Pathology

4
PATHOLOGY
Neil J. Sebire, Baljeet Kaur, Michael Wells

4.1 INTRODUCTION

Trophoblastic tumors are malignant fetal allografts in maternal

tissues and present unique biological, immunological and
pathological problems. One of the main functions of trophoblast is to
gain access to the maternal circulation, and normal trophoblast
infiltrates, invades vessels and can even be transported to the lungs
[1-3] in a fashion which is otherwise only seen in malignant
neoplasms. Invasion and metastases are criteria used to diagnose
malignancy in other neoplasms but are not usually applicable to
trophoblast. In addition, trophoblastic tumors are relatively rare and
unfamiliar to both physician and pathologist in non-specialized
centers and the frequent difficulties and potential dangers of
obtaining adequate samples from deeply invasive and hemorrhagic
lesions can make pathological diagnosis difficult or impossible.
These facts justify the well-established approach of treating patients
on the basis of clinical criteria and serological human chorionic
gonadotropin (hCG) estimations. It also means that some patients
will be treated and cured without our ever knowing whether the
disease treated was an invasive hydatidiform mole (IM) or a
choriocarcinoma (CC). Terms such as gestational trophoblastic
disease (GTD) and gestational trophoblastic neoplasia (GTN)
accurately describe this situation [4, 5].
The increasing use of ultrasound in the diagnosis and management
of abnormal pregnancies has resulted in earlier evacuation of moles
[6, 7] and earlier chemotherapy in GTN [5]. Early evacuation has
meant a decrease in the number of molar pregnancies which present
with the symptoms and signs of overgrowth of trophoblast and
excessive hCG secretion, such as uterine size larger than dates,
hyperemesis, toxemia or hyperthyroidism [8,9], and most complete
hydatidiform moles (CHMs) now present as miscarriage or
terminations of abnormal anembryonic pregnancies towards the end
of the first trimester in which a mole may or may not be suspected
and when pathological criteria useful to diagnose late second
trimester moles are no longer valid [6,7]. The success of
chemotherapy has resulted in a marked reduction in the number of
pathological specimens available for study and few pathologists can
today claim to have seen an IM or a CC in a hysterectomy specimen.
However, the aggressive behavior of trophoblastic tumors unchecked
by chemotherapy is well known from earlier accounts [10-16]. In
recent years, genetic studies have provided us with additional
information, which has helped both to understand the nature of these
abnormalities and to test and improve the morphological criteria,
which remain the basis of pathological diagnosis.

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4.2 NORMAL TROPHOBLAST

Trophoblast populations of normal placenta are composed of

cytotrophoblast, syncytiotrophoblast and intermediate trophoblast.
[17] Villous trophoblast covers chorionic villi (Figure 4.1) and
consists predominantly of cytotrophoblast and syncytiotrophoblast.
The cytotrophoblast is the trophoblastic stem cell. These rather
primitive mononuclear cells have a clear cytoplasm (which reflects
their paucity of cellular organelles) and a high mitotic rate. They
usually express cytokeratins but produce little or no hormones.
Cytotrophoblast shows no Inhibin alpha expression throughout
gestation [18]. Syncytiotrophoblast differentiates from fusion of
cytotrophoblast and is composed of multinucleated cells with
abundant dense cytoplasm. It secretes abundant hCG, some human
placental lactogen (hPL) and placental alkaline phosphatase (PLAP)
but has little capacity for further proliferation. Inhibin alpha is highly
expressed by syncytiotrophoblast in the first trimester but
progressively decreases towards term. This links with the observation
that serum levels of Inhibin peak at 7-8 weeks, decline in mid
trimester and rise again towards term [18]. Production of hCG
decreases while hPL and PLAP increase as pregnancy advances [19]
and the amounts of villous trophoblast in relation to the amounts of
villous stroma (Figure 4.1) gradually decrease with increasing
gestational age [20]. Trophoblast also synthesizes estrogen and
progesterone [21]. Intermediate trophoblast can be further subdivided
into villous intermediate trophoblast located in the villous columns,
implantation site intermediate trophoblast located in the placental site
and chorionic-type intermediate trophoblast located in the chorionic
laeve of the fetal membranes.[17] Cytotrophoblast again acts as the
stem cell in the villi which are in contact with the placental bed. Here
the cytotrophoblast merges imperceptibly with the trophoblastic
columns. The proliferative activity of the villous intermediate
trophoblast decreases towards the villous tips. At the base of the
trophoblastic columns the trophoblast infiltrates the decidua, spiral
arteries and myometrium to become the implantation site
intermediate trophoblast. [17]. The implantation site intermediate
trophoblast (placental site trophoblast; PST) is composed of
mononuclear and multinucleated cells with a dense eosinophilic
cytoplasm (Figure 4.2), morphologically different from villous
cytotrophoblast and syncytiotrophoblast and defined
immunocytochemically by positive staining for hPL and
cytokeratins, but containing scanty hCG and PLAP.

