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350 Neuroendocrine Tumors, Pathology of the Vulva
https://t.me/med1917
LCNEC even in the presence of neuroendocrine
immunoreactivity. SMARCA4, SMARCA2, and
SMARCB1 expression are retained by immunohistochemistry (Alvarado-Cabrero et al. 2020,
pp. 457–458). Gain or amplificationinchromosome 3q has been described in cervical LCNEC
(Kawauchi et al. 2005), and defects in the mismatch repair system are common in endometrial
LCNEC (Pocrnich et al. 2016).
Differential Diagnosis
The differential diagnosis includes LCNEC aris-
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 11 Large cell neuroendocrine carcinoma. Immuno-
histochemistry shows that the tumor cells are positive for
CD56
ing from other organs including the lung and
gastrointestinal tract. A thorough review of the
patients’ clinical history is paramount as these
tumors share similar morphologic and immunohistochemical characteristics.
References and Further Reading
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 12 Large cell neuroendocrine carcinoma. Immuno-
histochemistry shows that the tumor cells are positive for
synapatophysin
the diagnosis of LCNEC (Alvarado-Cabrero
et al. 2020). When CD56 is the only marker
expressed, histological features typical of
LCNEC must be present to establish the diagnosis (Alvarado-Cabrero et al. 2020). Diffuse
block-type p16 immunoreactivity, secondary to
high-riskHPV,iscommonincervicalLCNECs
but may also be seen in LCNECs of other sites
(Alvarado-Cabrero et al. 2020, pp. 457–458).
Detection of high-risk HPV may be useful in
confirming a cervical primary (AlvaradoCabrero et al. 2020). Cases without neuroendocrine morphology should not be regarded as
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Non-neoplastic Lesions of the
Placenta, Pathology of the
Placenta
Katelyn Dannheim1, Sonja Chen2and
Natalia Belova
1
Department of Pathology, Massachusetts
General Hospital Harvard Medical School,
Boston, MA, USA
2
Department of Pathology and Laboratory
Medicine, Nationwide Children’s Hospital,
The Ohio State University College of Medicine,
Columbus, OH, USA
3
Palm Beach County Medical Examiner’sOffice,
West Palm Beach, FL, USA
“The placenta is the perennial Holy Grail, a putative diary of intrauterine life promising to explain
the mysteries underlying poor pregnancy outcome.”–Raymond W. Redline, MD, “Classifications of placental lesions.”
This chapter describing non-neoplastic placental pathologies is largely based on the “Classification of placental lesions” by Raymond
W. Redline, MD, and the “Sampling and Definitions of Placental Lesions: Amsterdam Placental
3
Workshop Group Consensus Statement,” by
T. Yee Khong, MD, et al., which are used as
references throughout.
Of note, the latter recommends that minimum
sampling for histologic examination consists of
at least four blocks with sections of a membrane
roll from rupture site to placenta disc edge, two
cross sections of umbilical cord (one from the
fetal end and another approximately 5 cm from
the placental insertion end), and three fullthickness cr oss sections of placental pare nchyma taken from the central two-thirds of the
disc. One of the full-thickness cross sections
should be taken from an area close to th e umbilical cord insertion site. If the disc thickness is
greater than the length of a cassette, fullthickness sections can be divi ded into two cassettes, or the upper third (chorionic plate and
underlying tissue) and lower third (basal p late
and adjacent tissue) can be submitted detached
but together in a ca ssette. Lesions should be
sampled in additional blocks.
In the context of this chapter, we refer to those
who bear children as “women” and “mothers,”
though we would like to acknowledge that not
all those who bear children identify as female.
Placental Vascular Processes
“The placenta is essentially an interhemal membrane mediating the exchange of nutrients and
waste products between the maternal and fetal
circulations. It is therefore not surprising that
abnormalities in the structure and function of
these circulatory beds are dominant patterns of
placental injury.”–Raymond W. Redline, MD,
“Classifications of placental lesions.”
This section discusses various vascular processes leading to collections of patterns of placental dysregulation and injury, with malperfusion/
hypoxia thought to be at the center of pathogenesis. These are divided into maternal/uteroplacental
and fetal etiologies, and can be further subdivided,
depending on the approach to conceptualization
(e.g., developmental, malperfusion, and loss of
integrity; global/partial and segmental/complete;
early and late; acute and chronic; preuterine ,
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 353
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uterine, and postuterine) (Redline 2015; Khong
et al. 2016; Stanek 2013).
Maternal Stromal-Vascular Lesions
Developmental
Definition
Pathologies resulting from defects in differentiation, migration, and expansion of extravillous and
villous trophoblast (Redline 2015).
