect) Treatment • varies according to inborn error of metabolism but includes dietary restrictions, enzyme replacement etc. • in the presentation of acute decompensation potentially caused by an inborn error of metabolism, discontinue feeding to prevent further build up of toxic metabolites

Metabolic disease must be ruled out in any newborn who becomes acutely ill after a period of normal behaviour and development, or with a family history of early infant death even if the newborn screen is negative

MG10 Medical Genetics

Toronto Notes 2020

References

Table 8. Presentation and Management of Select Metabolic Disorders Phenylketonuria

Galactosemia

Maple Syrup Urine Disease

Glycogen Storage Disease Type 1 (Von Gierke Disease)

Epidemiology

1:10,000; autosomal recessive disease (mutations in PAH)

1:60,000; autosomal recessive disease

1:185,000; autosomal recessive disease (mutations in BCKDHA, BCKDHB, and DBT genes), 1:25,000 Ashkenazi Jewish, 1:400 Mennonites

1:100,000; autosomal recessive disease, 1:20,000 in Ashkenazi Jewish

Etiology

Deficiency of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine leading to build-up of phenylalanine and its toxic metabolites Mothers who have PKU may have infants with multiple congenital abnormalities

Most commonly due to deficiency of galactose-1phosphate uridyltransferase leading to an inability to process lactose/galactose

Reduction or elimination of protein complex needed for amino acid leucine, isoleucine, and valine breakdown, leading to toxic build-up

Mutations in G6PC (cause of GSD1a) and SLC37A4 (cause of GSD1b) prevent effective conversion of glucose-6phosphate to glucose. Glucose6-phosphate is converted to glycogen and fat which subsequently accumulates in cells, especially in the liver and kidneys

Clinical Feature

Baby is normal at birth, then develops a musty odour, eczema, hypertonia, tremors and mental retardation Hypopigmentation due to low tyrosine levels (fair hair, blue eyes)

Signs of liver and renal failure, jaundice, failure to thrive, and cataracts with ingestion of lactose/galactose

Feeding intolerance, failure to thrive, vomiting, lethargy, and maple syrup odour in urine and cerumen

Complications: Increased risk of sepsis, especially E. coli If the diagnosis is not made at birth, liver and brain damage may become irreversible

May progress to irreversible mental retardation, hyperactivity, severe failure to thrive, seizures, coma, cerebral edema, and death if inadequately treated

Typically presents between 3-6 mo of age with hepatomegaly, hypoglycemia, poor fasting tolerance, growth failure and “doll-like” facies (full cheeks with thin extremities)

PKU screening at birth Dietary restriction of phenylalanine starting within the first 10 d of life; especially important during pregnancy to maintain normal phenylalanine levels to prevent maternal PKU effects on fetus Large neutral amino acid (tyrosine) replacement, BH4 enzyme treatment, phenylalanine lyase treatment are other options

Screened for in many newborn screening programs Elimination of galactose from the diet (e.g. dairy, breast milk) Most infants are fed a soybased diet

MSUD is screened in most newborn screening programs. Serum amino acid evaluation (leucine, isoleucine, alloleucine, valine) and urine organic acid analysis Protein-restricted, highcarbohydrate diet to limit branched amino acid intake A trial of thiamine therapy in addition may be recommended for some infants

Diagnosis and Management

Complications: Lactic acidosis, hyperuricemia, hyperlipidemia, delayed puberty, renal disease, hypoglycemic seizures, hepatic adenomas, ostoeporosis Evaluate hypoglycemia, lactic acidemia, hypertriglyceridemia and hepatomegaly Treat with nutrition therapy (small frequent feedings, avoid fructose/ sucrose/galactose), continuous overnight feedings, raw cornstarch (for slow, sustained glucose release), vitamin supplementation, frequent blood glucose monitoring

References Amato RSS. Nelson’s essentials of pediatrics, 4th ed. Philadelphia: WB Saunders, 2002. Human genetics and dysmorphology. 129-146. Blake KD, Prasad C. CHARGE syndrome, orphanet. J Rare Diseases 2006;1. Biggar W. Duchenne muscular dystrophy. Pediatr Rev 2006;27:83-88. Chudley AE, Conry J, Cook JL, et al. Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis. CMAJ 2005;172(5 Suppl):S1-21. Committee on Practice Bulletins–Gynecology, Committee. "Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome." Obstet Gynecol 2017;130.3:e110. Daly MB, Pilarski R, Berry M, et al). NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2. J Natl Compr Canc Ne 2017;15(1):9-20. De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for Marfan syndrome. Am J Med Genet 1996;62(4):417-26. Elieff MP, Lopez-Beltran A, Montironi R, et al. Familial cancer syndromes. Humana Press, 2008. Molecular genetic pathology. 449-466. Evans DGR, Salvador H, Chang, VY, et al. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 2 and related disorders. Clin Cancer Res 2017;23(12):e54-e61. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2014;80(2):197-220. Grati FR, Malvestiti F, Ferreira, JC, et al. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genetics in Medicine 2014;16(8):620-624. Hersh JH. Health supervision for children with neurofibromatosis. Pediatrics 2008;121(3):633-642. http://www.bccancer.bc.ca/screening/Documents/HCP_GuidelinesManuals_vonHippelLindauSyndrome.pdf. http://geneticseducation.ca/educational-resources/gec-ko-on-the-run/non-invasive-prenatal-testing/. Kruszka P, Regier D. Inborn Errors of Metabolism: From Preconception to Adulthood. American Family Physician 2019;99(1):25-32. Moeschler JB, Shevell M. Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 2014 Sep;134(3):e903-18. Nicholson JF. Nelson’s essentials of pediatrics, 4th ed. Philadelphia: WB Saunders, 2002. Inborn errors of metabolism. 153-178. Sobel E, Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. American journal of human genetics 1996;58(6):1323. Therrell BL, Adams J. Newborn screening in North America. J Inherit Metab Dis 2007;30(4):447-465. US National Library of Medicine.(2019. Glycogen Storage Disease Type 1. https://ghr.nlm.nih.gov/condition/glycogen-storage-diseases-type-i. US National Library of Medicine. 2019. Sickle cell disease. https://ghr.nlm.nih.gov/condition/sickle-cell-disease. Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955-957. Vasen HF, Tomlinson I, Castells A. Clinical management of hereditary colorectal cancer syndromes. Nature Reviews Gastroenterology and Hepatology 2015;12(2):88.

MI

Medical Imaging Mana Modares, Taryn Rohringer, and Daniel Schlam, chapter editors Vanessa Sheng and Jaya Tanwani, associate editors Mellisa Allwood and Milica Milakovic, EBM editors Dr. Nasir Jaffer, Dr. John Kavanagh, and Dr. Eugene Yu, staff editors

Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Imaging Modalities . . . . . . . . . . . . . . . . . . . . . . . . 2 X-Ray Imaging Ultrasound Magnetic Resonance Imaging Positron Emission Tomography Scans Contrast Enhancement

Breast Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Modalities Breast Interventional Procedures Breast Findings References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Chest Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Chest X-Ray Computed Tomography Chest Lung Abnormalities Pulmonary Vascular Abnormalities Pleural Abnormalities Mediastinal Abnormalities Tubes, Lines, and Catheters Abdominal Imaging . . . . . . . . . . . . . . . . . . . . . . . 10 Abdominal X-Ray Approach to Abdominal X-Ray Abdominal Computed Tomography Approach to Abdominal Computed Tomography Contrast Studies Specific Visceral Organ Imaging “itis” Imaging Angiography of Gastrointestinal Tract Genitourinary System and Adrenal . . . . . . . . . . 16 Urological Imaging Gynecological Imaging Adrenal Mass Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Modalities Approach to CT Head Selected Pathology Musculoskeletal System . . . . . . . . . . . . . . . . . . 21 Modalities Approach to Bone X-Rays Trauma Arthritis Bone Tumour Infection Metabolic Bone Disease Nuclear Medicine . . . . . . . . . . . . . . . . . . . . . . . . . 25 Brain Thyroid Respiratory Cardiac Abdomen and Genitourinary System Bone Interventional Radiology. . . . . . . . . . . . . . . . . . . 28 Vascular Procedures Nonvascular Interventions

MI1 Medical Imaging

Toronto Notes 2020

MI2 Medical Imaging

Toronto Notes 2020

Acronyms

Acronyms FDG AP ARDS AV AXR BOOP

18-fluorodeoxyglucose anteroposterior acute respiratory distress syndrome arteriovenous abdominal x-ray bronchiolitis obliterans organizing pneumonia CHF congestive heart failure CNS central nervous system CSF cerebrospinal fluid CT computed tomography CTA computed tomographic angiogram CVD collagen vascular disease CVP central venous pressure CXR chest x-ray DDH Developmental dysplasia of the hip DEXA dual-energy x-ray absorptiometry DMSA dimercaptosuccinic acid DSA digital subtraction angiography