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Figure 4.1 Villous trophoblast forming polar trophoblastic columns in early

pregnancy. It consists of mononuclear cytotrophoblast and multinucleated
syncytium as well as villous intermediate trophoblast.

Figure 4.2 Placental site trophoblast infiltrating myometrium. In this area it is

predominantly composed of mononuclear intermediate trophoblast. X 180.

Most placental site trophoblast does not express Inhibin.[18]

Modern techniques [19,22,23] have therefore resolved the argument
about the origin of these cells [24,25] in favour of trophoblast and
the term implantation site intermediate trophoblast is now well
established. The functions and biological differences between the
various types of trophoblast are under study and include the
production of proteolytic enzymes which facilitate tissue invasion,
thromboplastin and plasminogen activator, which control fibrin
formation and may be important in maintaining vascular patency
and expression of human leukocyte antigen (HLA) type I, whose
role in the success of the fetal allograft is still unknown [26-28].

4.3 CLASSIFICATION OF TROPHOBLASTIC LESIONS

(TABLE 4.1)

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The common pathology of these lesions is an excessive

proliferation of trophoblast. In hydatidiform moles this essentially
consists of chorionic villi covered by abnormal villous trophoblast.
There are two distinct morphological and genetic types of
hydatidiform mole:
Complete mole (CHM), a diploid, hyperdiploid or tetraploid
conception in which all of the nuclear genome is derived from the
father in the majority of cases [29,30]; and Partial Mole (PHM), a
triploid and rarely tetraploid conception with at least two sets of
paternal and one set of maternal chromosomes [31-33]. CHM is so
named because traditionally, when hydrops is fully developed the
majority of villi were involved, whereas in fully developed PHM,
hydrops remains characteristically focal. (Such a distinction on the
basis of hydrops alone does not hold true in the first trimester, when
most HMs are now evacuated and examined). About 85% CHMs
and >99% PHMs are associated with no significant comsequences
following evacuation but a minority progress, manifest as
gestational trophoblastic neoplasia (GTN) and require
chemotherapy. IM is usually a CHM and rarely a PHM which
invades the myometrium, but is rarely encountered in the setting of
modern obstetric and gynaecological practice.
Typically, CC is composed predominantly of cells resembling
villous cyto and syncytiotrophoblast but, unlike in moles, no
chorionic villi are present (except in the rare setting of
intraplacental choriocarcinoma, IPCC). The tumour invades vessels
and metastasizes aggressively, usually being fatal without
treatment. [13]. PSTT can also proliferate excessively. Exaggerated
forms of placental site reaction may remit spontaneously or be
cured by simple curettage. Placental site trophoblastic nodule
(PSN) or plaque has been described (until lately) as benign non-
neoplastic lesions with neither local recurrence nor progression to
GTN. No specific treatment or follow-up was deemed necessary
[34]. Recent advancements in this field are included elsewhere in
the chapter (4.17) Rarely, such trophoblastic lesions may progress
and invade in a malignant fashion [35]; placental site trophoblastic
tumour (PSTT). [36]. Since PSTT is relatively chemoresistant, it is
encountered more commonly that typical CC in hysterectomy
specimens. Finally, a variant of PSTT has been described,
epithelioid trophoblastic tumour (ETT), possibly the malignant
counterpart of PSN. [37].

