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xii Editors Biography
https://t.me/med1917
International Society of Gynecologic Pathologists
(ISGyP) Global Advisory Network, Officer-atLarge on the Board Committee of ISGyP, and
member of Financing Committee of ISGyP.
Dr. Stolnicu actively worked to finalize the Memorandum of Understanding (MoU) between the
ESP and ISGyP. She works as part of Project
ECHO, a joint educational venture of International Gynecologic Cancer Society and ISGyP,
serving as a pathology mentor through remote
sessions with cancer centers in Caribbean countries. She is also a member of the expert panel of
International Collaboration on Cancer Reporting
(ICCR) Carcinoma of the Cervix dataset and a
member of the Pathology National Committee in
Romania. She serves as a member of editorial
board and/or reviewer for many peer-reviewed
journals, has authored and coauthored more than
400 publications in indexed, peer-reviewed
journals, and is editor/author of 25 medical
books in the field of gynecologic and breast
pathology, including the 2020 WHO classification
of the female genital tract tumors.
Rouba Ali-Fehmi is a Professor of Pathology
and the Director of Breast Pathology and Breast
Pathology Fellowship at the University of Michigan. She is also a member of Global Reach at
Michigan Medicine and a member of the Center of
Global Health Equity at the University of Michigan. She previously acted as Vice Chair of the
Department of Pathology at Karmanos Cancer
Institute and Wayne State University, where she
also served as the Surgical Pathology Fellowship
Director. Dr. Ali-Fehmi serves as a UNICEF USA
Midwest board member and is an active member
of multiple national and international professional
societies. She is also the former president of the
Michigan Society of Pathologists (2012–2014).
Dr. Ali-Fehmi is very interested and dedicated
to teaching and research. Over the course of her
career, she has mentored many gynecologic
oncology and pathology fellows, which ultimately led to more than 140 peer-reviewed publications and presentations, both at national and
international meetings. Her research has received
many NIH grants in breast and GYN pathology.
Editors Biography xiii
https://t.me/med1917
She is also very active in the International
Academy of Pathology – Arab Division, where
she gives interactive lectures and workshops in
most Arab countries. Dr. Ali-Fehmi has served as
the liaison to the Middle East at the Global Health
Research Collaborative at Wayne State University, where in 2010, she established a Clinical
Training Research Associate (CTRA) program,
which empowers selected IMGs from predominantly middle- and lower-income Middle Eastern
countries by spending 1–2 years focusing on clinical scientific research. This CTRA program has
helped over 36 young doctors match into residency programs, all of whom went on to subsequently work and specialize in different locations
around the country and overseas.
Dr. Ali-Fehmi is also the former president of
the National Arab American Medical Association
(NAAMA) and the founder and current chair of
NAAMA NextGen. She has also pioneered many
research studies to investigate medical and healthrelated topics in the Arab American population,
including obesity in the Arab American population, the rate of HPV in Arab American women,
and COVID-19 vaccine attitudes among Arab
Americans which was presented at the White
House. Dr. Ali-Fehmi together with NextGen students has supported Syrian refugees’ education,
highlighted by the “Keys for Syrian Kids” project.
Series Editor Biography
https://t.me/med1917
J. H. J. M. van Krieken is a pathologist with
special expertise in the fields of hematopathology
and the pathology of the gastrointestinal tract. He
was Professor of Tumor Pathology since 1999 and
kept from 2005 to 2015 the Chair of Pathology at
the Radboud University Nijmegen Medical Centre in Nijmegen. He furthermore served as Chairman of the Board of the Oncology Institute of the
Radboud University, Nijmegen, from 2008 to
2016. From 2016 to 2023, he was the Rector
Magnificus (Vice Chancellor) of the Radboud
University. He was the Treasurer/Secretary of the
European Association for Hematopathology from
2000 to 2008, from 2003 to 2011 the Treasurer,
from 2013 to 2015 the President of the European
Society for Pathology (ESP), and from 2015 to
2017 the past-President of the ESP. Furthermore,
he coordinated the ESP quality assessment program from 2008 to 2018 and was the Chair of IQN
path from 2005 to 2008. He is (co)author of more
than 600 papers in peer-reviewed journals
(H-index 98), has written chapters in books on
pathology and oncology, is editor of a Dutch textbook on oncology, serves on the editorial board of
the American Journal of Surgical Pathology, was
Managing Editor of Virchows Archive from 2009
to 2015, and was the Chief Editor of the Journal of
Hematopathology from 2008 to 2018. Since 2011,
he is member of the German Academy of Sciences
Leopoldina, and since 2014 of Academia Europea
and Honorary Fellow of the Royal Society of
Pathology of Great Britain and Ireland.
