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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
HUMAN PAPILLOMAVIRUS INFECTION
Verruca vulgaris shows exophytic growth with marked
hyperkeratosis, papillomatosis, and a prominent layer
of stratum granulosum. The underlying squamous
epithelium has bland cytologic features.
Viral Infections: Morphological Diagnosis of Viral Infections
TERMINOLOGY
Abbreviations
Human papillomavirus (HPV)
Definitions
Latin + Greek: "Papilla" (nipple) + "oma" (morbid
growth, tumor)
Latin: "Virus" (poison, slimy liquid, a potent juice)
Classification Systems
Bethesda system squamous intraepithelial lesion
(SIL) terminology for cytology &/or cervical biopsy
diagnosis
HPV typing for risk stratification
ETIOLOGY/PATHOGENESIS
Infectious Agents
Papillomavirus genus of Papillomaviridae family
HPV infects only humans
Other vertebrate mammals have papillomavirus
infections and associated tumors from different
species-specific strains
> 100 HPV types identified; ~ 40 types cause cutaneous
or mucosal infections based on tissue tropism
Pathogenesis
Highly epitheliotropic: Productive infections only
within stratified epithelia of skin, anogenital tract, and
oral cavity
Life cycle
Infects basal cells in epithelium; early HPV genes E1,
E2, E4, E5, E6, and E7 are expressed, and viral DNA
replicates from episomal DNA
Late genes L1, L2, and E4 are expressed in upper
I
epithelial layers
Expression of L1 and L2 encapsidate viral genomes
to form progeny virions in nucleus
1
Condyloma shows koilocytes characterized by
enlarged, hyperchromatic nuclei with smudgy chromatin
and clear perinuclear vacuoles (perinuclear halos).
Binucleation is occasionally seen.
Shed viruses then initiate a new infection
Persistent infection with high-risk HPV types may
progress to precancerous lesions and invasive cancer
13 high-risk/oncogenic HPV genotypes according to
WHO: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
and 66
Other studies have proposed that 15 HPV genotypes
are high-risk: HPV types 16, 18, 31, 33, 35, 39, 45, 51,
52, 56, 58, 59, 68, 73, and 82
Low-risk HPV types: 6, 11, 40, 42, 43, 44, 53, 54, 61,
72, 73, and 81
Coinfection with multiple HPV types can occur
Most infections are transient; studies suggest that
40-90% of cases clear within 1 year
It is unclear whether persistent HPV detection actually
represents continuing HPV infection or a state of
latent viral infection during which virus undergoes
intermittent reactivation
CLINICAL ISSUES
Epidemiology
Most common sexually transmitted infection in the
world
Anogenital infections and lesions
Cervix
HPV prevalence increases following sexual debut,
peaks at young reproductive age (~ 18-30 years),
followed by an age-related decline
Some studies report a 2nd but more modest peak
of prevalence in older women (~ 45-54 years, and
sometimes > 54 years)
Infection with any 1 of the high-risk/oncogenic
HPV types is a necessary but not sufficient cause
of cervical cancer
HPV DNA detected in up to 99.7% of cervical
cancers from all geographic areas
Other anogenital sites: Vagina, vulva, penis, anus
40
HUMAN PAPILLOMAVIRUS INFECTION
Etiology
Double-stranded DNA viruses
High-risk/oncogenic according to WHO: HPV types
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66
Persistent infection with high-risk HPV types may
progress to precancerous lesions and invasive cancer
Clinical Issues
Associated with majority of cancers in cervix,
vagina, anus, and in subset of cases in vulva, penis,
oropharynx
Cervical cancer constitutes the main burden of HPVrelated disease
Preventive vaccination against the most common
disease-causing HPV types (6, 11, 16, and 18) is
available
Key Facts
Ancillary Tests
p16 is generally positive in HPV-associated
precancerous and cancerous lesions
HPV in situ hybridization
HPV DNA tests
Diagnostic Checklist
Warts: Acanthosis, prominent vascular cores,
parakeratosis, hyperkeratosis (skin)
Low-grade dysplasia: Koilocytic changes (enlarged,
hyperchromatic nuclei with smudgy chromatin and
perinuclear halos) in superficial epithelial layers
High-grade dysplasia: Epithelium exhibits loss of
maturation, frequent mitoses, cells with high nuclear
to cytoplasmic ratio and irregular nuclear contour
Viral Infections: Morphological Diagnosis of Viral Infections
Model of pathogenesis is very similar to that of
cervical cancer
Vagina: HPV DNA is detected in 64-91% of cancers
and 82100% of their precursor lesions (most
common type: 16)
Vulva: Basaloid or warty squamous cell
carcinomas (SCCs) are 60-90% positive for HPV
(most common type: 16), while keratinizing SCCs
seen more often in older women are associated
with HPV infection in < 10% of cases
Penis: Basaloid or warty SCCs are up to 100%
positive for HPV (most common type: 16) while
keratinizing SCCs, which account for the majority
of penile cancers in Europe and America, show
lower HPV prevalence (~ 3040%)
Anus: Up to 90% of cases attributed to HPV (most
common types: 16 and 18)
Risk factors
Sexual behavioral risk factors including
unprotected sexual intercourse and increased
number of lifetime and recent sex partners
Immunocompromise, smoking,
Infection by other genital tract pathogens such as
Chlamydia trachomatis, certain viral factors such as
HPV viral load.