Superficial Implantation
Synonyms
Defective deep placentation; Restricted extravillous trophoblast invasion; Shallow placental
implantation.
Definition
A developmental defect in placentation leading to
a disease of the placental vascular bed characterized by inadequate invasion and transformation of
the basal plate arteries (a.k.a. spiral arteries) by
extravillous trophoblast (Brosens et al. 2011;
Stanek and Biesiada 2012).
Clinical Features
• Incidence
Absent or partial transformation of the spiral
arteries has been seen in association with preeclampsia, fetal intrauterine growth restriction (IUGR), preterm labor and preterm
premature rupture of membranes (PPROM),
abruptio placentae, and second-trimester
spontaneous abortion (Brosens et al. 2011).
Increased placental site trophoblastic giant
cells have been seen in association with preeclampsia, abnormal Dopplers, induction of
labor, cesarean section deliveries, fetal
growth restriction, maternal diabetes, and
neonatal mortality (Stanek and Biesiada
2012). Shallow placental implantation has
also been implicated in placenta creta (see
“Morbidly Adherent Placentas (Placenta
Accreta Spectrum)” below).
• Age
While shallow placentation is not widely
known to be associated with a particular mater-
nal or gestational age, advanced maternal age
(>35 years) is associated with a higher risk of
preeclampsia (its most classically clinically
associated syndrome) (Rana et al. 2019). Addi-
tionally, the prevalence of multinucleate tro-
phoblastic giant cells has been shown to have
a negative correlation with gestational age
(Stanek and Biesiada 2012).
• Sex
There is no known correlation with a particular
fetal sex.
• Site
Placental basal plate; evaluated sections should
be non-marginal, as there is less transformation
of the spiral arteries in the periphery of the
basal plate (Brosens et al. 2011).
• Treatment
Treatment varies depending on the underlying
clinical syndrome, symptoms, and severity.
• Outcome
Superficial implantation contributes to placen-
tal dysfunction that leads to maternal vascular
malperfusion (discussed in further detail
below), which confers an increased risk of
IUGR, preterm labor, PPROM, preterm birth,
mid-trimester spontaneous abortion, and fetal/
neonatal death (Redline 2015; Brosens et al.
2019). More long-term outcomes include
increased risk of recurrence in subsequent
pregnancies and, specifically in the setting of
preeclampsia, risk of cardiovascular disease in
both the mothers and offspring (Redline 2015;
Harris et al.
Macroscopy
Lesions associated with maternal vascular
malperfusion are associated with placental hypoplasia and are often seen concurrently with placental infarction and retroplacental hemorrhage
(discussed in further detail below) (Khong
et al. 2016).
Microscopy
The histologic characteristics of superficial
implantation are those of inadequate
2019).
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actin can be helpful to differentiate decidua, trophoblast, and myometrium, respectively.
Molecular Features
Genetic testing is not used routi nely in the diagnosis of superficial implantation.
Differential Diagnosis
Take care to not mistake the physiologic fibrinoid
replacement that occurs during remodeling of
basal plate spiral arteries for fibrinoid necrosis/
atherosis.
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 1 Basal plate arteries with persistent
muscularization
transformation of the basal plate arteries,
increased decidual/implantation site multinucleated trophoblasts, and increased extravillous
trophoblast (see “Increased Immature Extra-
villous Trophoblast”) (Stanek 2019).
Basal plate arteries with inadequate transformation demonstrate persistent muscularization
(Fig. 1) and/or atherosis (fibrinoid necrosis with
intramural foamy macrophages), which should be
differentiated from the fibrinoid replacement that
occurs in normal physiologic remodeling/transformation (Khong et al. 2016). This is discussed
in further detail in the “Decidual Arteri opathy”
section below.
Increased implantation site multinucleate trophoblastic giant cells are defined as clusters of
greater than three trophoblastic cells with greater
than 3 nuclei in the decidua basalis or parietalis
(Stanek 2013; Stanek and Biesiada 2012). This
histologic feature was recently shown to be the
only statistically significant feature differentiating
early-onset and late-onset preeclampsia; this same
analysis suggested that shallow placental implantation may reflect a unifying mechanism for the various types of preeclampsia (Stanek 2019).
Immunophenotype
Immunohistochemical stains and special stains
are not usually needed for the diagnosis of superficial implantation, although occasionally CD10,
cytokeratin cocktail or p63, and smooth muscle
Decidual Arteriopathy
Synonyms
Decidual arteriolopathy; Decidual vasculopathy.
