Cytology: Diagnostic Principles and Clinical Correlates

659 Pages·2020·47.519 MB·English

by  M.D. Cibas, Edmund S., M.D. Ducatman, Barbara S.

Cytology
Diagnostic Principles and Clinical Correlates
Fifth Edition
Edmund S. Cibas, MD
Professor of Pathology
Harvard Medical School;
Director of Cytopathology
Department of Pathology
Brigham and Women’s Hospital
Boston, Massachusetts
Barbara S. Ducatman, MD
Chief, Pathology and Laboratory Medicine Service Line
Physician Executive, Beaumont Medical Group
Beaumont Health;
Chair of Pathology
Beaumont Hospital-Royal Oak
Royal Oak, Michigan;
Professor and Chair of Pathology
Oakland University William Beaumont School of Medicine
Rochester, Michigan
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
CYTOLOGY: DIAGNOSTIC PRINCIPLES AND CLINICAL CORRELATES,
FIFTH EDITION ISBN: 978-0-323-63636-0
Copyright © 2021 by Elsevier Inc. All rights reserved.
Previous edition copyrighted 2014.
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To Todd Bryant Stewart and Alan M. Ducatman
v
Contributors
Gamze Ayata, MD Christopher A. French, MD
Assistant Professor of Pathology Associate Professor of Pathology
Harvard Medical School; Harvard Medical School
Pathologist Brigham and Women’s Hospital
Beth Israel Deaconess Medical Center Boston, Massachusetts
Boston, Massachusetts
Vickie Y. Jo, MD
Kurt D. Bernacki, MD Assistant Professor of Pathology
System Medical Director, Surgical Pathology Brigham and Women’s Hospital
Beaumont Health; Harvard Medical School
Medical Director, Surgical Pathology Boston, Massachusetts
Beaumont Hospital- Royal Oak
Royal Oak, Michigan; Jeffrey F. Krane, MD, PhD
Assistant Professor of Pathology Professor of Pathology
Oakland University William Beaumont School of David Geffen School of Medicine at UCLA
Medicine Los Angeles, California
Rochester, Michigan
Amy Ly, MD
Edmund S. Cibas, MD Assistant Professor of Pathology
Professor of Pathology Harvard Medical School;
Harvard Medical School; Director of Fine Needle Aspiration Biopsy Service,
Director of Cytopathology Pathology
Brigham and Women’s Hospital Massachusetts General Hospital
Boston, Massachusetts Boston, Massachusetts
Barbara S. Ducatman, MD Vaishali Pansare, MD
Chief, Pathology and Laboratory Medicine Service Line Medical Director, Outreach
Physician Executive, Beaumont Medical Group Beaumont Health;
Beaumont Health; Chief of Pathology
Chair of Pathology Beaumont Hospital-Grosse Pointe and Beaumont
Beaumont Hospital-Royal Oak Hospital-Troy
Royal Oak, Michigan; Grosse Pointe and Troy, Michigan;
Professor and Chair of Pathology Associate Professor of Pathology
Oakland University William Beaumont School of Oakland University William Beaumont School of
Medicine Medicine
Rochester, Michigan Rochester, Michigan
William C. Faquin, MD, PhD Martha Bishop Pitman, MD
Professor of Pathology Professor of Pathology
Harvard Medical School Harvard Medical School;
Massachusetts General Hospital; Director of Cytopathology
Director, Head and Neck Pathology Massachusetts General Hospital
Massachusetts Eye and Ear Infirmary Boston, Massachusetts
Boston, Massachusetts
vi
Contributors vii
Xiaohua Qian, MD, PhD Paul E. Wakely, Jr., MD
Assistant Professor of Pathology Professor of Pathology
Harvard Medical School; The Ohio State University College of Medicine
Director, Fine-Needle Aspiration Biopsy Service Wexner Medical Center
Brigham and Women’s Hospital Columbus, Ohio
Boston, Massachusetts
Helen H. Wang, MD, DrPH
Andrew A. Renshaw, MD Professor of Pathology
Pathologist Harvard Medical School;
Baptist Hospital and Miami Cancer Institute Pathologist
Miami, Florida Beth Israel Deaconess Medical Center
Boston, Massachusetts
Marina Vivero, MD
Assistant Professor of Pathology Tad J. Wieczorek, MD
Harvard Medical School; Instructor in Pathology
Associate Pathologist Harvard Medical School;
Brigham and Women’s Hospital Pathologist
Boston, Massachusetts Brigham and Women’s Hospital
Boston, Massachusetts
Preface
We hope this book will serve as a useful guide for the diagnosis. We have retained the bulleted “capsule summa-
pathologist in practice and for the trainee—resident or fel- ries,” particularly for summarizing cytomorphologic features
low—who is looking to obtain expertise in the subspecialty and differential diagnoses. We have continued to emphasize
of cytopathology. It has been 6 years since the publication clinical correlation (hence, the title) because good cytolo-
of the fourth edition of Cytology: Diagnostic Principles and gists are those who understand the clinical implications of
Clinical Correlates. Since then, cytology has continued to their interpretations.