Other factors: Host hormonal status (e.g., long-
term oral contraceptive use) has been shown
to associate with risk of cervical cancer, but
findings on its relationship with HPV prevalence
or incidence have not been consistent among
studies
Oropharyngeal lesions
~ 60% of oropharyngeal SCC in USA, especially
of tonsils and base of tongue, are associated with
HPV (most common: Type 16, followed by type
18)
HPV-positive oropharyngeal cancers have been
on the rise, while HPV-negative cancers have
decreased over same time period in USA
More common in men than in women
Occur in a younger population than non-HPV-
associated cancers and are primarily associated
with sexual behavioral risk factors instead of
alcohol and tobacco use
Primary and secondary immunodeficiency disorders,
e.g., HIV infection, may predispose patients to HPV
infections and to development of malignancies
Presentation
Benign cutaneous lesions
Warts (common on hands and feet)
Anogenital tract: Flat condyloma, condylomata
acuminata (exophytic condyloma), often
multifocal; generally asymptomatic but bleeding
can occur
Skin: Verruca vulgaris
Deep plantar warts (myrmecia) are usually painful
Verrucous cysts: Rare benign epithelial cyst that
resembles a wart inverted into a cyst, associated with
HPV infection
Epidermodysplasia verruciformis (EV): Rare genetic
disorder
Specific mutations in TMC6 (EVER1) and TMC8
(EVER2) associate with repeated and persistent
HPV infection
HPV-induced wart-like skin lesions in childhood,
with malignant transformation during adulthood
in ~ 50% of cases
Benign mucosal lesions
Recurrent respiratory papillomatosis: Most common
benign laryngeal tumor in children
HPV acquired during passage through birth canal
of an infected mother
Oropharyngeal papillomas: Associated with HPV
types 6 and 11
Dysplasia/intraepithelial lesion
Low-grade squamous intraepithelial lesion (LSIL)
< 15% of LSIL progress to HSIL
High-grade squamous intraepithelial lesion (HSIL)
~ 10-20% progress to invasive cancer if left
untreated
Malignancies
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HPV-associated cervical cancer constitutes main
burden of HPV-related cancer
HPV infection is associated with cancer
development in majority of cases in vagina, anus,
and in subset of cases in vulva, penis, oropharynx
Currently no clinically approved tests for detection
of oropharyngeal HPV infection
Laboratory Tests
Seroreactivity is not useful for diagnosis of HPV, as
many women who are HPV DNA positive may have no
detectable antibodies
Treatment
Small warts can be removed with freezing or other
local treatments
Dysplasia and malignancy in anogenital region
must be screened for detection, as lesions are largely
asymptomatic
Prognosis
Viral Infections: Morphological Diagnosis of Viral Infections
Most warts are benign but are prone to recurrence
HPV-associated anogenital lesions can be managed
with screening, early detection, and removal
HPV-associated oropharyngeal cancers have better
prognosis than non-HPV-associated ones
In immunocompromised patients, clinical course may
be more aggressive
Prevention
Prior infection with HPV does not provide immunity
Bivalent (HPV types 16 and 18) and tetravalent (HPV
types 6, 11, 16, 18) preventive vaccines are available
and are recommended for teenagers before sexual
debut/HPV exposure
Good vaccine coverage should reduce risk of genital
HPV-associated lesions and may combat rapid rise of
oropharyngeal cancer
MICROBIOLOGY
Virus Characteristics
Nonenveloped double-stranded, circular DNA virus
55 nm in size, 10-200 virions per infected cell
8,000 bp genome with multiple open reading frames
producing 9 gene products
E1, E2, E4, E5, E6, E7 (viral regulatory proteins)
