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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
POLYOMAVIRUS INFECTIONS
Solid (most common), trabecular, and diffuse
growth patterns
PML
Multifocal demyelination with relative axon sparing,
loss of oligodendrocytes, and macrophages in area of
demyelination
Cytologic Features
PVN
Intranuclear inclusions in tubular epithelium
MCC
Small round blue cells with large prominent nuclei
and scant cytoplasm
Nuclei with diffusely dispersed chromatin and
numerous mitoses
PML
Enlarged, glassy, dark-staining inclusions in
oligodendrocytes or cerebellar granule neurons
Viral Infections: Morphological Diagnosis of Viral Infections
ANCILLARY TESTS
Cytology
Decoy cells (urine): Enlarged nuclei with basophilic
nuclear inclusion
Creutzfeldt cells: Multinucleated reactive astrocytes
Immunohistochemistry
Antipolyomavirus Abs: SV40 large T antigen
MCC
Positive: Cytokeratin (AE1/AE3, CAM5.2, CK20)
and neuroendocrine markers (synaptophysin,
chromogranin A, neuron specific enolase)
Negative: Thyroid transcription factor 1, S100, CEA,
and lymphocyte markers
Immunofluorescence
PVN
Granular staining of tubular basement membranes
for IgG, C3, and C4d
Electron Microscopy
PVN
Virus particles (40-50 nm diameter) in epithelial cell
nuclei and cytoplasm
Marked interstitial inflammation, no intranuclear
inclusions, and negative polyomavirus IHC
MCC
Small cell lung cancer
IHC positive for TTF-1 and negative for CK20
Small cell malignant melanoma
IHC positive for S100 and negative for cytokeratin
Cutaneous lymphoma
IHC positive for lymphocyte markers and negative
for cytokeratin
Ewing sarcoma
IHC positive for CD99; FISH positive for t(11;22)
(q24;q12) (90%)
PML
Multiple sclerosis
No viral inclusions, IHC negative for JC virus,
more likely to affect spinal cord, optic nerve, and
immediate periventricular region
Infarct
No viral inclusions, ischemic neurons, loss of axons
and myelin, more cortical based
High-grade glioma
No viral inclusions, demyelination with macrophage
influx rare, cellular atypia more abundant
SELECTED REFERENCES
1. Czapiewski P et al: Merkel cell carcinoma - Recent advances
in the biology, diagnostics and treatment. Int J Biochem
Cell Biol. Epub ahead of print, 2014
2. Hughes MP et al: Merkel cell carcinoma: epidemiology,
target, and therapy. Curr Dermatol Rep. 3:46-53, 2014
3. Berger JR et al: PML diagnostic criteria: consensus
statement from the AAN Neuroinfectious Disease Section.
Neurology. 80(15):1430-8, 2013
4. Dalianis T et al: Human polyomaviruses in disease and
cancer. Virology. 437(2):63-72, 2013
5. DeCaprio JA et al: A cornucopia of human polyomaviruses.
Nat Rev Microbiol. 11(4):264-76, 2013
6. Gheuens S et al: Progressive multifocal
leukoencephalopathy: why gray and white matter. Annu
Rev Pathol. 8:189-215, 2013
7. Kuypers DR: Management of polyomavirus-associated
nephropathy in renal transplant recipients. Nat Rev
Nephrol. 8(7):390-402, 2012
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DIFFERENTIAL DIAGNOSIS
PVN
Acute tubulointerstitial rejection (type 1)
Prominent interstitial inflammation and tubulitis
with negative polyomavirus IHC
Adenovirus tubulointerstitial nephritis
Prominent interstitial inflammation, viral
cytopathic effect, and necrosis with negative
polyomavirus IHC
Acute tubular necrosis
Nuclear enlargement and reactive atypia of tubular
epithelium, no prominent interstitial inflammation,
no inclusions, and negative polyomavirus IHC
Acute interstitial nephritis
POLYOMAVIRUS INFECTIONS
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Light and Electron Microscopy
Viral Infections: Morphological Diagnosis of Viral Infections
(Left) This section of kidney
shows several nuclei with
the characteristic cytopathic
effect of polyomavirus
infection. (From DP:
Kidney.) (Right) High-power
electron micrograph of a
tubular epithelial cell nucleus
shows a cluster of polyoma
virions measuring ~ 50 nm.