xv
Contributors
https://t.me/med1917
Evi Abada Department of Pathology, Wayne State University School of
Medicine, Detroit, MI, USA
Nour Abd Almohsen Wayne State University, Detroit, MI, USA
Eman Abdulfatah University of Michigan, Ann Arbor, MI, USA
Rouba Ali-Fehmi Wayne State University, Detroit, MI, USA
Ghassan Allo Department of Pathology and Laboratory Medicine, Henry
Ford Health, Detroit, MI, USA
Noorah Almadani University of British Columbia, Vancouver, BC, Canada
Isabel Alvarado-Cabrero Department of Pathology, Mexican Oncology
Hospital, Mexico City, Mexico
Aleodor Andea Department of Pathology, University of Michigan, Ann
Arbor, MI, USA
Saimah Arif Princess Alexandra Hospital NHS Trust, Harlow, Essex, UK
Sudeshna Bandyopadhyay Detroit Medical Center, Wayne State University,
Detroit, MI, USA
Michaela Bártů Institute of Pathology, First Faculty of Medicine, Charles
University and General University Hospital, Prague, Czechia
Natalia Belova Palm Beach County Medical Examiner’sOffice, West Palm
Beach, FL, USA
Scott C. Bresler Pathology, University of Michigan, Ann Arbor, MI, USA
Laura Casey Department of Cellular Pathology, The Royal London Hospi-
tal, Barts Health NHS Trust, London, UK
Momal Chand Pathology, Ascension St. John Hospital, Detroit, MI, USA
Sonja Chen Department of Pathology and Laboratory Medicine, Nationwide
Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
Sarah Chiang Memorial Sloan Kettering Cancer Center, New York, NY,
USA
xvii
xviii Contributors
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Jennifer Crimmins Department of Pathology, Duke University Medical
Center, Durham, NC, USA
Fayez Daaboul Wayne State University/Detroit Medical Cen ters, Detroit,
MI, USA
Katelyn Dannheim Department of Pathology, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA
Ben Davidson Department of Pathology, Norwegian Radium Hospital, Oslo
University Hospital, Oslo, Norway
University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo,
Norway
Bojana Djordjevic Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences
Centre, Toronto, ON, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, ON, Canada
Pavel Dundr Institute of Pathology, First Faculty of Medicine, Charles
University and General University Hospital, Prague, Czechia
Raji Ganesan Birmingham Women’s and Children’s NHS Trust, Birming-
ham, UK
Nikola Hájková Institu te of Pathology, First Faculty of Medicine, Charles
University and General University Hospital, Prague, Czechia
Oudai Hassan Henry Ford Health System, Detroit, MI, USA
Lynn Hoang Anatomical Pathology, Vancouver General Hospital, Vancou-
ver, BC, Canada
University of British Columbia, Vancouver, BC, Canada
Sanam Husain Henry Ford Health System, Detroit, MI, USA
Deepti Jain Wayne State University, Detroit, MI, USA
Mir Yousufuddin Ali Khan Wayne State University, Detroit, MI, USA
Mira Kheil Department of Pathology, Wayne State University, Detroit, MI,
USA
Takako Kiyokawa Department of Pathology, The Jikei University School of
Medicine, Minato-ku, Tokyo, Japan
Andrew Kumar Wayne State University, Detroit, MI, USA
Nicholas R. Ladwig University of California – Sa n Francisco, San
Francisco, CA, USA
Nissreen Mohammad University of British Columbia, Vancouver, BC,
Canada
Contributors xix
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Kristýna Němejcová Institute of Pathology, First Faculty of Medicine,
Charles University and General University Hospital, Prague, Czechia
Vaishali Pansare Department of Pathology, Corewell Health East Beaumont
Troy and Grosse Pointe, Grosse Pointe, MI, USA
Department of Pathology and Laboratory Medicine, OUWB School of Medicine, Rochester, MI, USA
Vishakha Pardeshi Detroit Medical Centre, Detroit, MI, USA
Wayne State University, Detroit, MI, USA
Joseph T. Rabban University of California – San Francisco, San Francisco,
CA, USA
Maria Angelica Selim Department of Pathology, Duke University Medical
Center, Durham, NC, USA
Naveena Singh Department of Cellular Pathology, The Royal London Hospital, Barts Health NHS Trust, London, UK
Stephanie L. Skala Department of Pathol ogy, University of Michigan, Ann
Arbor, MI, USA
Simona Stolnicu Univers ity of Medicine, Pharmacy, Sciences and Technology “George E Palade” of Targu Mures, Targu Mures, Romania
Ivana Stružinská Institute of Pathology, First Faculty of Medicine, Charles
University and General University Hospital, Prague, Czechia
Tala Tawil Wayne State University, Detroit, MI, USA
Nairi Tchrakian Department of Cellular Pathology, The Royal London
Hospital, Barts Health NHS Trust, London, UK
Jason Wong Department of Cellular Pathology, East Suffolk and North
Essex NHS Foundation Trust, Ipswich, UK
Neeraja Yerrapotu Detroit Medical Center, Wayne State University, Detroit,
MI, USA
Feras Zaiem Detroit Medical Center/Wayne State University, Detroit, MI,
USA
A
https://t.me/med1917
Abnormal (Nonmolar) Villous
Lesions, Pathology of the
Placenta
Joseph T. Rabban
University of California – San Francisco, San
Francisco, CA, USA
Definition
Abnormal (nonmolar) villous lesion refers to a
spectrum of nonmolar settings (hydropic degeneration or nonmolar fetal aneuploidy) in which a
gestation exhibits chorionic villous architectural
alterations that mimic partial hydatidiform mole
(PHM) and/or early first trimester complete
hydatidiform mole (CHM) (Fig. 1).