Definition
Pathologic changes of the muscularized
uteroplacental arteries without normal physiologic transformation, primarily characterized by
mural hypertrophy and/or atherosis of the vessel
wall (Hecht et al. 2016).
Clinical Features
• Incidence
Associated with preeclampsia, maternal diabetes, maternal thrombophilia (such as antiphospholipid antibody syndrome/systemic
lupus erythematosus), and other autoimmune
disorders (Chan et al. 2017). One study examining over sixteen thousand placentas delivered from 1998 to 2014 at a single institution
reported that acute atherosis was identified in
0.4% of uncomplicated pregnancies, 10.2% of
pregnancies with preeclampsia, 9% with fetal
death, 2.5% with mid-trimester spontaneous
abortion, 1.7% with small for gestational age
neonates, and 1.2% with spontaneous preterm
labor and premature preterm rupture of membranes (Kim et al. 2015b).
• Age
Decidual arteriopathy has not been shown to be
associated with a particular gestational age
(Chan et al. 2017). However, advanced
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 355
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maternal age (>35 years) is associated with a
higher risk of preeclampsia (itsmost classically
clinically associated syndrome) (Rana
et al. 2019).
• Sex
Decidual arteriopathy has not been shown to be
associated with a particular fetal sex.
• Site
Predominantly identified in the marginal
decidual vessels within membrane roll sec-
tions; however, studies have suggested that
~9% of cases may only show findings within
the basal plate. Therefore, additional sampling
of the basal plate may b e warranted when a
clinical history and/or gross placental exami-
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 2 Low power view of basal plate
arteries with fibrinoid necrosis
nation is suggestive of uteroplacental
malperfusion.
• Treatment
Treatment varies depending on the underlying
clinical syndrome, symptoms, and severity.
• Outcome
Decidual arteriopathy contributes to placental
dysfunction that leads to maternal vascular
malperfusion (discussed in further detail
below), which confers an increased risk of
intrauterine growth restriction (IUGR), pre-
term labor, premature preterm rupture of mem-
branes (PPROM), preterm birth, mid-trimester
spontaneous abortion, and fetal/neonatal death
(Redline 2015; Brosens et al. 2019). More
long-term outcomes include increased risk of
recurrence in subsequent pregnancies, and spe-
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 3 High power view of basal plate
arteries with fibrinoid necrosis
cifically in the setting of preeclamps ia, risk of
cardiovascular disease in both the mothers and
offspring (Redline 2015; Harris et al. 2019).
lipid-laden/foamy macrophages; Figs. 4 and 5),
mural hypertrophy, chronic perivasculitis, arterial
thrombosis, and persistence of intramural endo-
Macroscopy
Lesions associated with maternal vascular
malperfusion are associated with placental hypoplasia and are often seen concurrently with placental infarction and retroplacental hemorrhage
(discussed in further detail below) (Khong
et al. 2016).
vascular trophoblast in the third trimester. Much of
the literature combines the findings of superficial
implantation with the category of decidual
arteriopathy, namely incomplete basal plate artery
remodeling with persistent mural smooth muscle
leading to acute atherosis (Khong et al. 2016;
Chan et al. 2017).
N
Microscopy
Decidual arteriopathy is characterized by fibrinoid
necrosis (Figs. 2 and 3), acute atherosis
(characterized by fibrinoid necrosis with intramural
Immunophenotype
Immunohistochemical staining is not routinely
used for the diagnosis of decidual arteriopathy,
although desmin staining has been shown to be
356 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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Molecular Features
Genetic testing is not used routi nely in the diagnosis of decidual arteriopathy.
Differential Diagnosis
Take care to not mistake the physiologic fibrinoid
replacement that occurs during remodeling of
basal plate spiral arteries for fibrinoid necrosis/
atherosis.
Increased Immature Extravillous
Trophoblast
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 4 Low power view of basal plate
arteries with acute atherosis
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 5 High power view of basal plate
arteries with acute atherosis
diminished in the setting of advanced mural
hypertrophy and atherosis, and CD31 and CD34
can show granular staining patterns suggestive of
endothelial cell fragmentation (Hecht et al. 2016).
Finally, soluble fms-like tyrosine kinase 1 (sFlt-
1), an anti-angiogenic factor implicated in the
pathogenesis of preeclampsia, has shown to have
increased expression by immunohistochemistry in
placentas of women with preeclampsia (Weel
et al. 2016), as well as a subset of those without
preeclampsia but with small for gestational age
infants concurrently found to have histologic evidence of placental insufficiency, including decidual vasculopathy (Spiel et al. 2017).
Synonyms
Excess of proliferative immature intermediate trophoblast; Excessive transitional extravillo us trophoblast; Increased extravillous trophoblast.