The pathogenesis of trophoblastic tumours is relatively poorly

understood because of their rarity and lack of experimental models
(38, 39). Studies on gene expression profiles in human trophoblastic
subpopulations have elucidated the normal differentiation of
trophoblast and relation to intermediate trophoblastic tumours (40).
These studies have led to the hypothesis that trophoblastic tumours
may recapitulate the development of trophoblast in different
locations in the normal early placenta and implantation site (41, 42),
such that both ETT and PSN are related to the intermediate
trophoblast of chorion leave type, whereas PSTT and EPSR are

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related to the intermediate trophoblast of the normal implantation

site. Based on morphological and immunohistochemical studies,
PSN may represent the benign counterpart of ETT and EPSR the
counterpart of PSTT. However, it is more likely that such
phenotypes simply represent patterns of trophoblast differentiation.
Furthermore, lack of a clear biological link between PSTT and
EPSR was demonstrated in a recent study (43).

Table 4.1. Abnormal trophoblastic proliferations.

Abnormality Embryo Hydrops Trophoblast
Partial hydatidiform mole (PHM) Yes Focal Some excess
Complete and invasive hydatidiform mole No Extensive Marked excess
(CHM)
Choriocarcinoma No No villi Neoplastic
Exaggerated Placental site reaction (EPSR) No No villi Self-limiting
Placental site trophoblastic tumor (PSTT) No No villi Neoplastic
Placental site trophoblastic nodule (PSN) No No villi Undetermined
Significance*
Epithelioid trophoblastic tumor (ETT) No No villi Neoplastic

4.4 MOLAR PREGNANCY (FIGURES 4.3, 4.4)

Hydatidiform moles are intrinsically abnormal conceptions [44-47] characterized

histopathologically by excessive proliferation of trophoblast, and genetically by
relative placental over-expression of paternally derived genes. Most complete
hydatidiform mole arise when an ovum without maternal chromosomes is fertilised
by one sperm that then duplicates its DNA (46XX androgenetic karyotype) and are
less frequently from fertilisation by two sperm (46XY androgenetic karyotype).
Although nuclear DNA is entirely paternal, mitochondrial DNA remains maternal in
origin. However recently biparental CHM’s have been described where patients
present with recurrent disease which might be familial or sporadic. Most common
mutation in these cases involves leucine-rich region of NLRP7 at chromosome
19q13.3–13.4 (figure 4.3)

Partial hydatidiform moles are almost always triploid (diandric monogynic triploids)
and majority result from fertilisation of a seemingly healthy ovum by two sperm
(heterozygous PHM). Diploid partial moles probably do not exist, with most
reported cases being misdiagnosed complete moles (48).However not all triplodies
are PHM. A significant proportion (up to one third) of triploid gestation is non-molar
digynic monoandric in their genetic composition (49)

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 Pathology

Figure 4.3: Karyotype derivation of complete and partial hydatidiform moles and rare biparental
repetitive complete hydatidiform mole
CHM=complete hydatidiform mole. PHM=partial hydatidiform mole. biCHM=rare
biparental complete hydatidiform mole. Paternal (black) and maternal (red) derived genes
are shown. (Figure ref: 48)

4.5 COMPLETE HYDATIDIFORM MOLE

CHM produces voluminous and haemorrhagic evacuation specimen and in advanced
gestational age shows classic “bunch of grapes”appearrance. No foetal parts are
usually seen in CHM.

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Figure 4.4 Complete mole presenting as an enlarged uterus with abnormally dilated
endometrial cavity in a 55 years old female with uncontrolled vaginal bleeding. Hydropic
change is generalized and no foetus is present.
(http://www.elearning.virtualpathology.leeds.ac.uk/casesubmission/femalegt/Abnormal
%20beta-hCG%20in%20a%2055-year-old%20woman.pdf)

In the classical, fully developed CHM pathological examination shows enlarged,

oedematous villi often completely surrounded by excessive circumferential villous
trophoblast (Figure 4.5), in which nuclear pleomorphism is usually more intense than
in normal pregnancy. Clusters of similar trophoblast fragments are also often seen
amongst villi. Fluid tends to collect in ‘cisterns’ in the middle of villi, resulting in
localization of other components of villous stroma beneath the cytotrophoblastic
layer (Figure 4.6), which shows few or no blood vessels, and this hydropic change
tends to be generalized. This description is accurate for CHMs evacuated in the mid-
late second trimester but CHMs are now evacuated at much earlier gestations than
previously, [7] at an average of 10 weeks’. The most useful features by which to
recognize these early CHMs are as follows. [7][50-52]

Figure 4.5 Hydrops and cistern formation in complete mole evacuated

at 18 weeks gestation. Hydropic change is generalized and no residual
vessels are present. X20.