grow and evolve as a discipline devoted to the diagnosis A major enhancement of the prior edition was the inclu-
of cellular tissue obtained by minimally invasive methods sion of a dedicated chapter on fine-needle aspiration tech-
(e.g., scraping, brushing, aspiration), thus the need for this nique and specimen handling, accompanied by a video
updated edition. demonstration. This fifth edition is enhanced by a new
We have retained many of the qualities of the prior edi- chapter on bone cytology that we trust readers will find
tions. This edition again aims to be concise yet compre- useful.
hensive. We have emphasized brevity and clarity. The text Once again, we hope we have conveyed the beauty,
is grounded in an understanding of surgical pathology strength, and challenge of cytology. With this book we have
and current diagnostic terminology. Where relevant, we strived to take some of the mystery out of cytology, but
have illustrated the value of established ancillary studies. mysteries remain, their solutions still obscure. If this text
Although the book is multiauthored, the chapters follow a inspires the reader to explore and even solve some of them,
similar format: indications, sample collection and prepara- we will consider ourselves doubly rewarded.
tion methods, terminology for reporting results, accuracy
(including common pitfalls that lead to false-negative and Edmund S. Cibas, MD
false-positive diagnoses), a description of normal elements, Barbara S. Ducatman, MD
and, finally, a how-to guide for the diagnosis of benign 2019
and malignant lesions, with an emphasis on differential
viii
Acknowledgments
We owe a great debt to many individuals for their help with served as a resource for information set forth in this chap-
this book. ter. Readers who want more information on pathology cod-
To Bill Schmitt, Michael Houston, Lauren Klein, Anne ing can contact Ms. Cox (Cox Consulting) at brenda@cox
Snyder, Humayra Rahman Khan, and Kamatchi Madhavan consultant.onmicrosoft.com for information. Subscription
at Elsevier, who shepherded this book gently to completion: information for the Pathology Service Coding Handbook
a thousand thank-yous. You exemplified the spirit of team- can be obtained at www.apf-connect.org.
work, and we enjoyed working with each of you. We are indebted to many members of the staff of the
Maryann Kennedy’s administrative skills and hard work Brigham and Women’s Hospital and West Virginia Univer-
at the Brigham and Women’s Hospital contributed immea- sity School of Medicine and Hospital—the cytotechnolo-
surably to this edition. Thanks also to Sandy George and gists, cytopathologists, and trainees—who inspire us with
Deanna Reynolds at West Virginia University, who were their devotion to cytopathology and who continue to chal-
invaluable in providing their assistance. lenge us. In particular, we acknowledge Kristen DeRobbio,
We extend our thanks to Olga Pozdnyakova, MD, PhD, CT (ASCP), Dorothy Nappi, CT (ASCP), and Grace Goffi,
for her contributions to the video that accompanies Chapter CT, MIAC, who have helped us train so many pathology
8. We also thank Jessica L. Wang, MD, and Bonnie Choy, residents and fellows over the years. Without their help we
MD, for their assistance with the visual material for this would not have our extraordinary collections of cytology
chapter. Mark Rublee and David Sewell (Motion Video, teaching cases from which so many of the images in this
Philadelphia, Pa.), who shot and edited the video, were book are derived.
indispensable, and we thank them for the high standards Finally, to our friends, families, and loved ones, especially
and professionalism they brought to the project. Todd Stewart and Alan Ducatman, who tolerated the long
We are grateful to Dr. David Wilbur for his review, with evening and weekend hours that deprived them (temporar-
helpful suggestions, of the Automated Screening section of ily!) of a large share of our time. This book would not exist
Chapter 1. Ryan Callaghan, Global Product Manager for without their love, support, and strength.