Definition
Increased immature extravillous trophoblast
(EVT) in various placental sites, occasionally
with cystic degenerative change (Redline and
Patterson 1995; Stanek 2011a, b).
Of note, per the Amsterdam Placental Workshop Group Consensus Statement, the evidence is
not yet conclusive that histologic features of
increased EVT are indicative of maternal vascular
malperfusion, though they have been seen in association with clinical conditions andother placental
lesions typically associated with uteroplacental
malperfusion (Stanek 2011a, b).
Clinical Features
• Incidence
Increased EVT has been seen in associated
with preeclampsia and maternal diabetes.
• Age
Increased EVT has been reported to most com-
monly be seen at the end of the second and
beginning of the third trimester; there is no
association with a particular maternal age
(Stanek 2011a).
• Sex
Increased EVT has not been shown to be asso-
ciated with a particular fetal sex.
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 357
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• Site
Increased EVT can be seen in villous tissue
(trophoblast islands, placental septae), the chorionic membrane, and the basal plate
(implantation site) (Redline and Patterson
1995; Stanek 2011a, b).
• Treatment
Treatment varies depending on the underlying
clinical syndrome, symptoms, and severity.
• Outcome
Increased EVT has been associated with
increased risk of oligohydramnios and fetal
growth restriction (Stanek 2011a).
Macroscopy
Cysts of the septae and chorionic plate can some-
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 6 An example of a trophoblastic
island with extravillous trophoblast
times be appreciated grossly. Some studies have
reported low placental weight and associate placental infarction (Stanek 2011a).
(placental site giant cells or implantation site syncytial trophoblast); transitional and mature EVT
are differentiated by vacuolation ofthe former, but
Microscopy
Trophoblast growing in association with ch orionic villi is termed villous trophoblast, while all
other trophoblast is EVT. There are three main
categories of trophoblast: cytotrophoblast, the trophoblast stem cell; syncytiotrophoblast, the terminally differentiated trophoblast creating the outer
layer of the chorionic villi; and EVT.
Cytotrophoblast makes up the inner layer of the
chorionic villi, where it gives rise to the syncytiotrophoblast; it also makes up the inner layer
of the anchoring villi at the basal plate, where it
proliferates into cell columns that differentiate
into EVT. Of note, EVT was previously referred
to as “intermediate” trophoblast, as it was thought
to share morphologic and functional features of
both cytotrophoblast and syncytiotrophoblast
(Shih and Kurman 2001; Lee et al. 2007).
are both found in intraplacental trophoblas tic
islands (Fig. 6) (transitional tends to be located
more central, mature more peripheral), the basal
plate, and the chorionic membrane (transitional
tends to be located closer to the amnion, mature
further away) (Shih and Kurman 2001; Lee et al.
2007).
Excessive extravillous trophoblasts are defined
as greater than 5 cell islands and/or placental septa
containing 50 trophoblastic cells per section of
grossly unremarkable placenta or a membrane
migratory trophoblas tic layer consistently more
than seven cells thick (Stanek 2011a, 2013).
Microscopic chorionic (pseudo) cysts (Fig. 7)
are considered significant when there are greater
than 3 microscopic chorionic lakes per section of
membrane roll or grossly unremarkable placental
parenchyma (Stanek 2011a, 2013).
EVT can be further subcategorized as follows:
column trophoblast is contiguous with
cytotrophoblast at the apices of cell columns
extending from anchoring villi of the basal plate
early in gestation; implantation site trophoblast
is peripheral to column trophoblast and invades
the uterine stroma (interstitial trophoblast) or
the maternal spiral arterioles (endovascular trophoblast), with occasional multinucleation
Immunophenotype
Immunohistochemistry is not routinely used for
the diagnosis of increased EVT; however, it can be
used to differentiate the different types of trophoblast. Cytotrophoblast is diffusely positive for p63
and negative for inhibin and MelCAM. It demonstrates extremely high proliferation rate (100%)
by Ki-67 in trophoblast cell columns and in the
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358 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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Malperfusion
Synonyms
Maternal vascul ar malperfusion (recommended
terminology per the Amsterdam consensus);
Maternal vascular underperfusion, uteroplacental
underperfusion; Placental hypoxia; (Utero)Placental insufficiency.