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Figure 4.6 complete moles. Fluid collects in the middle, forming cisterns, and the
stroma is compressed against the trophoblastic layers which show circumferential
hyperplasia.

(a) Circumferential trophoblast hyperplasia. Abnormal trophoblast

hyperplasia is a constant finding in CHM when the sample is adequate
and it is recognized by the presence of more than two layers of
trophoblast forming sprouts or more extensive circumferential masses
(Figure 4.7). Patients who eventually need chemotherapy have, on
average, higher serum hCG values than those who do not [7] and,
initially a correlation between more abundant and more pleomorphic
trophoblast and worse prognosis was reported [12, 53] but this has not
been confirmed by further studies [54-57] and is probably explained by
the fact that excess trophoblast is only loosely attached to villi and the
amounts in the sample may not be representative of the whole, or
indeed, of what is left in utero. Serial hCG estimations are a better
indication of residual trophoblast activity rather than histological
grading systems. In our experience, excess trophoblast is, if anything,
usually easier to detect in younger than in older CHMs, since fully
developed hydrops in older moles is sometimes associated with
attenuation of trophoblastic layers. It should be noted that even for
CHM, not all villi will necessarily demonstrate circumferential
trophoblast proliferation; in one study this affected 30% of CHM villi
(57)

(b) Generalized hydrops may not be fully developed in early

gestation CHMs. It is important to stress that complete hydrops, from
which CHM derives its name and which results in the characteristic
‘bunch of grapes’ macroscopical appearance of classical mole, (Figure
4.3) requires time to develop. Most CHMs exhibited generalized
hydrops when they were evacuated at around 16-20 weeks GA, but with
current evacuation at 10-12 weeks’, hydrops in most specimens is only
focal. Many CHMs referred to our institution have been erroneously
called PHMs initially on this account. (Figure 4.7).

(c) Early gestation CHM may exhibit stromal blood vessels. The
presence of vessels in CHM is a major source of diagnostic confusion. It
is true to say that when CHMs were evacuated late, most had no vessels.
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 Pathology

[58]. Several publications have however described the frequent presence

of vessels in androgenetic CHMs at early gestational ages [6, 7, 51-52,
59]. In our experience it is rare to see avascular CHMs before the 12th
week of gestation [7]; in most cases the vessels are collapsed and
empty, although occasionally they are open and rarely may contain
nucleated red cells (see below for discussion of this unusual finding).
Since villous vascular development is initially independent of a fetal
circulation, in our experience whether a mole has vessels or not depends
primarily on its GA and, if a fetus is present, on the time lapsed since
fetal death occurred. In a large study we found a higher proportion of
avascular PHMs than avascular CHMs, reflecting the longer GA of
PHMs [7].

Figure 4.7 Complete mole evacuated at seven weeks gestation. There is budding of the
trophoblastic layers mimicking the secondary villi of early placental development but excess
trophoblast is present both on villi and between villi. These polyploid villi are very
characteristic of young complete moles. Stromal vessels are a constant finding at this stage.
.

(d) In CHM, stromal karyorrhexis is very common even at early

gestations. Karyorrhexis (nuclear debris) in villous stroma of otherwise
well-preserved villi is almost always seen in early CHMs and is useful in
diagnosis. [4, 28, 50-51]. It should not be confused with cell necrosis in
vessels, which is also common in PHMs and HAs after fetal death and it
should not be considered in isolation as an absolute diagnostic criterion,
since necrosis of stromal cells is possible in other circumstances.
However, it is so common and intense in CHM and so rare and slight in
PHM and HAs that its presence should make one think of the possibility
of CHM, particularly when the material available is scanty.