L1, L2 (viral capsid proteins)
Culture
There is no role for culture in routine diagnosis of HPV
MACROSCOPIC FEATURES
Warts
Small (1-2 mm) to large (4 cm) lesions on any
epithelial surface (most common is skin) with hard,
horny to soft, ropy surface
Dysplasia/Squamous Intraepithelial Lesion
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(SIL)
Acetowhite lesion or leukoplakia on colposcopy
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HUMAN PAPILLOMAVIRUS INFECTION
Malignancy
Early lesions may be flat or slightly raised
Large lesions can produce polypoid/fungating mass
MICROSCOPIC PATHOLOGY
Histologic Features
Anogenital lesions
Low-grade dysplasia/LSIL
Equivalent to condyloma, cervical intraepithelial
neoplasia 1 (CIN 1), vaginal intraepithelial
neoplasia 1 (VaIN 1), vulvar intraepithelial
neoplasia 1 (VIN 1), penile intraepithelial
neoplasia 1 (PIN 1), anal intraepithelial neoplasia
1 (AIN 1)
Koilocytic changes (enlarged, hyperchromatic
nuclei with smudgy chromatin and perinuclear
halos) in the superficial epithelial layers
Cell maturation preserved in upper 2/3 of
epithelium
Exophytic condyloma: Acanthosis with papillary
or verrucous architecture, prominent vascular
cores, parakeratosis, hyperkeratosis (skin)
High-grade dysplasia/HSIL
Equivalent to cervical intraepithelial neoplasia 2/3
(CIN 2/3), vaginal intraepithelial neoplasia 2/3
(VaIN 2/3), vulvar intraepithelial neoplasia 2/3
(VIN 2/3), penile intraepithelial neoplasia 2/3 (PIN
2/3), anal intraepithelial neoplasia 2/3 (AIN 2/3)
Loss of cellular maturation in lower 2/3 (grade 2)
to full-thickness (grade 3) epithelium
Immature cells with high N:C ratio, irregular
nuclear contour
Frequent mitoses; abnormal mitoses may be
present
Malignancies associated with HPV
Heterogeneity in cell type, growth type, and
degree of differentiation, depending on cancer site
and histologic subtype
e.g., cervix: Adenocarcinoma in situ and variants,
adenocarcinoma (e.g., usual type, villoglandular
type, endometrioid type), SCC and variants
e.g., anal/vaginal SCC, vulvar and penile SCC
(basaloid and warty)
HPV-associated oropharyngeal papillomas or
cancers
Papilloma: Papillary fronds, fibrovascular cores;
koilocytic changes may be present
Oropharyngeal SCC: Nonkeratinizing SCC is
often causally related to HPV while majority of
keratinizing SCC is unrelated to HPV
Skin lesion: Verruca vulgaris
Focal epidermal hyperplasia with hyperkeratosis,
parakeratosis, papillomatosis
Koilocytes in upper epithelial layers
Myrmecia (palmoplantar) warts show characteristic
intracytoplasmic inclusions in association with
ground-glass or basophilic nuclei in superficial
keratinocytes
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HUMAN PAPILLOMAVIRUS INFECTION
Viral Infections: Morphological Diagnosis of Viral Infections
Cytologic Features
LSIL
Nuclear enlargement > 3x size of normal nucleus
Common multinucleation and variable nuclear
hyperchromasia
Koilocytosis
HSIL
High N:C ratio and chromatin clumping
Hyperchromatic clusters, syncytial-like aggregates,
or single cells
Nuclear hyperchromasia and variations in nuclear
size and shape
Squamous cell carcinoma
Nonkeratinizing
Single cells or syncytial aggregates with poorly
defined cell borders
Coarsely clumped chromatin; nucleoli may be
seen
Tumor diathesis consisting of necrotic debris, old
blood, and inflammatory cells
Keratinizing
Marked variation in nuclear pleomorphism
Coarsely granular chromatin; nucleoli may be
seen
Tumor diathesis
ANCILLARY TESTS
Immunohistochemistry
Condyloma acuminatum/exophytic LSIL
p16: Weak or negative
Ki-67 (nuclear): Positive in lower 2/3 of epithelium
LSIL
p16: Diffusely weak or strong staining in basal layer
Ki-67 (nuclear): Positive in lower 2/3 of epithelium