18

DTPA DWI ECD eGFR ERCP

diethylene triamine pentaacetic acid diffusion-weighted image ethyl cysteinate dimer estimated glomerular filtration rate endoscopic retrograde cholangiopancreatography FLAIR fluid-attenuated inversion recovery GI gastrointestinal GPA granulomatosis with polyangiitis GU genitourinary HCC hepatocellular carcinoma HIDA hepatobiliary iminodiacetic acid HMPAO hexamethylpropyleneamine oxime HSG hysterosalpingogram IBD inflammatory bowel disease ICS intercostal space ICV ileocecal valve IPF interstitial pulmonary fibrosis IVP intravenous pyelogram

KUB LA LV MAA MAG3 MCA MR MRA MRCP

kidneys, ureters, bladder left atrium left ventricle macroaggregated albumin mertiatide middle cerebral artery magnetic resonance magnetic resonance angiogram magnetic resonance cholangiopancreatography MRI magnetic resonance imaging MS multiple sclerosis MUGA multiple gated acquisition PA posteroanterior PBD percutaneous biliary drainage PET positron emission tomography PFT pulmonary function test PICC peripherally-inserted central catheter POCUS point-of-care ultrasound

PTA PTC

percutaneous transluminal angioplasty percutaneous transhepatic cholangiography RA right atrium RAIU radioactive iodine uptake RV right ventricle SPECT single photon emission computed tomography SVC superior vena cava TB tuberculosis TNK tenecteplase tPA tissue plasminogen activator TRUS transrectal ultrasound TVUS transvaginal ultrasound U/S ultrasound VCUG voiding cystourethrogram V/Q ventilation/perfusion

Imaging Modalities X-Ray Imaging • x-rays are a form of electromagnetic energy of short wavelength • as x-ray photons traverse matter, they can be absorbed (a process known as “attenuation”) and/or scattered • the density of a structure determines its ability to attenuate or “weaken” the x-ray beam ■ air < fat < water < bone < metal • structures that have high attenuation (e.g. bone) appear white on the resulting images Plain Films • x-rays pass through the patient and interact with a detection device (film) to produce a 2-dimensional projection image • structures closer to the film appear sharper and less magnified • contraindications: pregnancy (relative) • advantages: inexpensive, non-invasive, readily available, portable, reproducible, fast, easily read • disadvantages: radiation exposure (minimal), generally poor at distinguishing soft tissues Fluoroscopy • continuous x-rays used for guiding angiographic and interventional procedures, in contrast examinations of the GI tract, and in the OR for certain surgical procedures (e.g. orthopedic, urological) • on the fluoroscopic image, black and white are reversed so that bone and contrast agents appear dark and radiolucent structures appear bright • advantages: real-time visualization of structures • disadvantages: increased radiation dose; however, the use of pulsed fluoroscopy reduces fluoroscopy time by 76% and radiation dose by 64% as compared with continuous fluoroscopy Computed Tomography • x-ray beam opposite a detector moves in a continuous 360º arc as patient is advanced through the scanner ■ anatomical structures are then reconstructed • attenuation is quantified in Hounsfield units: ■ windowing and leveling: adjusting the “window width” (range of Hounsfield units displayed) and “window level” (midpoint value of the window width) to maximally visualize certain anatomical structures (e.g. CT chest can be viewed using “lung”, “soft tissue”, and “bone” settings) • contraindications: pregnancy (relative), adverse reactions to contrast agents (e.g. allergy, renal failure) • advantages: delineates soft tissues, excellent at delineating bones and identifying lung/liver masses, may be used to guide biopsies, spiral/helical multidetector CT has fast data acquisition and allows 3D reconstruction, CTA non invasive compared to conventional angiography • disadvantages: high radiation exposure, soft tissue characterization is not as good in comparison with MRI, IV contrast injection, anxiety of patient when going through scanner, higher cost, less available than plain film, typically requires expertise/radiologist interpretation

Typical Effective Doses from Diagnostic Medical Exposures (in adults)* Diagnostic Procedure Type

Equivalent Number of Chest X-Rays

Approximate Equivalent Period of Natural Background Radiation** (~3 mSv/yr)

5 10 50 75 1 0.5 20 35 35 30 0.25 150

12 d 3 wk 4 mo 6 mo 2d 1d 7 wk 3 mo 3 mo 10 wk white matter (“fatty” myelin) > CSF > air (= dark)

Magnetic Resonance Imaging • imaging technique that does not use ionizing radiation and can produce images in virtually any plane • patient is placed in a magnetic field generated by electric current; protons. typically from water molecules, align themselves along the plane of magnetization due to their intrinsic polarity. A pulsed radiofrequency beam is subsequently turned on and deflects all the protons off their aligned axes. When the radiofrequency beam is turned off, the protons return to their pre-excitation axis, giving off the energy they absorbed. This energy is measured with a detector and interpreted by software to generate MR images • the MR image reflects the signal intensity picked up by the receiver. This signal intensity is dependent on: 1. hydrogen density: tissues with low hydrogen density (e.g. cortical bone, lung) generate little to no MR signal compared to tissues with high hydrogen density (e.g. water) 2. magnetic relaxation times (T1 and T2): reflect quantitative alterations in MR signal strength due to intrinsic properties of the tissue and its surrounding chemical and physical environment

Remember that water is “white” on T2 as “World War II”

Methods to Reduce the Risk of ContrastInduced Nephropathy • Optimal: 0.9% NaCl at 1 ml/kg/h for 12 h pre-procedure and 12 h post-contrast administration • For same-day procedure: 0.9% NaCl or NaHCO3 at 3 ml/kg/h for 1-3 h preprocedure and for 6 h post-contrast administration

Table 1. Differences Between Diffusion, T1- and T2-Weighted MR Imaging Imaging Techniques

Contrast Enhancements

Main Application

Advantages

Diffusion-Weighted Imaging

Contrast dependent on the molecular motion of water Decreased diffusion is hyperintense (bright), whereas increased diffusion is hypointense (dark)

Neuroradiology

Sensitive for detection of acute ischemic stroke and differentiating an acute stroke from other neurologic pathologies Acute infarction and abscess collections appear hyperintense due to restricted diffusion

T1-Weighted

Fluid is hypointense (dark) and fat is hyperintense (bright)

Body soft tissues

Often considered an anatomic scan since they provide a reference for functional imaging

T2-Weighted

Fluid is hyperintense (bright) and fat is hypointense (dark)

Body soft tissues

Often considered a pathologic scan since they will highlight edematous areas associated with certain pathologies

Positron Emission Tomography Scans • nuclear tracers are employed to prodce images of functional processes in the body • current generation models integrate PET and CT technologies into a single imaging device (PET-CT) that collects both anatomic and functional information during a single acquisition • positron-producing radioisotopes, such as 18F, are chemically incorporated into a metabolically active molecule (e.g. glucose). These are then injected into the patient, where they travel to and accumulate in the tissues of interest. As the radioactive substance decays, γ rays are produced, and are detected by the PET scanner • contraindications: pregnancy • advantages: shows metabolism and physiology of tissues (not only anatomic); in oncology, allows for diagnosis, staging, and restaging; has predictive and prognostic value; can evaluate cardiac viability • disadvantages: cost, ionizing radiation, availability

Contraindications to IV Contrast MADD Failure Multiple myeloma Adverse reaction previously DM Dehydration Failure (renal, severe heart)

MI4 Medical Imaging

Toronto Notes 2020

Chest Imaging

Contrast Enhancement Table 2. Contrast Agents Imaging Modality Types

Advantages

Disadvantages

Contraindications

1. Barium (oral or rectal)

Radio-opaque substance that helps to delineate intraluminal anatomy; may demonstrate patency, lumen integrity, or large filling defects

Previous adverse reaction to contrast; barium enema is contraindicated in toxic megacolon, acute colitis, and suspected perforation

2. Iodine (IV injection)

Delineates intraluminal anatomy; may demonstrate patency, lumen integrity, or large filling defects; under fluoroscopy, may also give information on function of an organ