(e) Early gestation CHM have characteristic ‘budding’

architecture. (Figure 4.7) Secondary villi sprout from primary villi in a
fashion resembling that of early placentation [50, 52]. Unlike in normal
placentation, where villi are regular in size, radiate from a central cavity
and have polar trophoblast, the secondary villi of CHM are irregular in
size and distribution and have circumferential excess trophoblast. These
irregular villi are often mistaken for the scalloped villi of a PHM and,
although the differences between them are lengthy and difficult to
describe, they can be readily appreciated by comparing Figure 4.7 with
Figure 4.10 and 4.11.
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 Pathology

Figure 4.8 Irregular trophoblastic inclusion in complete mole. Trophoblastic invaginations

often result in pseudoinclusions but these are irregular or oval and different from those
seen in partial mole (see Figure 4.11). X50.

Figure 4.9 Complete mole in early gestation. Trophoblastic invaginations and budding
occasionally result in a characteristic lobulated appearance. X100.

(f) Transverse sectioning of irregular villi in CHM often results

in oval or irregular pseudoinclusions of trophoblast (Figure 4.8).
These are often cystic and large and appear morphologically different
from the more regular small round inclusions seen in PHM (see Figure
4.12).
(g) The stroma of CHM is usually mucoid with little fibrosis.
Before the development of hydrops, the villous stroma in CHM contains
only a little reticulin around blood vessels [6,7]. With development of
hydrops a little collagen may be seen in the condensed stroma at the
periphery of cisterns but, unlike in PHM, fibrosis is not usually a feature
of villous stroma even with advancing gestational age. In early gestation
CHMs the combination of basophilic mucoid stroma and invaginations of
trophoblast from secondary villi may result, in cross-sections, in a
characteristic lobulated appearance superficially resembling a fragmented
intracanalicular breast fibroadenoma.

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(h) In most CHMs no evidence of embryonic development is

found. CHMs are characteristed by excess trophoblast but no embryo.
However, we and others [6,7,60, 61] have very rarely found nucleated
fetal red cells, amnion or other embryonic tissues in specimens which are
morphologically typical CHMs and genetically androgenetic [62]. Some
of these may represent examples of CHM with unsuspected twin
pregnancies but in others the presence of fetal red cells in molar villi
remains unexplained and the possibility that some embryonic
development may rarely occur in CHM has not yet been adequately
excluded. For practical purposes the presence of embryo, amnion or fetal
red cells in mole is strongly suggestive of PHM but CHM is not excluded
absolutely and the latter should be considered if other histological
features suggest it, or if the mole is diploid on flow cytometry (FC).
Furthermore, extremely rare mosaicism for CHM with fetus has now also
been reported.

i) Abnormal implantation site fragments are often present. The

implantation site in CHM often demonstrates lack of the normal
endovascular plugging in association with florid interstitial trophoblast
infiltration, with or without pleomorphism. These features, of themselves,
have no clinical or prognostic significance when associated with CHM
villi but can provide additional diagnostic information.

Ideally, a morphological diagnosis of CHM based on these macroscopical

and microscopical features should be confirmed by genetic studies but
this is seldom necessary in practice; if required, additional support for
diagnosis of CHM rather than PHM can be derived from the finding of a
diploid DNA complement by FC [63-67]. This can now be performed
from fixed or paraffin-embedded material [68]. Furthermore,
confirmation of CHM can simply be achieved using p57KIP2
immunostaining, which is imprinted and expressed in the majority of
villous cytotrophoblast and stromal nuclei in all non-CHM conceptions
but is absent in CHM. (See later section)

4.6 THE MORPHOLOGY OF GENETICALLY UNUSUAL

COMPLETE HYDATIDIFORM MOLE

No morphological differences have been found between XX and XY

CHMs [52]. Most CHMs have a diploid karyotype but some are tetraploid
[69, 70] and very rarely triploid but androgenetic [66, 71]. Examination
by FC and interphase cytogenetics of large numbers of cells from CHMs
[7,72-75] has shown hyperdiploid and tetraploid fractions not easily
explained by cells in division and which may represent aneuploid cell
populations in about 40% of CHMs. This fits well with the common
observation of large pleomorphic nuclei in molar trophoblast and has
been confirmed by in situ hybridization studies [72, 73] but it does not
mean that all the cells in the CHM are tetraploid and does not conflict
with earlier cytogenetic studies which showed diploid karyotypes in most
CHMs. Very rarely, moles with morphology indistinguishable from that
of androgenetic CHM are found to have a normal diploid biparental