HSIL
p16: Positive in full-thickness epithelium
Ki-67 (nuclear): Positive in full-thickness epithelium
Adenocarcinoma in situ and variants, cervix
p16: Generally positive
Squamous cell carcinoma, cervix
Positive for CK7, p63, and p16 (except verrucous
variant)
Adenocarcinoma, usual type, and other variants,
cervix
p16: Generally positive; except gastric type
(generally negative), and minimal deviation variant
(positivity seen in ~ 30% of cases)
HPV-associated oropharyngeal squamous cell
carcinoma
Positive for p16 and HPV in situ hybridization (ISH)
Significant minority of tumors are p16 positive and
HPV ISH negative
In Situ Hybridization
Useful for detecting HPV DNA in cytologic and
histologic samples
DIFFERENTIAL DIAGNOSIS
Differential Diagnosis for Warts
Malignancy: Distinguished by presence of severe
cellular atypia and tissue invasion
Verrucous carcinoma: No koilocytic changes; typically
p16 negative
Differential Diagnosis for LSIL
Reactive epithelial changes: p16 negative, while LSIL
shows positivity for p16
HSIL: Full-thickness positivity for Ki-67 and loss of
maturity, high cellular atypia; while LSIL maintains
cellular maturation in the upper 2/3 of the epithelium
and is positive for Ki-67 generally in the lower 2/3 of
the epithelium
Differential Diagnosis for HSIL
Atrophy in cervix: Nuclei in atrophy shows uniform
size and spacing with minimal nuclear pleomorphism
or mitotic activity
Radiation change in cervix: Uniformly spaced cells
with enlarged nuclei, low N:C ratio, absence of mitosis
Reactive epithelial changes: p16 negative, while HSIL
shows diffuse positivity for p16
Invasive squamous cell carcinoma: Irregular epithelialstromal interface, and loss of cell polarity in invasive
cancer
Differential Diagnosis for Squamous Cell
Carcinoma
Differential diagnoses vary by cancer site
In cervix
Florid squamous metaplasia with gland
involvement in cervix: Distinguished by absence
of nuclear atypia and mitoses
Placental site nodule: Exhibits no keratinization,
rare to absent mitoses, and positivity for inhibin
Small cell neuroendocrine carcinoma: Small cells
with scant cytoplasm, nuclear molding, mitoses,
and frequent apoptosis; p63(-) and chromogranin
and synaptophysin (+)
In anus/skin
Squamous cell carcinoma in situ: Not invasive
Verrucous carcinoma: Broad-based "pushing"
invasion with minimal cytologic atypia and rare
mitoses
Basosquamous carcinoma: Has areas of basal cell
carcinoma and SCC/atypical squamous cells, often
linked by a transition area
In oropharynx
Squamous cell carcinoma in situ: Not invasive
Verrucous carcinoma: Broad-based "pushing"
invasion, minimal cytologic atypia, and rare
mitoses
DIAGNOSTIC CHECKLIST
HPV DNA Testing
Cotesting (concurrent to Pap smear) in women aged
30-65 years
Clinically Relevant Pathologic Features
~ 15 HPV genotypes are considered high risk/
oncogenic
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HUMAN PAPILLOMAVIRUS INFECTION
Human Papillomavirus Types and Associated Lesions
Most Common HPV Type(s) Disease Association
1, 2, 4, 63 Plantar warts (soles of feet; painful, deep)
2, 7, 22 Common warts (hands and palms)
3, 8, 10 Flat warts
2, 3, 5, 8, 9, 10, 12, 14, 15, 17; types 5, 8, and 14d are most
commonly associated with malignant transformation
6, 11 Oropharyngeal papilloma
6, 11 Respiratory papillomatosis
16, 18 Oropharyngeal cancer
6, 11, 42, 44 Anogenital warts
6, 16, 18, 31, 53, 58 Anal dysplasia/intraepithelial lesion
16, 18 Anal cancer
6, 11 Condyloma acuminatum
16, 31, 6, 11 Low-grade squamous intraepithelial lesions
16, 18, 31, 52 High-grade squamous intraepithelial lesions
16, 18, 31, 45 Cervical, vulvar, penile cancers (squamous and adenocarcinoma): Highest risk; cervical