Previous adverse reaction to contrast, renal failure, DM, pregnancy, multiple myeloma, severe heart failure and dehydration eGFR 0.5), tracheal shift, tortuous aorta, widened mediastinum • hila: pulmonary vessels, mainstem and segmental bronchi, lymph nodes • lungs: parenchyma, pleura, diaphragm ■ comment on abnormal lung opacity, pleural effusions or thickening ■ right hemidiaphragm usually higher than left due to liver ■ right vs. left hemidiaphragm can be discerned on lateral CXR due to heart resting directly on left hemidiaphragm • please refer to Toronto Notes website for supplementary material on how to approach a CXR

Chest X-Ray Interpretation Basics ABCDEF AP, PA or other view Body position/rotation Confirm name Date Exposure/quality Films for comparison Analysis ABCDEF Airways and hilar Adenopathy Bones and Breast shadows Cardiac silhouette and Costophrenic angle Diaphragm and Digestive tract Edges of pleura Fields (lung fields)

Anatomy Localizing Lesions for Parenchymal Lung Disease • silhouette sign: when two objects of the same radiolucency contact each other, they become indistinguishable on imaging and result in the loss of normal interfaces (i.e. the silhouette expected at an anatomical border disappears). The silhouette sign can be used to identify lung pathology (consolidation, atelectasis, mass) and localize disease to specific lung segments. This sign is not only used in the chest, but can also be an aid to interpreting imaging studies throughout the body • spine sign: on lateral films, vertebral bodies should appear progressively radiolucent (dark) as one moves down the thoracic vertebral column; if they appear more radio-opaque, it is an indication of pathology (e.g. consolidation in overlying lower lobe) • air bronchogram: branching pattern of air-filled bronchi on a background of opacification/fluid-filled airspaces Table 3. Localization Using the Silhouette Sign Interface Lost

Location of Lung Pathology

SVC/right superior mediastinum

RUL

Right heart border

RML

Right hemidiaphragm

RLL

Aortic knob/left superior mediastinum

LUL

Left heart border

Lingula

Left hemidiaphragm

LLL

cl

tr sp

co a1 a2

p3 p4

cl co

st svc ca aa apw rbr lpa pa rpa

mi

st

ivc

rv

lv

rv

di

aa lpa rpa rbr

g

sc mf

lbr la vb

lv ivc

di

cpa

as

mi

ra vb

tr

cpa

di cpa

PA view

Figure 2. Location of fissures, mediastinal structures, and bony landmarks on CXR

Lateral view

Legend a1 anterior 1st rib a2 anterior 2nd rib aa aortic arch apw aorto-pulmonary window as anterior airspace ca carina cl clavicle co coracoid process cpa costophrenic angle di diaphragm g gastric bubble ivc inferior vena cava la left atrium lbr left mainstem bronchus lpa left pulmonary artery lv left ventricle mf major fissure mi minor fissure p3 posterior 3rd rib p4 posterior 4th rib pa main pulmonary artery ra right atrium rbr right mainstem bronchus rpa right pulmonary artery rv right ventricle sc scapula sp spinous process st sternum svc superior vena cava tr trachea vb vertebral body

MI6 Medical Imaging

LUL

LLL

RUL

RUL RML

LLL

LUL LLL

RML RLL RLL

Front AP

Right-Lateral

Back AP

RLL

Left-Lateral

RUL: Right Upper Lobe; RML: Right Middle Lobe; RLL: Right Lower Lobe; LUL: Left Upper Lobe; LLL: Left Lower Lobe

© Anas Nader 2009

LUL

RUL RML

Toronto Notes 2020

Chest Imaging

Soft Tissue Window

Figure 3. Location of lobes of the lung

Computed Tomography Chest

Bone Window

Approach to CT Chest • soft tissue window ■ thyroid, chest wall, pleura ■ heart: chambers, coronary artery calcifications, pericardium ■ vessels: aorta, pulmonary artery, smaller vasculature ■ lymph nodes: mediastinal, axillary • bone window ■ vertebrae, sternum, ribs: fractures, lytic lesions, sclerosis • lung window ■ trachea: patency, secretions ■ bronchi: anatomic variants, mucus plugs, airway collapse ■ lung parenchyma:, nodules, fibrosis,interstitial changes,consolidation ■ pleural space: effusions • please refer to Toronto Notes website for supplementary material on how to approach a CT chest

Lung Window

Figure 4. CT thorax windows

Table 4. Types of CT Chest Advantage

Disadvantage

Contrast

Indication

Standard

Scans full lung very quickly (3 cm

15 mm, eccentric cavity, and shaggy internal margins

No

Satellite Lesions

No

Yes

Figure 10. Pulmonary nodule: bronchogenic carcinoma

Pulmonary Vascular Abnormalities Pulmonary Edema • pathogenesis: fluid accumulation in the airspaces of the lungs • findings ■ vascular redistribution/enlargement, cephalization, pleural effusion, cardiomegaly (may be present in cardiogenic edema and fluid overloaded states) ■ fluid initially collects in interstitium • loss of definition of pulmonary vasculature • peribronchial cuffing • Kerley B lines • reticulonodular pattern • thickening of interlobar fissures ■ as pulmonary edema progresses, fluid collects in alveoli and causes diffuse airspace disease, often in a “bat wing” or “butterfly” pattern in perihilar regions (outermost lung fields tend to be spared) • differential diagnosis: cardiogenic (e.g. CHF), renal failure, volume overload, non-cardiogenic (e.g. ARDS)

Figure 11. Peribronchial cuffing

Pulmonary Embolism • pathogenesis: arterial blockage in the pulmonary arteries due to emboli from pelvic or leg veins, rarely from PICC lines, ports, air, fat, or amniotic fluid • findings ■ generally not possible to definitively diagnose on plain film. Diagnosis made by CT pulmonary angiogram or Ventilation/perfusion scinticrapthy. (VQ scan) ■ CXR: Westermark sign (localized pulmonary oligemia), Hampton’s hump (triangular peripheral infarct), enlarged right ventricle and right atrium, atelectasis, pleural effusion, and rarely pulmonary edema ■ definitive imaging study: CT pulmonary angiography to look for filling defect in contrast-filled pulmonary arteries ■ VQ scan: Can be used in patients with impaired renal function or in pregnancy

Pleural Abnormalities Pleural Effusion Table 6. Sensitivity of Plain Film Views for Pleural Effusion X-Ray Projection

Minimum Volume to Visualize

Lateral decubitus

25 mL: most sensitive

Upright lateral

50 mL: meniscus seen in the posterior costophrenic sulcus

PA

200 mL

Supine

Diffuse haziness

• a horizontal fluid level is seen only in a hydropneumothorax (i.e. both fluid and air within pleural cavity) • effusion may exert mass effect, shift trachea and mediastinum to opposite side, or cause atelectasis of adjacent lung • U/S is superior to plain film for detection of small effusions and may also aid in thoracentesis; POCUS is now standard of care in acute situations

Figure 12. Pleural effusion in lateral view

MI9 Medical Imaging

Chest Imaging

Pneumothorax • pathogenesis: gas/air accumulation within the pleural space resulting in separation of the lung from the chest wall • findings ■ upright chest film allows visualization of visceral pleura as curvilinear line paralleling chest wall, separating partially collapsed lung from pleural air. Occasional tracheal deviation to side of pneumothorax, except in tension pneumothorax ■ more obvious on expiratory (increased contrast between lung and air) or lateral decubitus films (air collects superiorly) ■ more difficult to detect on supine film; look for the “deep (costophrenic) sulcus” sign, “double diaphragm” sign (dome and anterior portions of diaphragm outlined by lung and pleural air, respectively), hyperlucent hemithorax, sharpening of adjacent mediastinal structures ■ mediastinal shift may occur in tension pneumothorax • differential diagnosis: spontaneous (tall and thin males, smokers), iatrogenic (lung biopsy, ventilation, central venous catheter insertion), trauma (associated with rib fractures), emphysema, malignancy, honeycomb lung • management: needle decompression in 2nd ICS midclavicular line or chest tube insertion in 5th ICS anterior axillary line, repeat CXR to ensure resolution Asbestos • asbestos exposure may cause various pleural abnormalities including benign plaques (most common; these may calcify), diffuse pleural fibrosis, effusion, and malignant mesothelioma