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genetic make-up [60, 76]. Fetal red cells have occasionally been seen in
vessels of such biparental diploid moles [60, 76] and we have seen two
such moles in the same patient [76]. We do not know if the diploid moles
with normal karyotype seen in the same patient by Vejerslev et al [77]
also represent examples of the same condition, but most were diagnosed
as PHM and had significant fetal development. A recent study comparing
features of these familial and biparental CHM to typical sporadic
androgenic CHM reported no consistent differences in features, although
in general, the extent of many changes was reduced in the biparental
group. (78)

4.7 PARTIAL HYDATIDIFORM MOLE

Traditionally, PHM produces less voluminous specimen than CHM and

villous hydrops is focal and noticeable only in advanced cases [79, 80]
[31]. Fetal parts or a fetus, often with congenital malformations or growth
retardation may be present .

Figure 4.10 Partial mole evacuated in the second trimester. A malformed fetus was
present and hydropic change involves only some of the villi (natural size).

PHM are unequivocally associated with increased risk of GTN, occurring in around 1
in 200 cases and CC derived from PHM is also well described. [81-84] Subsequent
studies [33, 51, 85, 86] indicated that PHM was almost always due to triploidy when
two chromosome sets came from the father and one from the mother. Triploidy is a
commoner genetic abnormality than androgenetic CHM [62] and since about 70-80%
of triploids are paternally derived (i.e. PHMs), PHM should be about twice as
common as CHM. In specialized centers the association of PHM with triploidy has
been well over 90% [7, 60, 65, 66]; tetraploid PHMs are rare [64] but most FC
studies include a small proportion of diploid specimens morphologically diagnosed as
PHMs.
Confusion between CHM and PHM results from the failure to update diagnostic
criteria for the earlier gestational age CHMs encountered in current practice. A
diagnosis of PHM based exclusively on the presence of blood vessels or partial
hydrops is often wrong and a diagnosis of PHM based on the presence of fetal tissues
or amnion is occasionally wrong and due to either twin pregnancy or to the rare
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androgenetic CHMs with fetal red cells, discussed earlier. Confusion between PHM
and HA is both conceptual and morphological. HAs include trisomies, monosomies,
translocations and maternally derived triploids [87, 88] and some have morphological
similarities with PHM. There is no evidence that they present a risk of GTN greater
than a normal pregnancy but they may be difficult to differentiate from PHM
especially in limited samples [6, 7]. As a group they are more frequent than PHM and
at present represent around l0% of cases initially registered as PHMs at a regional
centre. [7] Rarely, placental mesenchymal dysplasia can be confused with PHM but
in PMD the stem villi are hydropic and there is no excess trophoblast proliferation
[89, 90]

The main features useful in diagnosing PHMs are as follows:

(a) Trophoblastic excess is focal and less marked than CHM and may not be
detected if the specimen is not extensively sampled. Most classical PHMs were
evacuated in the second trimester when excessive trophoblast is usually
predominantly syncytiotrophoblast projecting from the surface of villi (Figure 4.11)
or invaginating into villous stroma to form pseudoinclusions (Figure 4.12); this
excess may be present in both hydropic and non-hydropic villi. Clusters of
pleomorphic extravillous trophoblast are not common but may be seen in PHM.
Since many PHM are also evacuated in the late first trimester, in many PHMs the
abnormal distribution of trophoblast may be more striking than its florid excess,
especially if there is limited sampling. In our experience hCG in PHM is usually
higher and remains elevated after evacuation for longer than after HA [7], and this is
also reflected in a higher tendency for GTN. There is no excess circumferential
trophoblast in HA but occasional sprouts of trophoblast around small villi may be
seen; however, polar trophoblast is very common in HA, whereas it is less common
to find it in PHM. In PHM the amounts of trophoblast, its proliferative activity, its
aneuploid fractions on FC and the persistence of elevated hCG after evacuation are
significantly less intense than in CHM [7, 67, 91-93]. It should be noted that in PHM,
abnormal trophoblast proliferation affects <10% of villi. (57). One recently described
case series showed that trophoblastic hyperplasia was present in <20% of their
genotyping proved PHM’s and 8% of trisomies showed moderate degree of
trophoblast hyperplasia (94)

Figure 4.11 Partial mole. Circumferential hyperplasia is in this case prominent but
consists mainly of syncytiotrophoblast. This hyperplasia can be very focal and may not
be detected unless sampling is extensive. X50.