Viral Infections: Morphological Diagnosis of Viral Infections
Epidermodysplasia verruciformis (TMC6 and TMC8 gene mutations lead to HPV
susceptibility)
adenocarcinoma; most strongly associated with HPV-18; cervical squamous cell
carcinoma: Most strongly associated with HPV-16 and -18
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Vaccination against primary cancer-causing types
(6, 11, 16, and 8) should reduce risk of genital HPVassociated lesions and may combat rapid rise of
oropharyngeal cancer
Pathologic Interpretation Pearls
Warts: Acanthosis with papillary or verrucous
architecture, prominent vascular cores, parakeratosis,
hyperkeratosis (skin)
Low-grade dysplasia: Koilocytic changes seen in
superficial epithelial layers, minimal mitoses
High-grade dysplasia: Cytologic atypia and immature
cells with high nuclear:cytoplasmic ratio, irregular
nuclear contour, frequent mitoses
Malignancies associated with HPV vary with cell type,
growth type, and degree of differentiation; generally
p16(+)
SELECTED REFERENCES
1.
Grnhj Larsen C et al: Correlation between human
papillomavirus and p16 overexpression in oropharyngeal
tumours: a systematic review. Br J Cancer. 110(6):1587-94,
2014
2. Bzhalava D et al: A systematic review of the prevalence
of mucosal and cutaneous human papillomavirus types.
Virology. 445(1-2):224-31, 2013
3. Darragh TM et al: The Lower Anogenital Squamous
Terminology Standardization project for HPV-associated
lesions: background and consensus recommendations from
the College of American Pathologists and the American
Society for Colposcopy and Cervical Pathology. Int J
Gynecol Pathol. 32(1):76-115, 2013
4. Centers for Disease Control and Prevention (CDC):
Human papillomavirus-associated cancers - United States,
2004-2008. MMWR Morb Mortal Wkly Rep. 61:258-61,
2012
5. Gillison ML et al: Prevalence of oral HPV infection in the
United States, 2009-2010. JAMA. 307(7):693-703, 2012
6. Hariri S et al: Human papillomavirus genotypes in highgrade cervical lesions in the United States. J Infect Dis.
206(12):1878-86, 2012
7. D’Souza G et al: The role of HPV in head and neck cancer
and review of the HPV vaccine. Prev Med. 53 Suppl 1:S5S11, 2011
8. Lewis JS Jr et al: p16 positive oropharyngeal squamous cell
carcinoma:an entity with a favorable prognosis regardless
of tumor HPV status. Am J Surg Pathol. 34(8):1088-96,
2010
9. Patel T et al: Epidermodysplasia verruciformis and
susceptibility to HPV. Dis Markers. 29(3-4):199-206, 2010
10. Trottier H et al: Epidemiology of mucosal human
papillomavirus infection and associated diseases. Public
Health Genomics. 12(5-6):291-307, 2009
11. Insinga RP et al: A systematic review of the prevalence and
attribution of human papillomavirus types among cervical,
vaginal, and vulvar precancers and cancers in the United
States. Cancer Epidemiol Biomarkers Prev. 17(7):1611-22,
2008
12. Pinto AP et al: Biomarker (ProEx C, p16(INK4A), and
MiB-1) distinction of high-grade squamous intraepithelial
lesion from its mimics. Mod Pathol. 21(9):1067-74, 2008
13.
de Sanjos S et al: Worldwide prevalence and genotype
distribution of cervical human papillomavirus DNA in
women with normal cytology: a meta-analysis. Lancet
Infect Dis. 7(7):453-9, 2007
14. Woodman CB et al: The natural history of cervical HPV
infection: unresolved issues. Nat Rev Cancer. 7(1):11-22,
2007
15. World Health Organization International Agency for
Research on Cancer (IARC): IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans: Volume 90:
Human Papillomaviruses. Geneva: WHO Press. 87-189,
2007
16. Solomon D et al: The Bethesda System for Reporting
Cervical Cytology: Definitions, Criteria, and Explanatory
Notes. 2nd edition. New York: Springer, 67-156, 2004
17.