Clinical Features
• Incidence
Unknown.
• Age
Unknown.
• Sex
Not applicable.
• Site
Not applicable.
• Treatment
None.
• Outcome
These are benign lesions. There is no known
increased risk for gestational trophoblastic dis-
ease compared to typical nonmolar gestations.
Macroscopy
The appearance of the chorionic villi may be
normal or may show mild to moderate
enlargement.
Microscopy
The chorionic villi exhibit a spectrum of enlargement and irregular shapes, including invaginations, trophoblastic inclusions, bulbous
projections, and cisterns. Some cases may be
accompanied by a mild degree of patchy villous
trophoblastic proliferation. Depending on the gestational age, fetal nucleated red blood cells may be
present in the villous blood vessels and/or other
fetal tissue may be present.
Immunophenotype
p57 immunostaining shows normal intact expression by the villous cytotrophoblast and villous
mesenchymal cells. This result dist inguishes
these lesions from early CHM but does not distinguish them from PHM.
© Springer Nature Switzerland AG 2023
S. Stolnicu, R. Ali-Fehmi (eds.), Gynecologic Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-030-97378-0
2 Adenocarcinoma and Precursors, Pathology of the Cervix
https://t.me/med1917
Abnormal (Nonmolar)
Villous Lesions,
Pathology of the
Placenta, Fig. 1 The
chorionic villi of this nonmolar gestation with fetal
aneuploidy exhibit irregular
contours and variable
enlargement that may
mimic molar pregnancy but
there is no trophoblast
proliferation or other classic
features of molar pregnancy
Molecular Features
Short tandem repeat genotype testing can be used
to exclude PHM (which is defined by diandric
triploid genotype) and CHM (which is defined
by diandric diploid genotype). Genotype testing
is not designed to formally diagnose karyotype
abnormalities, although some trisomies or monosomies may occasionally be detected, and therefore, while genotype testing is effective at
excluding a molar pregnancy from the differential
diagnosis, the results should not be expected to
provide a specific explanation for the etiology of
the nonmolar villous abnormalities.
Differential Diagnosis
CHM, PHM.
References
Colgan, T. J., Chang, M. C., Nanji, S., & Kolomietz,
E. (2017). DNA genotyping of suspected partial
Hydatidiform moles detects clinically significant aneuploidy. International Journal of Gynecological Pathol-
ogy, 36, 217–221.
Vang, R., Gupta, M., Wu, L. S., Yemelyanova, A. V.,
Kurman, R. J., Murphy, K. M., Descipio, C., &
Ronnett, B. M. (2012). Diagnostic reproducibility of
hydatidiform moles: Ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve
morphologic diagnosis. The American Journal of Sur-
gical Pathology, 36, 443–453.
WHO Classification of Tumours Editorial Board. (2020).
Female genital tumours. Lyon (France): International
Agency for Research on Cancer. (WHO classification
of tumours series, 5th ed.; vol. 4). https://publications.
iarc.fr/592.
Adenocarcinoma and
Precursors, Pathology of the
Cervix
Lynn Hoang
Anatomical Pathology, Vancouver General
Hospital, Vancouver, BC, Canada
University of British Columbia, Vancouver, BC,
Canada
HPV-Associated Adenocarcinoma In Situ
(AIS)
Synonyms
High-grade cervical glandular intraepithelial
neoplasia.
Definition
Noninvasive glandular dysplasia of the cervix,
caused by human papillomavirus (HPV) infection
(most commonly HPV 16 and 18).
Adenocarcinoma and Precursors, Pathology of the Cervix 3
https://t.me/med1917
Clinical Features
• Incidence
The incidence of AIS in the United States is
approximately 100–700 per 100,000 women
(Sherman et al. 2005).
• Age
The mean age is 35 years.
• Sex
Female.
• Site
AIS usually originates in the squamocolumnar
junction and proximal endocervical canal,
although some lesions can be located high up
in the endocervical canal or deep in the endocervical glands. Approximately 10–15% of
patients will have multifocal or “skip” lesions.