(From DP: Kidney.)
(Left) A segment of
ureter shows mucosal
inflammation and urothelial
cells with basophilic
nuclear inclusions
indicative of polyomavirus
infection. (Right)
Immunohistochemical
staining of urothelium
with SV40 large T antigen
highlights urothelial cells
ositive for polyomavirus
infection.
(Left) Merkel cell carcinoma
consists of expansile dermal
nodules with subepidermal
aggregates of tumor
cells. The most common
rowth pattern is solid,
followed by trabecular and
diffuse. (Right) Merkel cell
carcinomas consist of small
round blue cells with large
rominent nuclei, diffusely
dispersed chromatin, and
scant cytoplasm. Numerous
mitoses are present .
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Microscopic, Imaging, and Gross Features
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(Left) Merkel cell carcinoma
is present in a solid growth
attern consisting of small
round blue cells. (Right)
CK20 immunohistochemistry
is positive in Merkel cell
carcinomas and negative in
small cell lung carcinoma.
Viral Infections: Morphological Diagnosis of Viral Infections
(Left) Chromogranin A
immunohistochemistry
is positive in Merkel
cell carcinomas.
(Right) Synaptophysin
immunohistochemistry
is positive in Merkel cell
carcinomas.
POLYOMAVIRUS INFECTIONS
(Left) Axial T2WI MR from a
atient with PML shows focal
area of hyperintensity with
mild mass effect and patchy
internal enhancement in the
subcortical white matter of
the posterior frontal lobe.
(Right) Coronal section of
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right posterior frontal lobe
of an autopsied brain shows
the biopsy site , as well as
unctate and larger confluent
ray plaques in the subcortical
white matter
Folkerth, MD.)
. (Courtesy R.
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Microscopic Features
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Viral Infections: Morphological Diagnosis of Viral Infections
POLYOMAVIRUS INFECTIONS
(Left) Brain biopsy from a
PML patient shows a few
erivascular lymphocytes,
extensive macrophage
infiltrates, and disruption
of normal architecture.
(Courtesy R. Folkerth, MD.)
(Right) Macrophages and
lial cells contain "smudgy"
nuclear inclusions .
Occasional enlarged and
bizarre astrocytes are present
. (Courtesy R. Folkerth,
MD.)
(Left) Luxol fast blue (myelin)
and PAS stain shows area
of myelin loss. (Courtesy
R. Folkerth, MD.) (Right)
Immunohistochemistry
for polyomavirus shows
ositivity in glial nuclei
corresponding to the
"smudgy" change seen on
H&E. (Courtesy R. Folkerth,
MD.)
(Left) Macrophages contain
a small amount of LFB(+)
debris (blue) . (Courtesy
R. Folkerth, MD.) (Right)
Bodian silver impregnation
for axons shows relative
reservation of axons
in demyelinated area.
(Courtesy R. Folkerth, MD.)
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POX VIRUS INFECTIONS
A historic photograph of a patient with smallpox is
shown with the characteristic raised papules and central
umbilication. Note several areas where the lesions are
coalescing. (Courtesy J. Hicks, CDC PHIL.)
Viral Infections: Morphological Diagnosis of Viral Infections
TERMINOLOGY
Abbreviations
Vaccinia virus (VACV or VV)
Molluscum contagiosum virus (MCV)
Synonyms
Smallpox = variola, pox, red plague
Vaccinia = cowpox (ambiguous)
Definitions
English/German: "Pox," from "pock" or "pocc" (swell
up, blow up)
Pox (such as "smallpox") have "pus-filled, skin-eruptive
swellings"
Latin: "Variola," "varius," or "varus" (spotted or pimple)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Poxviridae: Largest of the DNA viruses
Orthopox group
Smallpox virus (variola): Eradicated (1977)
Vaccina (similar to cowpox)
Monkeypox virus
Parapox group
Pseudocowpox, orf, bovine papular stomatitis
virus
Yatapox group
Tanapox virus, Yaba monkey tumor virus
Molluscipox group
Molluscum contagiosum virus
Replicate within cytoplasm of host cell
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Scattered molluscum contagiosum papules of various
sizes and ages are shown on the skin. In the early stages,
they may be confused with the vesicles of herpesvirus
infection.