Muoz N et al: Epidemiologic classification of human
papillomavirus types associated with cervical cancer. N
Engl J Med. 348(6):518-27, 2003
18. Soyer HP et al: Verrucous cysts: histopathologic
characterization and molecular detection of human
papillomavirus-specific DNA. J Cutan Pathol. 20(5):411-7,
1993
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Gross Features
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Viral Infections: Morphological Diagnosis of Viral Infections
HUMAN PAPILLOMAVIRUS INFECTION
(Left) Condyloma
acuminatum appears as
a pink/brown polypoid
lesion, which may become
confluent with time.
(Courtesy L. Edwards,
MD.) (Right) Photo shows
a giant condyloma with
exophytic growth and
a "cobblestone" and
cauliflower-like appearance.
The lesion replaces most of
the distal penis. (From DP:
Genitourinary.)
(Left) Gross photo of this
vulvectomy specimen
shows a red, exophytic,
multinodular mass ,
which histology revealed
to be poorly differentiated
squamous cell carcinoma in
association with HSIL (VIN
2/3). (Right) Gross photo
shows an abdominoperineal
resection specimen from a
atient with perineal vulvar
invasive squamous cell
carcinoma in association
with VIN 3. Invasive cancer
manifests as a raised red/
ranular lesion .
(Left) Clinical photo shows
multiple pink flat scaly
apules in areas of
reviously treated warts on
hand dorsum. Histologic
examination confirms
recurrence of verruca
vulgaris. (Right) Gross
hoto of a tongue resection
specimen shows a white/
tan irregular firm lesion
with a central warty area.
Histologic examination
reveals verrucous carcinoma,
an entity of which only a
minority is positive for both
16 and HPV DNA, and
transcriptionally active highrisk HPV is uniformly absent.
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HUMAN PAPILLOMAVIRUS INFECTION
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Histology and Cytology
(Left) High magnification
of this myrmecia wart
(palmoplantar wart) shows
the characteristic large
intracytoplasmic inclusions
in association with
round-glass nuclei in
the superficial keratinocytes.
(Right) Medium magnification
of skin section shows verruca
vulgaris with superimposed
squamous dysplasia
in which loss of cellular
maturation, increased nuclear
size, hyperchromasia, and
irregular nuclear borders are
noted.
Viral Infections: Morphological Diagnosis of Viral Infections
(Left) Verrucous carcinoma
has a characteristic broad
ushing front of invasion,
shows no HPV koilocytic
changes, and is generally
negative for p16. Association
with invasive squamous cell
carcinoma can be present
and extensive sampling
should be done. (Right)
Condylomata acuminatum
typically shows papillomatous
epidermal hyperplasia
with hyperkeratosis ,
arakeratosis, fibrovascular
cores , broad regular
ushing borders, and
superficial koilocytotic atypia
.
(Left) Pap smear shows
atypical squamous cells
with enlarged nuclei,
irregular nuclear border,
and hyperchromasia.
One of the cells shows a
distinct perinuclear halo
. Findings are consistent
with LSIL. (Right) Medium
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magnification of cervix
shows LSIL characterized by
enlarged, hyperchromatic
nuclei with smudgy chromatin
and perinuclear halos.
Multinucleation and
increased cellular density
are common. Cell polarity is
enerally well preserved at the
base.
Cytology and Histology
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Viral Infections: Morphological Diagnosis of Viral Infections
HUMAN PAPILLOMAVIRUS INFECTION
(Left) Pap smear shows
a cell with enlarged,
hyperchromatic, irregularly
shaped nucleus and
abundant cytoplasm
consistent with LSIL. HSV
cellular changes including
multinucleated cells with
viral inclusions and ground-
lass nuclei are also
noted. (Right) Pap smear
shows HSV cellular changes
, as well as cells with
normal nuclear size but
irregular nuclear contour
and perinuclear halo
suggestive of possible HPV
infection. Biopsy shows no
SIL or neoplasm.