Mediastinal Abnormalities Mediastinal Mass • the mediastinum is divided into four compartments; this provides an approach to the differential diagnosis of a mediastinal mass • anterior border formed by the sternum and posterior border by the heart and great vessels ■ 4 Ts: thyroid, thymic neoplasm, teratoma, terrible lymphoma ■ cardiophrenic angle mass differential: thymic cyst, epicardial fat pad, foramen of Morgagni hernia • middle border (extending behind anterior mediastinum to a line 1 cm posterior to the anterior border of the thoracic vertebral bodies) ■ esophageal carcinoma, esophageal duplication cyst, metastatic disease, lymphadenopathy (all causes), hiatus hernia, bronchogenic cyst • posterior border (posterior to the middle line described above) • neurogenic tumour (e.g. neurofibroma, schwannoma), neurenteric cyst, thoracic duct cyst, lateral meningocele, Bochdalek hernia, extramedullary hematopoiesis • superior boundaries (superiorly by thoracic inlet, inferiorly by plane of the sternal angle, anteriorly by manubrium, posteriorly by T1-T4, laterally by pleura) • in addition, any compartment may give rise to lymphoma, lung cancer, aortic aneurysm or other vascular abnormalities, abscess, or hematoma Enlarged Cardiac Silhouette • heart borders ■ on PA view, right heart border is formed by right atrium; left heart border is formed by left atrium and left ventricle ■ on lateral view, anterior heart border is formed by right ventricle; posterior border is formed by left atrium (superior to left ventricle) and left ventricle • cardiothoracic ratio = greatest transverse dimension of the central shadow relative to the greatest transverse dimension of the thoracic cavity ■ using a good quality erect PA chest film in adults, cardiothoracic ratio of >0.5 is abnormal ■ differential of ratio >0.5 ◆ cardiomegaly (myocardial dilatation or hypertrophy) ◆ pericardial effusion ◆ poor inspiratory effort/low lung volumes ◆ pectus excavatum • ratio 7 cm, splayed carina (late sign) • RV enlargement: elevation of cardiac apex from diaphragm; anterior enlargement leading to loss of retrosternal air space on lateral; increased contact of right ventricle against sternum • LV enlargement: rounding of the cardiac apex; displacement of left cardiac boarder leftward, inferiorly, and posteriorly

Toronto Notes 2020

Figure 13. Pneumothorax

Elevated Hemidiaphragm Suggests PAL DIP Pregnancy Atelectasis Lung resection Diaphragmatic paralysis Intra-abdominal process Pneumonectomy Pleural effusion also may result in apparent elevation Depressed Hemidiaphragm Suggests TALC Tumour Asthma Large pleural effusion COPD

DDx Anterior Mediastinal Mass 4 Ts Thyroid Thymic neoplasm Teratoma Terrible lymphoma

Figure 14. Lateral CXR showing four mediastinal compartments

MI10 Medical Imaging

Abdominal Imaging

Toronto Notes 2020

Tubes, Lines, and Catheters • ensure appropriate placement and assess potential complications of lines and tubes • avoid mistaking a line/tube for pathology (e.g. oxygen rebreather mask for pneumothoraces) Central Venous Catheter • used for fluid and medication administration, vascular access for hemodialysis, and CVP monitoring • Ideally located at the SVC/Atrial junction to prevent inducing arrhythmias or perforating wall of atrium ■ if monitoring CVP, catheter tip must be proximal to venous valves • tip of well-positioned central venous catheter projects over silhouette of SVC in a zone demarcated superiorly by the anterior first rib end and clavicle, and inferiorly by top of RA • course should parallel that of the SVC; if appears to bend as it approaches wall of SVC or appears perpendicular, catheter may damage and ultimately perforate wall of SVC • complications: pneumothorax, bleeding (mediastinal, pleural), air embolism Endotracheal Tube • frontal chest film: tube projects over trachea and shallow oblique or lateral chest radiograph will help determine position in 3 dimensions • progressive gaseous distention of stomach on repeat imaging is concerning for esophageal intubation • tip should be located 2-4 cm above tracheal carina (avoids bronchus intubation and vocal cord irritation) • maximum inflation diameter 3 cm) Large bowel (>6 cm) Cecum (>9 cm)

Approach to Abdominal X-Ray • mnemonic: “Free ABDO” • “Free”: free air and fluid ■ free fluid ◆ small amounts of fluid: increased distance between lateral fat stripes and adjacent colon may indicate free peritoneal fluid in the paracolic gutters ◆ large amounts of fluid: diffuse increased opacification on supine film; bowel floats to centre of anterior abdominal wall ◆ ascites and blood (hemoperitoneum) are the same density on the radiograph, and therefore, cannot be differentiated ◆ free intraperitoneal air suggests rupture of a hollow viscus (anterior duodenum, transverse colon), penetrating trauma, or recent (6.5 cm) with mucosal changes (e.g. foci of edema, ulceration, pseudopolyps), loss of normal haustral pattern • “B”: bowel wall thickening ■ increased soft tissue density in bowel wall, thumb-like indentations in bowel wall (“thumbprinting”), or a picket-fence appearance of the valvulae conniventes (“stacked coin” appearance) ■ may be seen in IBD, infection, ischemia, hypoproteinemic states, and submucosal hemorrhage • “D”: densities ■ bones: look for gross abnormalities of lower ribs, vertebral column, and bony pelvis ■ abnormal calcifications: approach by location ◆ RUQ: renal stone, adrenal calcification, gallstone, porcelain gallbladder ◆ RLQ: ureteral stone, appendicolith, gallstone ileus ◆ LUQ: renal stone, adrenal calcification, tail of pancreas ◆ LLQ: ureteral stone ◆ central: aorta/aortic aneurysm, pancreas, lymph nodes ◆ pelvis: phleboliths (i.e. calcified veins), uterine fibroids, bladder stones • “O”: organs ■ kidney, liver, gallbladder, spleen, pancreas, urinary bladder, psoas shadow ■ outlines can occasionally be identified because they are surrounded by more lucent fat, but all are best visualized with other imaging modalities (CT, MRI) Biliary vs. Portal Venous Air “Go with the flow”: air follows the flow of bile or portal venous blood Biliary air is most prominent centrally over the liver Portal venous air is most prominent peripherally

Figure 16. Normal AXRs: (left) supine anteroposterior AXR, (middle) upright anteroposterior AXR, and (right) left lateral decubitus AXR

MI12 Medical Imaging

Toronto Notes 2020

Abdominal Imaging

Table 8. Abnormal Air on Abdominal X-Ray Air

Appearance

Common Etiologies

Extraluminal Intraperitoneal (pneumoperitoneum)

Upright film: air under diaphragm Left lateral decubitus film: air between liver and abdominal wall Supine film: gas outlines of structures not normally seen: Inner and outer bowel wall (Rigler’s sign) Falciform ligament Peritoneal cavity (“football” sign)

Perforated viscus Post-operative (up to 10 d to be resorbed)

Retroperitoneal

Gas outlining retroperitoneal structures allowing increased visualization: Psoas shadows Renal shadows

Perforation of retroperitoneal segments of bowel: duodenal ulcer, post-colonoscopy

Intramural (pneumatosis intestinalis)

Lucent air streaks in bowel wall, 2 types: 1. Linear 2. Rounded (cystoides type)

1. Linear: ischemia, necrotizing enterocolitis 2. Rounded/cystoides (generally benign): primary (idiopathic), secondary to COPD

Intraluminal

Dilated loops of bowel, air-fluid levels

Adynamic (paralytic) ileus, mechanical bowel obstruction

Loculated

Mottled, localized in abnormal position without normal bowel features

Abscess (evaluate with CT)

Biliary

Air centrally over liver

Sphincterotomy, gallstone ileus, erosive peptic ulcer, cholangitis, emphysematous cholecystitis

Portal Venous

Air peripherally over liver in branching pattern

Bowel ischemia/infarction

A

B

Table 9. Adynamic Ileus vs. Mechanical Obstruction Feature

Adynamic Ileus

Mechanical Obstruction

Calibre of Bowel Loops

Normal or dilated

Usually dilated

Air-Fluid Levels (erect and left lateral decubitus films only)

Same level in the same single loop

Multiple air fluid levels giving “step ladder” appearance, dynamic (indicating peristalsis present), “string of pearls” (row of small gas accumulations in the dilated valvulae conniventes)

Distribution of Bowel Gas

Air throughout GI tract is generalized or localized In a localized ileus (e.g. pancreatitis, appendicitis), dilated “sentinel loop” remains in the same location on serial films, usually adjacent to the area of inflammation

Dilated bowel up to the point of obstruction (i.e. transition point) No air distal to obstructed segment “Hairpin” (180°) turns in bowel

Abdominal Computed Tomography • indications for plain CT: renal colic, hemorrhage • indications for CT with contrast: ■ IV contrast given immediately before or during CT to allow identification of arteries and veins • portal venous phase: indicated for majority of cases • biphasic (arterial and portal venous phases): liver, pancreas, bile duct tumours • caution: contrast allergy (may pre-medicate with steroids and antihistamine) • contraindication: impaired renal function (based on eGFR) ■ oral contrast: barium or water-soluble (water soluble if suspected perforation) given in most cases to demarcate GI tract ■ rectal contrast: given for investigation of colonic lesions