CLINICAL ISSUES
Epidemiology
Vaccina-related complications occur in those
vaccinated for smallpox with vaccina virus
Monkeypox occurs primarily in Central Africa
Molluscum contagiosum occurs worldwide
Presentation
Vaccina
Generalized vaccinia
Generalized pustular eruption of skin ~ 1 week
following vaccination (rare)
Eczema vaccinatum
Severe widespread eruption of crusting skin rash
Follows exposure to vaccination or vaccinated
individual
Occurs in patients with history of eczema or
atopic dermatitis
Progressive vaccinia
Vaccinia gangrenosum or vaccinia necrosum
Progressive painless skin lesions with ulceration
and necrosis (rare)
Roseola vaccina
Post-vaccination site erythematous halo
Jennerian pustule
Occurs at site of vaccination at 5 days and
becomes pustular at 10 days
Associated with fever and lymphadenopathy
Generates B- and T-cell responses, which are key
to prevention of smallpox
Cross protection against cowpox and monkeypox
Monkeypox
Incubation period after exposure is 10-14 days
Cutaneous skin outbreak of vesicular lesions
(similar to smallpox in appearance) but with
lymphadenopathy
Exposure to infected animals by caretaking,
slaughter/ingestion, or proximity
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POX VIRUS INFECTIONS
Etiology
Orthopox
Vaccinia (similar to cowpox), monkeypox virus
Molluscipox
Molluscum contagiosum virus
Clinical Issues
Vaccinia-related complications occur in those
vaccinated for smallpox with vaccinia virus
Monkeypox occurs primarily in Central Africa
Molluscum contagiosum occurs worldwide
Eczema vaccinatum: Occurs in patients with history
of eczema or atopic dermatitis
Monkeypox: Cutaneous skin outbreak of vesicular
lesions (similar to smallpox in appearance) but with
lymphadenopathy
Human-to-human transmission may occur (10%) in
low-resource settings
Secondary bacterial skin infections (~ 20% in
unvaccinated patients)
Molluscum contagiosum
Incubation period can be from 2 months and as
long as 6 months
Small fleshy papules with depressed centered in
exposed areas of skin (genitals, arms and legs)
May report spread from contacted sites secondary to
disruption
Treatment
Vaccinia
Vaccinia immunoglobulin (VIG)
Cidofovir and adefovir (second-line for VIG failure,
investigational)
Monkeypox
Although no treatment exists, smallpox vaccination
may prevent infection by monkeypox virus and
reduces complications
Molluscum contagiosum
Cryotherapy, which may be painful but removes
lesions
Topical creams (not 100% effective)
Cimetidine (children)
Lesions can resolve spontaneously in 6-9 months
Prognosis
Variola
Eczema vaccinatum: May be fatal if not recognized
and treated immediately
Monkeypox
Mortality may be 10% in low-resource settings but is
usually nonfatal in developed nations
Molluscum contagiosum
Self-limited to diffuse skin dissemination
May be difficult to eradicate but no mortality
Key Facts
Microscopic Pathology
Pocks of vaccinia, smallpox, monkeypox
Molluscum contagiosum
Top Differential Diagnoses
Vaccinia, monkeypox, smallpox
HSV, VZV
MICROBIOLOGY
Variola
Enveloped, linear, double-stranded DNA virus
190 kb with 250 genes
Agent used for smallpox eradication with > 10 strains
used in research and vaccination settings
Monkeypox
Enveloped, linear, double-stranded DNA virus
197 kb with 190 genes
Virus is very similar to smallpox virus
Molluscum Contagiosum
Enveloped, linear, double-stranded DNA virus
4 subtypes (MCV-1 to MCV-4), with MCV-1 being
most common
190 kb with 182 genes
Although in different genera, similar to orf (sheep
poxvirus)
MACROSCOPIC FEATURES
Cutaneous Pox
Pox virus infections appear very similar clinically
with distribution and history being important
distinguishing factors
A "pock" or "pox" appears as a raised papule or pustule,