(Left) Cervical biopsy shows
squamous metaplasia
and epithelial changes
that mimic SIL but are
actually reactive changes in
tissue inflammation (with
crushed artifact ). Mature
lycogenated squamous
epithelium has no viral
changes. (Right) Cervical
biopsy reveals an inflamed
LSIL , confirmed by
ositive p16 stain. Subtle
koilocytic changes appear to
be present but nuclear atypia
can be difficult to confirm
on H&E in the setting of
inflammation.
(Left) High magnification of
ap smear shows atypical
cells with high nuclear to
cytoplasmic (N:C) ratio,
hyperchromasia, coarse
chromatin, irregular nuclear
membrane (occasional
nuclear grooves
indentation ), consistent
with HSIL. (Right) Cervical
biopsy shows crowded
cells with cytologic atypia
and loss of maturation
through the full thickness
of squamous epithelium,
consistent with HSIL. The
lesion would be diffusely
ositive for p16 and Ki-67
immunohistochemistry.
and
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HUMAN PAPILLOMAVIRUS INFECTION
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Immunohistochemistry, Cytology, and Histology
(Left) p16 immunostain
highlights the entire HSIL
lesion in this cervical biopsy.
(Right) HSIL cervical lesion
characteristically exhibits
mitotic activity through the full
thickness of epithelium, which
can be confirmed by positive
Ki-67 stain. Both the p16 and
Ki-67 immunostains are good
tools to differentiate HSIL from
its mimics, e.g., atrophy, when
diagnosis is challenging on
H&E sections.
Viral Infections: Morphological Diagnosis of Viral Infections
(Left) Pap smear shows HSIL
as a syncytial, hyperchromatic
cluster of cells with high
N:C ratio and irregular
nuclear contour. Part of the
cluster edge appears to be
flattened, suggesting possible
involvement of endocervical
land, which is confirmed on
concurrent biopsy. (Right)
Medium magnification of this
cervical biopsy reveals HSIL
involving a crypt gland
subjacent to the epithelial
surface.
(Left) Pap smear shows
squamous cell carcinoma
as a malignant cell cluster
with marked nuclear
leomorphism. Clinging
tumor diathesis is present
in the periphery of the
cluster. A malignant cell with
cytoplasmic keratinization
is noted. (Right) Pap smear
of this cervical keratinizing
squamous cell carcinoma
shows a bizarrely shaped
malignant cell that looks like
a tadpole. The background
is notable for tumor diathesis
consisting of necrotic debris
and inflammatory cells.
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HUMAN PAPILLOMAVIRUS INFECTION
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Cytology, Histology, and ISH
Viral Infections: Morphological Diagnosis of Viral Infections
(Left) Pap smear from a
atient with endocervical
adenocarcinoma (usual
type) and history of
abnormal Pap tests shows
a cluster of malignant
cells with overlapping
enlarged pleomorphic
nuclei, prominent nucleoli,
and irregular chromatin
distribution. (Right) Cervical
section of well-differentiated
adenocarcinoma (usual
type) shows packed,
irregularly spaced glands
with enlarged, crowded,
hyperchromatic nuclei. A
focus of lymphovascular
invasion is present.
(Left) Cervical section
shows endocervical
adenocarcinoma in
situ with enlarged,
hyperchromatic,
seudostratified nuclei
and minimal cribriform
architecture. No extension
below the level of normal
lands is noted. (Right)
Resection of this vocal
cord lesion reveals a
squamous papilloma
with hyperkeratosis
and prominent koilocytic
changes consistent with
HPV viral cytopathic effect.
(Left) Low magnification
of this tongue biopsy
shows well-differentiated
invasive nonkeratinizing
squamous cell carcinoma.
Follow-up work-up reveals
that the lesion is positive
for p16 and HPV in situ
hybridization (ISH). (Right)
High magnification of this
oropharyngeal squamous
cell carcinoma section on
HPV ISH shows positivity in
multiple intact cells .
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