C

Figure 17. (A) Rigler’s sign (B) “football” sign (C) string of pearls sign

Rigler’s sign courtesy of Dr Jeremy Jones, Radiopaedia. org, rID: 8041. Prof Frank Gaillard https://radiopaedia. org/cases/8041 Football sign courtesy of Dr Maxime St-Amant, Radiopaedia.org, rID: 18597. https://radiopaedia.org/ cases/18597 String of pearls courtesy of Dr Maulik S Patel, Radiopaedia.org, rID: 14006. https://radiopaedia.org/ cases/14006

Approach to Abdominal Computed Tomography • look through all images in gestalt fashion to identify any obvious abnormalities • look at each organ or structure individually, from top to bottom, evaluating the size and shape of each area of increased or decreased density • evaluate the following: ■ soft tissue window ◆ liver, gallbladder, spleen, and pancreas ◆ adrenals, kidneys, ureters, and bladder ◆ stomach, duodenum, small bowel mesentery, and colon/appendix ◆ retroperitoneum (aorta, vena cava, and mesenteric vessels; look for adenopathy in vicinity of vessels) ◆ peritoneal cavity for fluid or masses ◆ abdominal wall and adjacent soft tissue ■ lung window ◆ visible lung (bases) ■ bone window ◆ vertebrae, spinal cord, and bony pelvis

Figure 18. Sigmoid volvulus on plain film, “coffee bean sign”

Courtesy of Dr Henry Knipe, Radiopaedia.org, rID: 28620. https://radiopaedia.org/cases/28620

MI13 Medical Imaging

Toronto Notes 2020

Abdominal Imaging

Small bowel

Gallbladder

Spleen

Head of the pancreas

Left kidney

Liver c

Right kidney b

d a e

Blood vessels a. Aorta

Right crus of diaphragm

b. Inferior vena cava

Vertebra

c. Superior mesenteric vein

Psoas muscles

d. Superior mesenteric artery

Erector spinae muscles

e. Left renal artery

Figure 19. Axial abdominal computed tomography

CT and Bowel Obstruction • cause of bowel obstruction is rarely found on plain films; CT is the best imaging modality • the “3,6,9” rule is a very useful guide for determining when the bowel is dilated; the maximum diameter of the bowel is 3 cm for small bowel, 6 cm for large bowel, and 9 cm for cecum; this can also be useful to distinguish small and large bowel, and to assess for ‘impending’ cecal perforation (e.g. post-untreated Ogilvie’s syndrome) • closed-loop obstruction: an obstruction in two locations (usually small bowel) creating a loop of bowel obstructed both proximally and distally; complications (e.g. ischemia, perforation, necrosis) may occur quickly CT Colonography (virtual colonoscopy) • emerging imaging technique for evaluation of intraluminal colonic masses (i.e. polyps, tumours) • two CT scans of the abdomen (prone and supine) after the instillation of carbon dioxide into a prepped colon • computer reconstruction of 2D CT images into a 3D intraluminal view of the colon • lesions seen on 3D images correlated with 2D axial images • indications: surveillance in low-risk patients, incomplete colonoscopy, or staging of obstructing colonic lesions

Contrast Studies Table 10. Types of Contrast Studies Study

Organ

Procedure Description

Assessment

Findings

Cine Esophagogram

Cervical esophagus

Contrast agent swallowed Recorded for later playback and analysis

Dysphagia, swallowing incoordination, recurrent aspiration, post-operative cleft palate repair

Aspiration, webs (partial occlusion), Zenker’s diverticulum, cricopharyngeal bar, laryngeal tumour

Barium Swallow

Thoracic esophagus

Contrast agent swallowed under fluoroscopy, selective images captured

Dysphagia, rule out GERD, post-esophageal surgery

Achalasia, hiatus hernia, esophagitis, cancer, esophageal tear

Upper GI Series

Thoracic esophagus, stomach, and duodenum

Double contrast study: 1. Barium to coat mucosa 2. Gas pills for distention Patient NPO after midnight

Dyspepsia, investigate possible upper GI bleed, weight loss/ anemia, post-gastric surgery

Ulcers, neoplasms, filling defects

Enterography and Enteroclysis (MRI or CT)

Entire small bowel

Enterography: patient drinks 1-2 L of sorbitol, psyllium, or barium solution to distend small bowel Enteroclysis: NJ tube used to pump barium, psyllium, or sorbitol contrast media directly into small bowel

IBD, malabsorption, weight loss/anemia, Meckel’s diverticulum

Neoplasms, IBD, malabsorption, infection

Colorectal Cancer: CT Colonography and Colonoscopy for Detection-Systematic Review and Meta-Analysis Radiology 2011;259:393-405 Purpose: To assess the sensitivity of computed tomography (CT) colonography and optical colonoscopy (OC) for colorectal cancer (CRC) detection. Methods: Systematic review and meta-analysis of diagnostic studies evaluating CT colonography detection of CRC based on a priori eligibility criteria, in particular requiring both OC and histological confirmation of disease. Studies that also assessed true-positive and false-negative diagnoses with OC were used to calculate OC sensitivity. Sensitivity of CTC and OC for CRC was the main outcome. Results: 49 studies on 11,151 patients undergoing diagnostic study for detection of CRC were included. CTC has a sensitivity of 96.1% (95% CI 93.8%, 97.7%) and OC has a sensitivity of 94.7% (95% CI 90.4%, 97.2%) for the detection of CRC. Conclusion: CTC is highly sensitive for the detection of CRC and may be a better modality for the initial investigation of suspected CRC, assuming reasonable specificity.

MI14 Medical Imaging

Toronto Notes 2020

Abdominal Imaging

Specific Visceral Organ Imaging • for the management of urgent and emergent peritoneal masses, see, General Surgery, GS20 Liver • U/S: assessment of cysts, abscesses, tumours, biliary tree • CT ± IV: most popular procedure for imaging the liver parenchyma (primary liver tumours, metastases, cysts, abscesses, trauma, cirrhosis) • MR: also excellent in evaluation of primary liver tumours, liver metastases, other parenchymal conditions, and is particularly helpful in differentiating common benign hepatic hemangiomas from primary liver tumours and metastases • elastography: measures shear wave velocity by U/S (Fibroscan) or MRI (MR elastography) to noninvasively quantify liver fibrosis • findings: ■ advanced cirrhosis: liver small and irregular (fibrous scarring, segmental atrophy, regenerating nodules) ■ portal HTN: increased portal vein diameter, collateral veins, splenomegaly (≥12 cm), portal vein thrombosis, recanalization of the umbilical vein ■ porto-systemic shunts: caput medusae, esophageal varices, spontaneous spleno-renal shunt ■ U/S: cirrhosis appears nodular and hyperechoic with irregular areas of atrophy of the right lobe and hypertrophy of the caudate or left lobes ■ CT: fatty infiltration appears hypodense • in order to be visualized, some masses require contrast • upon identifying a liver lesion on imaging (e.g. U/S), the follow-up imaging modality should be CT or MR. CT would be four-phase non-contrast, arterial, venous, and delayed to distinguish the common benign liver lesion hemangioma from other tumours Table 11. Imaging of Liver Masses Mass

U/S

CT

Hepatic Adenoma

Well-defined mass with hyperechoic areas due to hemorrhage

Well-defined hypervascular lesion with enlarged central vessel becoming slightly isoattenuating in venous phase

Hemangioma

Homogeneous hyperechoic mass

Peripheral globular enhancement in arterial phase scans; central filling and persistent enhancement on delayed scans

Focal Nodular Hyperplasia

Well-defined mass, central scar seen in 50% of cases

Hypervascular mass in arterial phase and isoattenuation to liver in portal venous phase

Abscess

Ill-defined, irregular margin, hypoechoic contents

Low attenuation lesion with an irregular enhancing wall

Hydatid Cyst

Simple/multiloculated cyst

Low attenuation simple or multiloculated cyst; calcification

HCC

Single/multiple masses, or diffuse infiltration

Hypervascular; enhances in arterial and washes out in venous phase with portal venous tumour thrombus