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Figure 4.12 Partial mole. The irregular outline of villi has sharp angulations and the inclusions caused by
trophoblastic invaginations are rounded. X80.

(b) In PHM hydrops and cisterns characteristically involve only some of the villi.
The diagnostic confusion resulting from interpreting partially developed hydrops in
young CHMs as evidence of PHMs has already been discussed. In a small proportion
of PHMs hydrops is mild and cisterns may be small or absent in the sample,
especially at early gestations; sampling error is a possible explanation for this but in
some PHMs early fetal death may result in extensive fibrosis of villi rather than
marked hydrops. A common pitfall is to interpret in HA fragments of a gestational
sac which has lost its amnion as villi with large cisterns, but as a rule the wall of the
gestational sac contains more collagen than surrounding villi and the possibility of
HA should always be considered when the suspected cisterns are few and surrounded
by smaller villi, particularly when the placental material obtained is scanty. In
addition hydropic villi in non-molar miscarriage are usually round in outline and
hypocellular in contrast to the irregularly shaped and more cellular villi of PHM (See
later).

(c) Vessels, often containing nucleated fetal red cells, are a common finding in
PHM. Whereas the vessels of a CHM are often collapsed and inconspicuous, those of
a PHM are often open but they gradually decrease in numbers with increasing GA. In
some PHMs avascularity of some villi is associated with angiomatoid vessels in
others (Figure 4.13). These abnormal vessels, mistaken in early publications for
maze-like cisterns [51], are relatively specific for PHM but are identified in only
about 20% of cases. [7,51] Usually, angiomatoid vessels are empty, suggesting fetal
death long before evacuation. An unusual case of extensive angiomatoid changes
resulting in macroscopic grape-like vesicles has been reported in first trimester
miscarriage (94)

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Figure 4.13 Angiomatoid vessels in partial mole. These are commoner in older moles, and although
not pathognomonic of partial mole they are present in about 10- 20% of cases. X50.

(d) Karyorrhexis in villous stroma is seldom present or intense in PHM. This

excludes nuclear debris found within and in the wall of vessels and villi in which the
covering trophoblastic layers are already necrotic. The reluctance of some
publications to emphasize this as a useful diagnostic criterion for CHM is
understandable, since karyorrhexis is such a non-specific histological abnormality,
but its correlation with CHM is very high [7,50,51], although its significance has not
yet been explained.

(e) PHMs have abnormally shaped villi often described as scalloped or dentate
(Figures 4.11 and 4.12) and invaginations of trophoblast result in rounded
inclusions.

Unlike the abnormally shaped ‘budding’ villi of CHM (Figure 4.7) the irregularities
in outline in PHM are more angulated and appear in cross-section as rounded
inclusions which may be solid or cystic and which contrast with the more oval or
irregular inclusions of CHM. Infolding of trophoblastic layers in the hydropic villi of
a PHM may also result in pseudoinclusions similar to those of CM, which are
therefore less useful in differential diagnosis. Scalloping and round inclusions can be
seen in both hydropic and nonhydropic villi, and although the small villi of PHM are
often described as normal some can in fact be very abnormal and may show excess
trophoblast (Figure 4.14).

Unfortunately, irregular villi and round inclusions may also occur in non-molar HAs,
particularly in trisomies, including the two commonest forms trisomy 16 and 18, and
in monosomy 45X0 [95], but in these conditions usually there is no excess
trophoblast. (Figures 4.15,4.16)

(f) In PHM villous stroma contains abundant collagen and this increases with
GA. In PHMs evacuated at early gestations the stroma may be more immature and
mucoid, scalloping less intense and trophoblast more abundant, so that they may
resemble CHMs, but as a rule there is a fine mesh of reticulin fibers in non-hydropic
villi, with stromal cells often present in this mesh. Fibrosis increases with GA and is
present at the periphery of cisterns.