sometimes with a central umbilication
Variola/monkeypox may be disseminated
Mollusca contagiosa are usually distinct individual or
clusters of lesions
Viral Infections: Morphological Diagnosis of Viral Infections
Distinct fluid-filled vesicle with increased
inflammation
Cellular changes include enlargement and pink to
purple homogeneous nuclei (viral inclusions)
These 3 entities are within the differential
diagnoses of each other
May produce scattered vesicles to disseminated
vesicles and pustules
In vaccinia/variola/monkeypox, evolution of lesion
with loss of fluid and influx of neutrophils
In molluscum contagiosum, central depression from
necrosis of epithelial cells
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POX VIRUS INFECTIONS
V
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MICROSCOPIC PATHOLOGY
Histologic Features
Type-A viral inclusions (seen in cowpox among
human infections)
Large eosinophilic bodies appearing late in infection
cycle composed of a solitary protein (A-type
inclusion protein) that has embedded viral particles
and provides environmental protection
Type B (Guarnieri bodies)
Pink blobs in cytoplasm of smallpox or vacciniainfected epithelium
Pocks of vaccina, smallpox, parapox, and monkeypox
Endothelial cell activation with lymphocytes/
histiocytes/plasma cell infiltrate
Progresses to dilated vessels, edema, and epithelial
expansion (early vesicle)
Distinct fluid-filled vesicle with increased
inflammation
Viral Infections: Morphological Diagnosis of Viral Infections
Becomes pustule when neutrophils infiltrate
Ulceration (loss of vesicle) with inflammation
Ends with reepithelialization and scarring
Molluscum contagiosum
Hyperplasia of epidermis with necrosis of central
cells creates cup-shaped lesion
Cellular changes include enlargement and pink to
purple homogeneous nuclei
Lack of inflammation unless lesions have been
previously disturbed or disrupted
HSV, VZV
May produce scattered vesicles to disseminated vesicles
and pustules
Usually occurs in immunosuppressed patients &/or
unvaccinated children
Viral cytopathic effect in biopsy (classic herpetic
changes), which are distinct from molluscum
Other Vesicle-Forming Skin Diseases
Clinical history of exposure to vaccine, travel, or close
contact
Ancillary tests for blistering disease
(immunofluorescence)
Layer of separation in vesicle formation
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
History of vaccination (vaccinia vs. smallpox vs.
monkeypox)
History of exposure
Pathologic Interpretation Pearls
Vesicles or pustules occurring without viral cytopathic
effect in either vaccinated (vaccinia) or monkeypoxexposed Central African patients
Presence of Henderson-Patterson bodies (epithelial
cell ghosts), which are intact or part of an ulcer
(molluscum contagiosum)
Cytologic Features
Henderson-Patterson bodies are epithelial cell ghosts
Swollen squamous epithelial cells with large glassy
nuclei (viral inclusions)
ANCILLARY TESTS
accinia
History of vaccination or exposure is usually sufficient
to suspect diagnosis
May be confirmed with PCR, culture (of pock), or
direct fluorescent antibody testing for antigen (of pock
or vaccination site)
Monkeypox
Viral culture and isolation
PCR
DIFFERENTIAL DIAGNOSIS
accinia, Monkeypox, Smallpox
These 3 entities are within the differential diagnoses of
each other
Careful clinical history including exposure and
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vaccination history are paramount
Electron microscopy, immunohistochemistry, and
antiviral IgM and IgG cannot distinguish monkeypox
from smallpox
SELECTED REFERENCES
1. Kastenmayer RJ et al: Elimination of A-type inclusion
formation enhances cowpox virus replication in mice:
implications for orthopoxvirus evolution. Virology.