Metastases

Multiple masses of variable echotexture

Usually low attenuation on contrast-enhanced scan

Benign

Malignant

Spleen • U/S, CT, nuclear medicine scan (nuclear medicine only to distinguish ectopic splenic tissue from enhancing tumours) • CT for splenic trauma (hemorrhage) Pancreas • tumours ■ U/S: mass is more echogenic than normal pancreatic tissue ■ CT: preferred modality for diagnosis/staging • ductal dilation secondary to stone/tumour ■ MRCP: imaging of ductal system using MRI cholangiography; no therapeutic potential ■ ERCP: endoscope to inject dye into the biliary tree and x-ray imaging to assess pancreatic and biliary ducts; therapeutic potential (stent placement, stone retrieval) ◆ acute pancreatitis is a complication in 5% of diagnostic procedures and 10% of therapeutic procedures Biliary Tree • U/S: bile ducts usually visualized only if dilated, secondary to obstruction (e.g. choledocholithiasis, benign stricture, mass) • CT: dilated intrahepatic ductules seen as branching, tubular structures following pathway of portal venous system • MRCP, ERCP, PTC: further evaluation of obstruction and possible intervention

Normal liver appears more dense than spleen on CT. If less dense, suspect fatty infiltration

Liver Mass DDx 5 Hs HCC Hydatid cyst Hemangioma Hepatic adenoma Hyperplasia (focal nodular)

Revised Estimates of Diagnostic Test Sensitivity and Specificity in Suspected Biliary Tract Disease Arch Intern Med 1998;154:2573-2581 Purpose: To assess the sensitivity and specificity of tests used to diagnose cholelithiasis and acute cholecystitis, including ultrasonography (U/S), oral cholecystography, radionucleotide scanning with Technetium, magnetic resonance imaging (MRI) or computed tomography (CT). Methods: Meta-analysis of studies evaluating the use of different imaging modalities in the diagnosis of biliary tract disease. Main outcomes were sensitivity and specificity of the different imaging modalities, using the gold standard of surgery, autopsy, or 3 mo clinical follow-up for cholelithiasis. For acute cholecystitis, pathologic findings, confirmation of an alternate disease, or clinical resolution during hospitalization for cholecystitis were used as the standard. Results: Thirty studies were included. For evaluating cholelithiasis, U/S had the best unadjusted sensitivity (0.97; 95% CI 0.95-0.99) and specificity (0.95, 0.88-1.00) and adjusted (for verification bias) sensitivity (0.84; 0.76-0.92) and specificity (0.99; 95% CI 0.97-1.00). For evaluating acute cholecystitis, radionucleotide scanning has the best sensitivity (0.97; 0.96-0.98) and specificity (0.90; 0.86-0.95). Conclusion: U/S is the test of choice for diagnosing cholelithiasis and radionucleotide scanning is the superior test for diagnosing acute cholecystitis.

E D

B Gallbladder

Liver C

A

Figure 20. ERCP: biliary tree (A) common bile duct (B) cystic duct (C) common hepatic duct (D) right hepatic duct (E) left hepatic duct

MI15 Medical Imaging

Abdominal Imaging

Toronto Notes 2020

“itis” Imaging Acute Cholecystitis • pathogenesis: inflammation of gallbladder resulting from sustained gallstone impaction in cystic duct, or in the case of acalculous cholechystitis, due to gallbladder ischemia or cholestasis (see General Surgery, GS52) • best imaging modality: U/S (best sensitivity and specificity); nuclear medicine (HIDA scan) can help diagnose cases of acalculous or chronic cholecystitis • findings: most sensitive findings are presence of gallstones and positive sonographic Murphy’s sign (tenderness from pressure of U/S probe over visualized gallbladder). Secondary findings include thickened gallbladder wall (>3 mm), dilated gallbladder, and pericholecystic fluid • management: admit, NPO, IVF, analgesia, cefazolin, and early laparoscopic cholecystectomy Acute Appendicitis • pathogenesis: luminal obstruction → bacterial overgrowth → inflammation/swelling → increased pressure → localized ischemia → gangrene/perforation → localized abscess or peritonitis (see General Surgery, GS32) • best imaging modality: U/S or CT • findings ■ U/S: thick-walled appendix, appendicolith, dilated fluid-filled appendix, non-compressible; may also demonstrate other causes of RLQ pain (e.g. ovarian abscess, IBD, ectopic pregnancy) ■ CT: enlargement of appendix (>6 mm in outer diameter), enhancement of appendiceal wall, adjacent inflammatory stranding, appendicolith; also facilitates percutaneous abscess drainage • management: admit, NPO, IVF, analgesia, cefazolin + metronidazole, and appendectomy Acute Diverticulitis • pathogenesis: erosion of the intestinal wall (most commonly rectosigmoid) by increased intraluminal pressure or inspissated food particles → inflammation and focal necrosis → micro- or macroscopic perforation (see General Surgery, GS36) • best imaging modality: CT, although U/S is sometimes used • contrast: oral and rectal contrast given before CT to opacify bowel • findings: ■ cardinal signs: thickened wall, mesenteric infiltration, gas-filled diverticula, abscess ■ CT can be used for percutaneous abscess drainage before or in lieu of surgical intervention ■ sometimes difficult to distinguish from perforated cancer (send abscess fluid for cytology and follow-up with colonoscopy) ■ if chronic, may see fistula (most common to bladder) or sinus tract (linear or branching structures) • management: ranges from antibiotic treatment to surgical intervention; can use imaging to follow progression Acute Pancreatitis • pathogenesis: activation of proteolytic enzymes within pancreatic cells leading to local and systemic inflammatory response (see Gastroenterology, G46); a clinical/biochemical diagnosis • best imaging modality: imaging used to support diagnosis and evaluate for complications (diagnosis cannot be excluded by imaging alone) ■ U/S good for screening and follow-up ■ CT is useful in advanced stages and in assessing for complications (1st line imaging test) • findings: ■ U/S: hypoechoic enlarged pancreas (if ileus present, gas obscures pancreas) ■ CT: enlarged pancreas, edema, fat stranding with indistinct fat planes, mesenteric and Gerota’s fascia (renal fascia) thickening, pseudocyst in lesser sac, abscess (gas or thick-walled fluid collection), pancreatic necrosis (low attenuation gas-containing non-enhancing pancreatic tissue), hemorrhage • management: supportive therapy ■ CT-guided needle aspiration and/or drainage of abscess when clinically indicated ■ pseudocyst may be followed by CT and drained if symptomatic Chronic Pancreatitis • pathogenesis: (see Gastroenterology, G48) • best imaging modality: MRCP (can show calcification and duct obstruction) • findings: U/S, CT scan, and MRI may show calcifications, ductal dilatation, enlargement of the pancreas and fluid collections (e.g. pseudocysts) adjacent to the gland

Gallbladder Stone with shadowing

Figure 21. Ultrasound: Longitudinal view of an inflamed Gallbladder. Arrow heads show thickened walls and pericholecystic fluid

Figure 22. Ultrasound: inflamed appendix

Computed Tomography and Ultrasonography to Detect Acute Appendicitis in Adults and Adolescents Ann Intern Med 2004;141:537-546 Purpose: To review the diagnostic accuracy of computed tomography (CT) and ultrasonography (U/S) in the diagnosis of acute appendicitis. Methods: Meta-analysis of prospective studies evaluating the use of CT or U/S, followed by surgical or clinical follow-up in patients with suspected appendicitis. Patients aged ≥14 yr with a clinical suspicion of appendicitis were eligible. Sensitivity and specificity using surgery or clinical follow-up as the gold standard were the main outcomes studied. Results: Twenty-two studies were included. CT (12 studies) had an overall sensitivity of 0.94 (95% CI 0.91-0.95) and a specificity of 0.95 (0.93-0.96). U/S (14 studies) had an overall sensitivity of 0.86 (0.83-0.88) and a specificity of 0.81 (0.78-0.84). Conclusion: CT is more accurate for diagnosing appendicitis in adults and adolescents, although verification bias and inappropriate blinding of reference standards were noted in the included studies.