Women’s Health & Cancer at BD Life Sciences, kindly con-
tributed the BD FocalPoint images in Chapter 1. Edmund S. Cibas
We express our deep appreciation to Brenda Cox of Cox Barbara S. Ducatman
Consulting for her help with the complexities of billing in
Chapter 19. Ms. Cox is editor of the American Pathology
Foundation’s Pathology Service Coding Handbook, which
ix
1
Cervical and Vaginal Cytology
EDMUND S. CIBAS
The 20th century witnessed a remarkable decline in the goes to George N. Papanicolaou, an anatomist and Greek
mortality from cervical cancer in developed countries, immigrant to the United States. In 1928 he reported that
an achievement attributable to the implementation malignant cells from the cervix can be identified in vaginal
of the Papanicolaou (Pap) test. In the 1930s, before Pap test smears.8 Later, in collaboration with the gynecologist Her-
screening was introduced, cervical cancer was the most com- bert Traut, who provided him with a large number of clinical
mon cause of cancer deaths in women in the United States.1 samples, Papanicolaou published detailed descriptions of pre-
Today it is not even in the top 10, but it has not been eradi- invasive cervical lesions.9,10 Pathologists and clinicians initially
cated; there are still approximately 13,000 new cases of cervi- greeted this technique with skepticism, but by the late 1940s
cal cancer in the United States each year, with 4000 deaths.2 Papanicolaou’s observations had been confirmed by others.
Worldwide, cervical cancer incidence (over 500,000 cases The Canadian gynecologist J. Ernest Ayre suggested taking
annually) and mortality (over 300,000 deaths per year) rank samples directly from the cervix with a wooden spatula rather
fourth, after breast, lung, and colorectal cancers.3,4 Indeed, than from the vagina with a pipette as originally described by
in some countries (e.g., those in sub-Saharan Africa), cervical Papanicolaou.11 Eventually, cytologic smears were embraced as
cancer remains the most common type of cancer in women. an ideal screening test for preinvasive lesions, which, if treated,
Unfortunately, screening programs are rudimentary or nonex- would be prevented from developing into invasive cancer.
istent in many parts of the world: fewer than 5% of women The first cervical cancer screening clinics in the United
in developing countries have ever had a Pap test.5 In contrast, States were established in the 1940s.12 Although it was not
89% of women in the United States report having had a Pap evaluated in a controlled, prospective study, several pieces
test in the preceding 5 years.6 of evidence link the Pap test to the prevention of cervical
Around the world, Pap test screening is implemented in cancer. First, the mortality rate from cervical cancer fell dra-
two different ways, commonly referred to as opportunistic ver- matically after screening was introduced, by 72% in Brit-
sus organized. An organized screening program is planned at the ish Columbia13 and 70% in Kentucky.14 Second, there was
national or regional level. It specifies a target population and a direct correlation between the intensity of screening and
screening intervals and has a mechanism for inviting women the decrease in mortality. Among Scandinavian countries,
to attend screening services, informing them of their result, the mortality rate fell by 80% in Iceland, where screening
and referring them for treatment. Opportunistic screening, the was greatest; in Norway, where screening was lowest, the
system in place in the United States, for example, is done inde- mortality rate fell by only 10%.15 A similar correlation was
pendently of an organized or population-based program, often observed in high and low screening regions of Scotland16
for women who are visiting health services for other reasons. and Canada.17 In the United States, the decrease in deaths
Screening is recommended during a consultation or requested from cervical cancer was proportional to the screening rates
by the woman. Opportunistic screening tends to reach younger, in various states.18 Finally, women who do not develop
lower-risk women who are attending family planning and ante- invasive cancer are more likely to have had a Pap test than
natal services. Organized screening is more cost-effective than women with cancer. In a Canadian study the relative risk for
opportunistic screening, making better use of available resources women who had not had a Pap test for 5 years was 2.7,19
and ensuring that the greatest number of women benefit. and screening history was a highly significant risk factor
independent of other factors such as age, income, education,
sexual history, and smoking. In Denmark a woman’s risk of
The History of the Pap Test and Its Current
developing cervical cancer decreased in proportion to the
Practice number of negative smears she had had: by 48% with just
one negative smear, 69% with two to four negative smears,
The Pap test is the most successful cancer reduction program and 100% with five or more smears.20 More recently, pro-
ever devised.1,7 Credit for its conception and development spective studies from Japan and Sweden have provided
1
2 CHAPTER 1 Cervical and Vaginal Cytology
additional evidence that the Pap test significantly reduces virus/acquired immunodeficiency syndrome have higher
the incidence of and mortality from cervical cancer.21,22 rates of cervical cancer than the general population, it is rec-