452-453:59-66, 2014
2. McCollum AM et al: Human monkeypox. Clin Infect Dis.
2014 Jan;58(2):260-7. Epub 2013 Oct 24. Review. Erratum
in: Clin Infect Dis. 58(12):1792, 2014
3. Cann JA et al: Comparative pathology of smallpox and
monkeypox in man and macaques. J Comp Pathol.
148(1):6-21, 2013
4. Chen X et al: Molluscum contagiosum virus infection.
Lancet Infect Dis. 13(10):877-88, 2013
5. Reynolds MG et al: Outbreaks of human monkeypox
after cessation of smallpox vaccination. Trends Microbiol.
20(2):80-7, 2012
6. Damon IK: Status of human monkeypox: clinical disease,
epidemiology and research. Vaccine. 29 Suppl 4:D54-9,
2011
7. Connell CO et al: Congenital molluscum contagiosum:
report of four cases and review of the literature. Pediatr
Dermatol. 25(5):553-6, 2008
8. Huynh W et al: Post-vaccination encephalomyelitis:
literature review and illustrative case. J Clin Neurosci.
15(12):1315-22, 2008
9. Brown J et al: Childhood molluscum contagiosum. Int J
Dermatol. 45(2):93-9, 2006
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Microscopic Features
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Viral Infections: Morphological Diagnosis of Viral Infections
POX VIRUS INFECTIONS
(Left) A collection of
apules in molluscum
contagiosum is shown,
which appear to coalesce.
Spread of these lesions
may occur by disruption or
scratching to adjacent or
other body sites. (Right) An
early lesion of molluscum
contagiosum demonstrates
a small nodule arising in
the skin with a collar of
inflammation and very
early formation of epithelial
cell ghosts . At this stage,
the clinical appearance may
be nonspecific.
(Left) A well-developed
lesion of molluscum
contagiosum is shown
with a large, central, cupshaped body containing
hyperplastic epithelium
and ghosts cells ,
as well as small satellite
nodules adjacent . (Right)
medium magnification
of a disrupted lesion of
molluscum contagiosum
demonstrates intense
inflammation and
remnants of the ghost cells
. When disrupted, the
lesions may be difficult to
diagnose on biopsy if viral
cytopathic effect is scarce.
(Left) A medium-power
view shows the HendersonPatterson bodies, which are
epithelial cell ghosts seen
in Molluscum contagiosum.
s the infected cells
mature, they have a large
viral inclusion , which
becomes more eosinophilic
as the cells age and
eventually die . (Right) A
high-power view shows the
Henderson-Patterson bodies
, which are epithelial cell
hosts seen in molluscum
contagiosum.
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VARICELLA-ZOSTER VIRUS (HHV-3) INFECTIONS
Infected skin demonstrates the characteristic eosinophilic
Cowdry type A nuclear inclusion bodies . (Courtesy
Franz von Lichtenberg Collection of Infectious Disease
Viral Infections: Morphological Diagnosis of Viral Infections
Pathology, BWH.)
TERMINOLOGY
Abbreviations
Varicella-zoster virus (VZV)
Human herpesvirus-3 (HHV-3)
Definitions
Varicella: New Latin, diminutive of variola, denoting
"speckled"
Greek: "Zoster" (belt)
Disease Manifestations
Chickenpox
Herpes zoster/shingles
ETIOLOGY/PATHOGENESIS
Infectious Agents
Virus enters nasopharyngeal epithelium and
conjunctiva
Initial infection
Transmission via airborne droplets or direct contact
with lesions
Incubation period: 10-21 days
Skin infection that is self-limiting, lasting for 3-4
days, with 2-4 successive crops of vesicles appearing
during disease course
Recovery usually results in lifetime immunity to
disseminated infection
Reactivation of latent infection
Potential to reactivate from sensory nerve root
ganglia in CNS and cause herpes zoster
Potential for disseminated infection with
CNS involvement in young children or
immunocompromised adults
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Gross photograph of a vesicle demonstrates "dew drop
on a rose petal" appearance . (Courtesy Franz von
Lichtenberg Collection of Infectious Disease Pathology,
BWH.)