• Treatment
Patients diagnosed with AIS on biopsy or
endocervical curettage (ECC) will require an
excision (cold knife cone or loopelectrosurgical excision procedure [LEEP])
to remove the l es ion and exclude inva siv e
disease. A cold knife cone is wider and deeper
than a LEEP and provides for better margin
assessment, because LEEP margins can be
obscured by cautery. An ECC is usually
done after the cone or LEEP and is used to
reflect the margin status; a positive ECC is
considered a positive margin. For patients
who do not wish to retain fertility, hysterectomy is generally recommended. After hysterectomy, patients are followed with PAP
smears and HPV testing. In pregnant
women, excisions and ECC are discouraged
to avoid disruption of the pregnancy but can
be performed if there is a high clinical suspicion of invasive disease.
• Outcome
The risk of residual AIS, recurrent AIS, and
invasive adenocarcinoma is 2.6%, 20%, and
1%, respectively. If there are positive margins
after the cone or LEEP, the risks increase to
20%, 50%, and 5%, respectively (Salani
et al. 2009).
colposcopy, the findings are similar to those seen
in SIL but are more likely to involve the columnar
epithelium rather than the squamocolumnar junction. If lesions are higher up in the endocervical
canal, no lesion may be visible.
Microscopy
AISisaninsitulesion,andassuchitdoesnot
breach the basement membrane and retains normal
glandular architecture (Fig. 1).The cells are columnar and mucin deplete. The nuclei are pseudostratified, penicillate/fusiform, enlarged, and
hyperchromatic. Classically, apical (juxtaluminal)
mitotic figures and apoptotic bodies can be easily
appreciated (Fig. 2). AIS can show full or partial
gland involvement. Focal cribriform and papillary
intraglandular growth can be seen but tends to be
focal. More extensive complex architectural patterns or the presence of desmoplasia would prompt
a careful search for invasive adenocarcinoma.
Intestinal differentiation, in the form of Goblet
cells, Paneth cells, or enteroendocrine/argentaffin
cells, can be seen (Fig. 3). Ciliated AIS is rare but
can also occur. Accompanying high-grade squamous intraepithelial lesion (HSIL) is seen in
approximately half of cases.
Endocervical glandular dysplasia (EGD)
denotes lesions which have less convincing features for AIS (less nuclear atypia, mitoses, and
apoptotic bodies). The term is not used widely,
and in general, separation of lesions into benign or
A
Macroscopy
AIS is generally not visible on speculum examination and is usually detected via PAP smear. By
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 1 Adenocarcinoma in situ of the cervix.
Dysplastic columnar cells partially involve the endocervical gland and retain normal architecture
4 Adenocarcinoma and Precursors, Pathology of the Cervix
https://t.me/med1917
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 2 Adenocarcinoma in situ of the cervix. The
columnar cells are mucin deplete. The nuclei are pseudostratified, penicillate/fusiform, enlarged, and
hyperchromatic. Classical apical (juxtaluminal) mitotic figures and apoptotic bodies are easily appreciated
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 4 Adenocarcinoma in situ of the cervix,
showing block-like positivity for p16
Differential Diagnosis
Tubal and tuboendometrioid metaplasia appears
mucin deplete and thus can look relatively hyperchromatic on low-power examination. Higher
power examination will reveal ciliated, secretory,
and peg cells, akin to the fallopian tube. p16
shows a patchy “tiger-stripe” or “piano” pattern.
Endometriosis, reactive atypia including atypical oxyphilic metaplasia, and radiation atypia can
mimic AIS. These reactive lesions will show
patchy staining for p16 and ER positivity.
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 3 Adenocarcinoma in situ of the cervix.
Intestinal differentiation in the form of Goblet cells is seen
AIS is preferred rather than using this intermediary terminology.
Stratified mucin-producing intraepithelial
lesion (SMILE) is considered a form of AIS in
the most recent edition of the World Health Organization (WHO) Female Genital Tumors (5th Edition, 2020). See separa te section on SMILE for
details.
Immunophenotype
p16 shows block-like positivity, which can be
reduced in AIS that exhibits intestinal differentiation (Fig. 4). They show loss of staining for ER,
PR, vimentin, BCL2, and PAX2. ProEx C is positive (Negri et al. 2011).
Stratified Mucin-Producing
Intraepithelial Lesion (SMILE)
Synonyms
HPV-associated adenocarcinoma in situ.
Definition
A human papillomavirus (HPV)-associated preneoplastic lesion is thought to arise from pluripotent
reserve cells in the cervical transformation zone. In
the World Health Organization (WHO) 5th edition
classification, this is considered under the umbrella
of HPV-associated adenocarcinoma in situ.
Clinical Features
• Incidence
SMILE is a rare lesion, first described in 2000.
They constitute approximately 0.6–2.7% of
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