ommended that HIV-seropositive women have a Pap test
Screening Guidelines twice during the first year after diagnosis of HIV infection
and, if the results are normal, annually thereafter.26 Adher-
Cervical cancer screening guidelines differ around the world. ence to screening guidelines is critical for cervical cancer
In the United States, recommendations are issued by the prevention: in Sweden, for example, women who had not
American College of Obstetricians and Gynecologists,23 the had a Pap test within the recommended screening interval
US Preventive Services Task Force,24 and a consortium of had a higher risk of cervical cancer than those who had been
the American Cancer Society, the American Society for Col- screened (odds ratio 2.52).27
poscopy and Cervical Pathology (ASCCP), and the Ameri- Because of the strong association between HPV and
can Society for Clinical Pathology.25 Their guidelines differ cervical neoplasia (see “Squamous Intraepithelial Lesions”
in minor ways, but there is general agreement on the larger below), a test for high-risk HPV types can be used by itself
points, including longer screening intervals and a later age as an initial screen (so-called “primary HPV screening”). If
to start screening (age 21) than had been recommended in positive, partial genotyping (for HPVs 16 and 18) and Pap
the past (Table 1.1). For women 21 to 29 years of age, they cytologic study are performed; a referral to colposcopy is
recommend a Pap test every 3 years. For women between recommended if genotyping shows HPV 16 or 18, if the
ages 30 to 65, there are several options: a Pap test alone Pap cytology result is abnormal, or if a subsequent HPV
every 3 years; a test for high-risk types of the human papil- test shows persistence of virus.28 There is evidence that pri-
lomavirus (HPV) every 5 years; or a “cotest” (a Pap plus mary HPV screening is equivalent or superior to screening
an HPV test) every 5 years. The guidelines address women algorithms based on Pap cytologic study,29-31 and the US
with an average risk for cervical cancer. Women at higher Food and Drug Administration (FDA) has approved the
risk—those with a history of cervical cancer, in utero dieth- Roche cobas HPV Test and the BD Onclarity HPV Assay
ylstilbestrol (DES) exposure, and immunocompromise (due for primary HPV screening. The International Agency for
to organ transplantation, chemotherapy, long-term cortico- Research on Cancer and the World Health Organization
steroid treatment, or infection with the human immuno- have endorsed primary HPV testing, and in 2017 the Neth-
deficiency virus [HIV])—may benefit from more frequent erlands was the first country to implement it nationwide. 
screening. Because women with human immunodeficiency
Guidelines for Managing Women with
Abnormal Pap Results
TABLE Cervical Cancer Screening Guidelines in the
1.1 United States (for Women at Average Risk) In 2012, the ASCCP revised its guidelines for the manage-
ment of women with abnormal cervical cytologic study,
Circumstance Recommendation
HPV, and histopathologic results.32 These guidelines, men-
Age to begin Age 21. Women younger than age 21 tioned throughout this chapter in the relevant sections,
screening should not be screened, regardless
apply only to women whose abnormalities are detected dur-
of the age of sexual initiation
ing screening. Management is individualized for women
Women aged Every 3 years with cytology (liquid- with postcoital or unexplained abnormal vaginal bleeding,
21 to 29 based or smears) alone
pelvic pain, abnormal discharge, or a visible cervical lesion. 
Women aged Every 3 years with cytology alone, or
30 to 65 every 5 years with HPV, or every
HPV Vaccination
5 years with cytology and HPV
(“cotest”)
The development of prophylactic HPV vaccines has opened
Discontinuation Age 65 years if adequate prior a new opportunity for cervical cancer prevention. The vac-
of screening screening and no history of CIN
cines consist of empty protein shells called virus-like particles
2 or higher*
that are made up of the major HPV capsid protein L1; they
Screening Not recommended if no history of CIN contain no DNA and are not infectious. Two of the vaccines
after total 2 or higher
are Gardasil and Gardasil 9 (Merck & Co., Inc.). Gardasil is
hysterectomy
a quadrivalent vaccine against HPV types 6, 11, 16, and 18,
*ACOG and ACS/ASCCP/ASCP define “adequate prior screening” as and Gardasil 9 is a nine-valent vaccine against HPV types 6,
three consecutive negative cytology results or two consecutive negative 11, 16, 18, 31, 33, 45, 52, and 58. A third vaccine—Cervarix
cotest results within the previous 10 years, with the most recent test
(GlaxoSmithKline)—withdrew from the US market in 2016
performed within the past 5 years. “No history of CIN 2 or higher” defined
by ACS/ASCCP/ASCP as within the last 20 years. due to low market demand. They have all shown extraordi-
ACOG=American College of Obstetrics and Gynecology; ACS/ASCCP/ nary efficacy in preventing type-specific histologic CIN 2,3
ASCP= American Cancer Society/American Society for Colposcopy and
lesions, with no difference in serious adverse effects compared
Cervical Pathology/American Society for Clinical Pathology; CIN 2= cer-
vical intraepithelial lesion grade 2 with placebo.33,34 The American Cancer Society recommends
routine HPV vaccination for girls and boys ages 11 and 12