MI16 Medical Imaging

Toronto Notes 2020

Genitourinary System and Adrenal

Angiography of Gastrointestinal Tract • anatomy of the arterial branches of the GI tract ■ celiac artery: hepatic, splenic, gastroduodenal, left/right gastric ■ superior mesenteric artery: jejunal, ileal, ileo-colic, right colic, middle colic ■ inferior mesenteric artery: left colic, superior rectal • imaging modalities ■ conventional angiogram: invasive (usual approach via femoral puncture), catheter used • flush aortography: catheter injection into abdominal aorta, followed by selective arteriography of individual vessels ■ CT angiogram: modality of choice, non-invasive using IV contrast (no catheterization required)

Angiography requires active blood loss 1-1.5 mL/min under optimal conditions for a bleeding site to be visualized in cases of lower GI bleeding

Genitourinary System and Adrenal Urological Imaging KUB (Kidney, Ureter, and Bladder X-ray) • a frontal supine radiograph of the abdomen • indication: useful in evaluation of radio-opaque renal stones (all stones types except for uric acid and indinavir), indwelling ureteric stents/catheters, and foreign bodies in abdomen • findings: addition of IV contrast excreted by the kidney (intravenous urogram) allows better visualization of the urinary tract, but has been largely replaced by CT urography Abdominal CT Renal Masses • Bosniak classification for cystic renal masses • class I-II: benign and can be disregarded • class IIF: should be followed • class III-IV: suspicious for malignancy, requiring additional workup

Imaging Modality Based on Presentation • Acute testicular pain = Doppler, U/S • Amenorrhea = U/S, MRI (brain) • Bloating = Plain film/CT (if abnormal) • Flank pain = U/S, CT • Hematuria = U/S, Cystoscopy, CT • Infertility = HSG, MRI • Lower abdominal mass = U/S, CT • Lower abdominal pain = U/S, CT • Renal colic = U/S, KUB, CT • Testicular mass = U/S • Urethral stricture = Urethrogram

NON CONTRAST

Table 12. Bozniak Classification for Cystic Renal Masses Classes

Definition

Simple Renal Cysts Class I

Fluid-attenuating well-defined lesion, no septation, no calcification, no solid components, hair thin wall

Class II

Same as class I + fine calcification or moderately thickened calcification in septae or walls; also includes hyperdense cysts (3 cm Complex Renal Cysts Class III

Thick irregular walls ± calcifications ± septated, enhancing walls or septa with contrast

Renal Cell Carcinoma Class IV

VENOUS

Same as class III + soft tissue enhancement with contrast (defined as >10 Hounsfield unit increase, characterizing vascularity) with de-enhancement in venous phase ± areas of necrosis

• plain CT KUB indications: general imaging of renal anatomy, renal colic symptoms, assessment of renal calculi (size and location) and potential sequalae (infection and obstruction), and hydronephrosis prior to urological treatment • CT urography indications: investigation of cause of hematuria, detailed assessment of urinary tracts (excretory phase), high sensitivity (95%) for uroepithelial malignancies of the upper urinary tracts, assessment of renal calculi ■ phases: unenhanced, excretory • renal triphasic CT indications: standard imaging for renal masses, allows accurate assessment of renal arteries and veins, better characterization of suspicious renal masses, especially in differentiating renal cell carcinoma from more benign masses, and pre-operative staging ■ phases: unenhanced, arterial and venous (nephrographic), excretory Ultrasound • indications: initial study for evaluation of kidney size and nature of renal masses (solid vs. cystic masses, simple vs. complicated cysts); modality of choice for screening patients with suspected hydronephrosis (no IV contrast injection, no radiation to patient, and can be used in patients with renal failure); TRUS useful to evaluate prostate gland and guide biopsies; Doppler U/S to assess renal vasculature • findings: solid renal masses are echogenic (bright on U/S), cystic renal masses have smooth welldefined walls with anechoic interior (dark on U/S), and complicated cysts have internal echoes within a thickened, irregular wall

Figure 23. Triphasic CT of an angiomyolipoma: showing fat density with non-contrast scan, mildly enhancing with contrast

MI17 Medical Imaging

Toronto Notes 2020

Genitourinary System and Adrenal

Retrograde Pyelography • indications: visualize the urinary collecting system via a cystoscope, ureteral catheterization, and retrograde injection of contrast medium, visualized by radiograph or fluoroscopy; ordered when the intrarenal collecting system and ureters cannot be opacified using intravenous techniques (patient with impaired renal function, high grade obstruction or allergy to IV contrast) • findings: only yields information about the collecting systems (renal pelvis and associated structures), no information regarding the parenchyma of the kidney Voiding Cystourethrogram • bladder filled with contrast to the point where voiding is triggered • fluoroscopy (continuous, real-time X-ray) to visualize bladder during voiding • indications: males or young females with recurrent UTIs, hydronephrosis, hydroureter, suspected lower urinary tract obstruction, suspected bladder trauma or vesicoureteral reflux • findings: evaluation of bladder contractility and evidence of vesicoureteral reflux Retrograde Urethrogram • a small Foley catheter placed into penile urethral opening, followed by instillation of contrast and radiographic imaging • indications: used mainly to study strictures or trauma to the male urethra; first-line study if trauma with blood present at urethral meatus, scrotal hematoma present or high-riding prostate (signs of urethral injury) MRI • advantages: better contrast resolution and tissue discrimination, lack of exposure to ionizing radiation, safer contrast, ability to obtain imaging directly from multiple planes (coronal, sagittal, oblique) • indications: indicated over CT for depiction of renal masses in patients with previous nephron-sparing surgery, patients requiring serial follow-up (less radiation dosage), patients with reduced renal function, patients with solitary kidneys, clinical staging of prostate cancer (endorectal coil MRI)

NON CONTRAST CT

ARTERIAL PHASE

VENOUS PHASE

Figure 24. Triphasic CT of a renal cell carcinoma: showing arterial enhancing right renal lesion with venous washout (shunting)

Renal Nuclear Scan Table 13. Renal Scan Tests Type of Test

Uses

Radionuclide

Renogram

Assess renal function and collecting system: evaluation of renal failure, workup of urinary tract obstruction and renovascular HTN, investigation of renal transplant

IV 99mTc-pentetate (DTPA) or mertiatide (MAG3), and imaged at 1-3 s intervals with a gamma camera over the first 60 s to assess perfusion

Morphological

Assess renal anatomy: investigation of pyelonephritis and cortical scars

99m

Tc-DMSA Tc-glucoheptonate

99m

Gynecological Imaging

Figure 25. Retrograde urethrogram: demonstrating stricture in the membranous urethra

Ultrasound • transabdominal and transvaginal are the primary modalities, and are indicated for different scenarios • transabdominal requires a full bladder to push out air-containing loops of bowel ■ indications: good initial investigation for suspected pelvic pathology • TVUS provides a panoramic pelvic view and enhanced detail of deeper/smaller structures by allowing use of higher frequency sound waves due to reduced distances ■ indications: improved assessment of ovaries, first trimester development, and ectopic pregnancy Hysterosalpingogram • performed by x-ray images of the pelvis after cannulation of the cervix and subsequent injection of opacifying agent • indications: useful for assessing pathology of the uterine cavity and fallopian tubes, evaluating uterine abnormalities (e.g. bicornuate uterus), or evaluation of fertility (absence of flow from tubes to peritoneal cavity indicates obstruction) CT/MRI • indications: evaluating pelvic structures, especially those adjacent to the adnexa and uterus • invaluable for staging gynecological malignancies and detecting recurrence Sonohysterogram • transcervical saline introduction into uterine cavity to provide enhanced endometrial visualization during TVUS examination • indications: abnormal uterine bleeding, uterine cavity abnormalities that are suspected or noted on TVUS (e.g. leiomyomas, polyps, synechiae), congenital abnormalities of the uterine cavity, infertility, recurrent pregnancy loss • contraindications: pregnancy, pelvic infection

Figure 26. Transabdominal U/S: pregnancy, 18 wk fetus

Pregnancy should always be ruled out by β-hCG before CT of a female pelvis (or any organ system) is performed

Figure 27. Hysterosalpingogram: left hydrosalpinx

MI18 Medical Imaging

Toronto Notes 2020

Neuroradiology

Table 14. Typical and Atypical Findings on a Sonohysterogram Finding

Typical

Atypical

Polyps

A well-defined, homogeneous, polypoid lesion isoechoic to the endometrium with preservation of the endometrialmyometrial interface

Cystic components, multiple polyps, broad base, hypoechogenicity or heterogeneity

Leiomyoma

Well-defined, broad-based, hypoechoic, solid masses with shadowing. Overlying layer of endometrium is echogenic and distorts the endometrial-myometrial interface

Pedunculation or multilobulated surface

Hyperplasia and Cancer

Diffuse echogenic endometrial thickening without focal abnormality, although focal lesions can occur. Endometrial cancer is typically a diffuse process, but early cases can be focal and appear as a polypoid mass

Adhesions

Mobile, thin, echogenic bands that cut across the endometrial cavity

Thick, broad-based bands that can completely obliterate the endometrial cavity, as in Asherman’s syndrome

Adrenal Mass

Modality Based on Neuropathology Presentation • Cognitive decline = CT • Cord compression = MRI • Decreased level of consciousness = CT • Fish bone/other swallowed foreign body = CT • Low back pain, radiculopathy = MRI • Multiple sclerosis = MRI • Neck infection = CT • Orbital infection = CT • Rule out bleed = CT • Rule out aneurysm = CTA, MRA • Seizure = CT • Sinusitis = CT • Stroke = CT, MRI • Trauma = CT • Weakness, systemically unwell = CT