CLINICAL ISSUES
Epidemiology
Worldwide distribution; peak incidence in winter and
spring in temperate climates
Pre vaccine (1995), in USA there were 4 million cases
annually, with 11,000 hospital admissions and 100
deaths
Post vaccine (1995) incidence has decreased by 90% in
USA
Site
Primary viremia occurs in nasopharynx and lymph
nodes 4-6 days following infection and spreads to
reticuloendothelial system, followed by secondary
viremia in viscera and skin after 11-13 days
Skin
Persistence in CNS sensory nerve root ganglia
Rare sites of dissemination: Lungs, CNS
Presentation
Primary varicella-zoster infection
Following mild prodrome, pruritic rash
(maculopapular becoming vesicular) develops
initially on head, then spreads to trunk and
extremities
Reactivation of latent varicella-zoster infection (herpes
zoster)
Presents as a painful dermatomal vesicular rash
Laboratory Tests
Real-time quantitative PCR of skin lesions or other
sites (cerebrospinal fluid, bronchoalveolar lavage)
Direct fluorescent antibody testing of skin lesions
Serology: Varicella IgM and IgG titers
Tissue culture (low sensitivity and slow turn-around
time)
Treatment
Prevention with live attenuated vaccine
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VARICELLA-ZOSTER VIRUS (HHV-3) INFECTIONS
Etiology
Transmission via airborne droplets or direct contact
with lesions
Clinical Issues
Worldwide distribution, peak incidence in winter and
spring in temperate climates
Those infected are potentially contagious from 5 days
before to 1-2 days after appearance of rash
Supportive treatment of uncomplicated infection in
children
Prognosis
Majority of cases are uncomplicated infections of 3-4
days duration
Children < 1 year and adults are most at risk of
complications and death
Complications
Bacterial infection of skin lesions, pneumonia,
CNS infection, Reye syndrome, congenital varicella
syndrome, herpes zoster (shingles) and postherpetic
neuralgia
Key Facts
Majority of cases are uncomplicated infections of 3-4
days duration
Children < 1 year and adults are most at risk of
complications and death
Microscopic Pathology
Cytopathic effect
Cowdry type A intranuclear inclusions
Syncytia formation
MICROSCOPIC PATHOLOGY
Histologic Features
Cytopathic effect
Cowdry type A eosinophilic intranuclear inclusions
Syncytia formation
Ground-glass appearance
Lymphoid infiltrates
Acantholysis or necrosis of epithelium
Intraepidermal blister formation
Granulomatous reaction can be seen at sites of
previous zoster infection
Viral Infections: Morphological Diagnosis of Viral Infections
MICROBIOLOGY
Viral Features
Enveloped double-stranded linear DNA virus
125 kb genome
Virions 180-200 nm, spherical
Slow replication in tissue culture with low sensitivity
MACROSCOPIC FEATURES
General Features
Lesions appear as "dew drop on a rose petal"
1-4 mm in diameter
IMAGE GALLERY
DIFFERENTIAL DIAGNOSIS
Primary Varicella-Zoster Infection
HSV, impetigo, eczema with superimposed infection,
bacterial meningitis, bullous pemphigoid, pemphigus
vulgaris
Reactivation of Latent Varicella-Zoster
Infection (Herpes Zoster)
HSV, contact dermatitis, bullous pemphigoid,
pemphigus vulgaris
SELECTED REFERENCES
1. Science M et al: Central nervous system complications of
varicella-zoster virus. J Pediatr. 165(4):779-85, 2014
(Left) Severe vasculitis with fibrinoid necrosis and mononuclear inflammation are a result of varicella-zoster infection. (From DP: Neuro.)
(Center) Varicella-zoster encephalitis involves infection of astrocytes and oligodendrocytes in AIDS patients. (From DP: Neuro.) (Right) Varicella
encephalitis in AIDS can spread into small parenchymal vessels and glia, causing ovoid lesions. Note the central area of infarction and a
peripheral rim of demyelination . (From DP: Neuro.)
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