Definition
The downstream pathologies resulting from
abnormal spiral artery blood flow are secondary
to inadequate remodeling, which includes both
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 7 A placental septum with increased
extravillous trophoblast and a microscopic chorionic
(pseudo)cyst
underperfusion and high velocity and turbulent
flow. Three gross findings are more commonly
seen in the setting of maternal vascular
malperfusion, including placental hypoplasia
(placental weight usually less than 10th percen-
first trimester, but this diminishes later in gestation. Transitional EVT is positive for p63 with
subset (~50%) staining for inhibin, minor subset
(<10%) staining for MelCAM, and variable/low
proliferation rate (~10%) by Ki-67. Mature EVT
and implantation site EVT are positive for inhibin
and MelCAM, and negative for p63 with
low/negative proliferation rate by Ki-67. Column
trophoblast shows a gradi ent of MelCAM increasing from the base (negative cytotrophoblast) to the
tip (positive implantation site EVT); Ki-67
tile for gestational age, but almost always less
than 50th percentile), increased fetoplacental
weight ratio for gestational age, and villous
infarcts. Retroplacental hemorrhage is also an
associated gross finding. The histologic findings
can be divided into categories of global/partial
malperfusion with early and late effects, and
segmental/complete malperfusion, each of
which will be described below (Redline 2015;
Khong et al. 2016;Ernst2018;Redline
et al. 2021).
decreasing from the base (highly proliferative
cytotrophoblast) to the tip (differentiated implan-
Global/Partial
tation site EVT with low proliferation rate); and
p63 decreasing from the base (positive
Early: Distal Villous Hypoplasia
cytotrophoblast) to the tip (negative implantation
site EVT). Finally, syncytiotrophoblast is negative
for p63 and MelCAM with a low/negative prolif-
Synonyms
Terminal villous hypoplasia (Stanek 2013).
eration rate by Ki-67 (consistent with terminal
differentiation). It shows strong positivity for
inhibin early in pregnancy, but is predominantly
lost in term villi (~5% positive) (Lee et al. 2007).
Definition
Paucity of intermediate and distal villi in the basal
two-thirds of the placental parenchyma.
Molecular Features
Genetic testing is not used routi nely in the diagnosis of increased EVT.
Differential Diagnosis
Large cysts may mimic intervillous thrombi
grossly.
Clinical Features
• Incidence
Distal villous hypoplasia (DVH) is seen in
association with maternal hypertensive disease
and reduced or absent end diastolic umbilical
artery flow (Veerbeek et al. 2014).
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• Age
More commonly seen in association with
maternal vascular malperfusion in early preg-
nancy (<32 weeks gestational age) (Khong
et al. 2016).
• Sex
DVH has not been shown to be associated with
a particular fetal sex.
• Site
The lower (basal) two-thirds of the placental
parenchyma.
• Treatment
Treatment varies depending on the underlying
clinical syndrome, symptoms, and severity. If
evidence of severe global/partial maternal vas-
cular malperfusion is seen, the following may
be indicated in clinical management: evaluate
maternal cardiovascular status, glucose toler-
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 8 A low power view of DVH illustrat-
ing patchy paucity of villi, as seen at the top and bottom of
this field, compared to the background (Photomicrograph
courtesy of Laura Biederman, MD [Nationwide Children’s
Hospital])
ance, thrombophilia, and renal function; sug-
gest weight loss if applicable; consider aspirin
therapy, uterine artery Doppler, early third-
trimester placental ultrasounds, and early
delivery in subsequent pregnancies (Redline
2015).
• Outcome
Diffuse DVH (see below) is associated with
early-onset fetal growth restriction (Khong
et al. 2016). Severe global/partial maternal
malperfusion recurs in 10–25% of subsequent
pregnancies (Redline 2015).
N
Macroscopy
Lesions associated with maternal vascular
malperfusion are associated with placental hypoplasia and are often seen concurrently with placental infarction and retroplacental hemorrhage
(discussed in further detail below) (Khong
et al. 2016).
Microscopy
Best observed at low power comparing the upper
(subchorionic) third to the lower (basal) twothirds of a full-thickness section, it will appear
as increased intervillous space due to paucity of
the intermediate and distal villi compared to the
stem villi (Fig. 8). Many of the villi that rem ain
appear thin and elongated with decreased
branching (Fig. 9), increased syncytial knots,
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 9 Long, thin villi with decreased
branching arising in a background of villous paucity, characteristic of DVH (Photomicrograph courtesy of Laura
Biederman, MD [Nationwide Children’s Hospital])
and decreased vascularity. Features should
involve at least 30% of one full-thickness parenchymal slide. It can be graded as focal if it
involves one full-thickness slide, or diffuse if it
involves two or more full-thickness slides
(Khong et al. 2016;Ernst2018; Veerbeek et al.
2014).
Immunophenotype
Immunohistochemical stains are not routinely
used for the diagnosis of DVH.
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