• imaging modality: most often identified on CT scan as ‘incidentaloma,’ can also use CT/MRI to distinguish benign from malignant masses Table 15. Adrenal Mass Findings on CT and MRI Factors

Adrenocortical Adenoma

Adrenocortical Carcinoma

Pheochromocytoma

Metastasis

Diameter (CT)

Usually ≤3 cm

Usually ≥4 cm

Usually >3 cm

Variable around 40 yr ■ diagnosis usually requires a biopsy if primary not located ■ few benign tumours/lesions have potential for malignant transformation ■ MRI is good for tissue delineation and pre-operative assessment of surrounding soft tissues, neurovascular structures, and medullary/marrow involvement ■ plain film is less sensitive than other modalities but useful for assessing aggressiveness and constructing differential diagnosis Considerations and Tumour Characteristics • for specific bone tumours, see Orthopedic Surgery, OR46 • age: most common tumours by age group ■ 40 yr of age: metastases, multiple myeloma, and chondrosarcoma • multiplicity: metastases, myeloma, lymphoma, fibrous dysplasia, enchondromatosis • location within bone ■ epiphysis: giant cell tumour, chondroblastoma, geode, eosinophilic granuloma, infection ■ metaphysis: simple bone cyst, aneurysmal bone cyst, enchondroma, chondromyxoid fibroma, nonossifying fibroma, osteosarcoma, chondrosarcoma ■ diaphysis: fibrous dysplasia, aneurysmal bone cyst, brown tumours, eosinophilic granuloma, Ewing’s sarcoma

Figure 40. Rheumatoid arthritis (A) compared with osteoarthritis (B) X-ray findings

MI23 Medical Imaging

Toronto Notes 2020

Musculoskeletal System

• expansile ■ aneurysmal bone cyst, giant cell tumour, enchondromas, brown tumours, metastases (especially renal and thyroid), plasmacytoma • matrix mineralization ■ chondroid (popcorn calcification) or osseous • margin/zone of transition: area between lesion and normal bone • cortex: intact, disturbed • periosteal reaction: onion-skinning, sunburst, Codman’s triangle, periosteal neocortex • soft tissue mass Patterns of cortical disturbance Punched out Thin rim of sclerosis

Patterns of medullary destruction

Expansile

Periosteal new bone formation Onion-skin layered

Permeative

Codman's Triangle

Endosteal scalloping

Hair-on-end spiculated

Invisible margin Thick rim of sclerosis

Saucerization

Periosteal Reaction • “Onion skinning” = Ewing’s sarcoma • “Sunburst”, “hair on end” = osteosarcoma • “Codman’s triangle” = osteosarcoma, Ewing’s sarcoma, subperiosteal abscess

Sunburst divergent

Moth-eaten

Solid undulating

© Patrick Cervini 2002

Margination of lesions

Benign Lesions which may have Aggressive Features • Osteomyelitis • Osteoblastoma • Aneurysmal bone cyst • Langerhans cell histiocytosis • Myositis ossificans

Figure 41. Radiographic appearance of bone remodelling and destruction processes

Table 18. Characteristics of Benign and Malignant Bone Lesions Benign

Malignant

Thin sclerotic margin/sharp delineation of lesion Overlying cortex intact No or simple periosteal reaction No invasion of surrounding soft tissue

Poor delineation of lesion – wide zone of transition Loss of overlying cortex/bony destruction Periosteal reaction Invasion of surrounding soft tissue

Metastatic Bone Tumours • all malignancies have potential to metastasize to bone • metastases are 20-30x more common than primary bone tumours • metastasis can cause a lytic or a sclerotic reaction when seeding to bone • when a primary malignancy is first detected, a bone scan is often part of the initial workup • may present with pathological fractures or pain • biopsy or determination of primary is the only way to confirm the diagnosis • most common metastatic bone tumours: breast, prostate, lung, see Orthopedic Surgery, OR46

Lytic = decreased density Sclerotic = increased density

Table 19. Characteristic Bone Metastases of Common Cancers Lytic

Sclerotic

Expansile

Peripheral

“KLM flies to periphery”

Breast Lung Thyroid Kidney Multiple myeloma

Prostate Breast Lymphoma Lung Bowel Medulloblastoma Treated tumours

Thyroid Renal

Kidney Lung Melanoma (KLM: flies to the periphery)

Kidney Lung Melanoma

Infection Osteomyelitis • MRI is the imaging modality of choice for demonstrating bone, bone marrow, and soft tissue abnormalities • 99mTc, followed by 111In-labeled white cell scan or gallium radioisotope scan • plain film changes visible 8-10 d after process has begun ■ soft tissue swelling ■ local periosteal reaction ■ pockets of air (from anaerobes) may be seen in the tissues, may also suggest necrotizing fasciitis ■ mottled and nonhomogeneous with a classic “moth-eaten” appearance ■ endosteal scalloping ■ cortical destruction ■ peripheral sclerosis (late sign)

MI24 Medical Imaging

Toronto Notes 2020

Musculoskeletal System

Bone Abscess • overlying cortex has periosteal new bone formation • sharply outlined radiolucent area with variable thickness in zone of transition • variable thickness periosteal sclerosis • sequestrum: a piece of dead bone within a Brodie’s abscess (rare form of osteomyelitis on bone metaphyses) • a sinus tract or cloaca may communicate between the abscess through the cortex to the surface of the bone • best imaging modality: MRI for bone, bone marrow, and soft tissue abnormalities; CT for sequestra and cortical erosions

Metabolic Bone Disease Osteoporosis • reduction in amount of normal bone mass; fewer and thinner trabeculae; diffuse process affecting all bones • DEXA: gold standard for measuring bone mineral density ■ T-score: the number of standard deviations from the young adult mean, most clinically valuable ◆ osteopenia: –2.5< T-score 2 red cells per HPF >4 white cells per HPF

Bland Sediment = Less Likely Parenchymal Kidney Disease Only hyaline casts Small quantities of crystals Small amount of bacteria 4 WBCs per HPF • indicates inflammation or infection • if persistent sterile pyuria present (i.e. negative culture), consider: chronic urethritis, prostatitis, interstitial nephritis, calculi, allergic cystitis, interstitial cystitis, papillary necrosis, renal tuberculosis, viral infections, N. gonorrhoeae, C. trachomatis infection

Estimating Urine Osmolality Last 2 digits of the specific gravity x 30 = urine osmolality approximately (e.g. specific gravity of 1.020 = 600 mOsm)

24 h Urine Collection • Discard first morning specimen • Collect all subsequent urine for the next 24 h • Refrigerate between voids • Collect second morning specimen and take to lab immediately

Positive dipstick for leukocyte esterase and nitrites is highly specific for diagnosing a UTI

Nitrite Negative Bacteria • Enterococci • Staphylococci

Nitrite Positive Bacteria • Enterobacteriacae (e.g. E. coli)

NP7 Nephrology

Electrolyte Disorders

Toronto Notes 2020

Eosinophils • detected using Wright’s or Hansel’s stain (not affected by urine pH) • consider AIN, atheroembolic disease Oval Fat Bodies • renal tubular cells filled with lipid droplets • seen in heavy proteinuria (e.g. nephrotic syndrome) 2. CASTS • cylindrical structures formed by intratubular precipitation of Tamm-Horsfall mucoprotein; cells may be trapped within the matrix of protein Table 3. Interpretation of Casts Casts Hyaline casts RBC casts WBC casts Pigmented granular casts (heme granular casts, muddy brown) Fatty casts

Interpretation Physiologic (concentrated urine, fever, exercise) Glomerular bleeding (Proliferative GN, vasculitis) Infection (pyelonephritis) Inflammation (interstitial nephritis) ATN Acute proliferative GN Nephrotic syndrome (>3.5 g/d)

3. CRYSTALS • uric acid: consider acidic urine, hyperuricosuria, tumour lysis syndrome • calcium phosphate: alkaline urine • calcium oxalate: consider hyperoxaluria, ethylene glycol poisoning, nephrolithiasis • sulfur: sulfa-containing antibiotics

Urine Biochemistry • commonly measure: Na+, K+, Cl–, osmolality, and pH • spot urine more useful to assess renal physiology, 24 h urine collection more reflective of mineral balance • no “normal” values; electrolyte excretion depends on intake and current physiological state • results must be interpreted in the context of a patient’s current state, for example: 1. ECF volume depletion: expect low urine [Na+] (kidneys should be retaining Na+) ■ urine [Na+] >20 mmol/L suggests a renal problem or the action of a diuretic ■ urine [Na+]