(g) An embryo or fetus, often malformed, frequently dies in early pregnancy and
may not be identifiable in the specimen. Fetal tissues were only present in 20% of a
15
 Pathology

series of PHMs reviewed by our centre [7], but there were fetal red cells in molar villi
in nearly 50% and chorioamniotic membranes in 40%. Fetal red cells may persist in
vessels long after fetal death and are sometimes seen together with a necrotic embryo.
The finding of fetal tissues with a mole is often interpreted as proof of PHM and
although in most cases this is true, the possibilities of androgenetic CHM with twin
pregnancy and CHM with unexplained fetal red cells in molar villi (see section 4.5)
should be considered if the features of the mole are not those of a PHM.
As in CHM, cytogenetic, molecular genetic and interphase cytogenetic studies [73,
96,97] can be helpful for accurate diagnosis. In their absence FC is helpful for
differentiating between diploid CHMs and triploid PHMs and between the latter and
non-molar diploid HAs, particularly when placental material is scanty.

Figure 4.14 Non-hydropic villi in a partial mole are often referred to as normal, but some can be very
abnormal and show excess trophoblast and irregular outline. X50.

Figure 4.15 Irregular villi and rounded trophoblastic inclusions in Patau’s syndrome The inclusions are
few and small. The irregular outline is less angular than in partial mole, there is no excess trophoblast
and hydrops is often minimal or absent.

16
 Pathology

Figure 4.16 Trophoblastic inclusions consisting of single cells resembling intermediate

trophoblast are common in trisomies and rare in partial mole. X150.

4.8 DIFFRENTIAL DIAGNOSIS OF HYDATIFORM MOLES

Villous dysmorphism (abnormal villous morphology, AVM) can be seen in

specimens from miscarriage or surgical/medical termination of pregnancy
(STOP/MTOP) secondary to chromosomal abnormalities. Most commonly
encountered chromosomal abnormalities include trisomy 16, 21, 7, 13, 8, 18, 4, 2
and12. A combination of 2 or more abnormalities may also be acquired. These on
histology show markedly irregular villous contour with simple trophoblastic
pseudo-inclusions and variable degree of hydropic change. Cisterns are unusual
and trophoblastic hyperplasia is very rare but has been reported in approximately
14% and 8% cases respectively in a large series by Buza etal. (94).Trisomies for
chromosomes 7, 15, 21 and 22 may also show trophoblastic hyperplasia
equivalent in severity to that seen in partial or complete moles (49). No single
morphological feature is helpful in differentiating HM from chromosomally
abnormal gestation. A constellation of features is helpful. Buza et al have shown
that combination of features including 2 villous populations, round or oval
trophoblastic pseudoinclusions, and cistern formation increased the specificity to
94% with a positive predictive value (PPV) of 79%. The most specific
morphologic features for PHM according to this study were combination of
cistern formation and chorionic villous size >2.5 mm, reaching 96% specificity
and 90% PPV (94)

Digynic triploid gestations can mimic PHM not only at the morphologic level, but
also on DNA ploidy analysis. Dysmorphic villi with irregular contours,
trophoblastic pseudo-inclusions and syncytiotrophoblast sprouts are a feature and
these are usually non-hydropic. Most villi are vascular and contain nucleated red
blood cells. One third of all triploids are digynic, non-molar gestations, without
an increased risk of GTN, hence need no follow-up. Genotyping is helpful in
excluding PHM in difficult cases but p57 and ploidy analysis play no role (49,
98)

Placental mesenchymal dysplasia, also known as “pseudo-partial mole”, is a form

17
 Pathology

of androgenetic/biparental mosaicism that mimics PHM in second or third

trimester of pregnancy (98, 99, and 100). Villous hydrops of stem villi, often with
cistern formation, is seen along with thrombosis and or aneurysmal dilatation of
stem villous vessels. Terminal villi appear normal or show chorangiomatoid
changes and no abnormal trophoblast proliferation is noted. Villous stroma
consists of spindle and stellate mesenchymal cells in a myxoid background.
P57staining may be negative or discordant.

Twin pregnancy with coexisting normal fetus and CHM may mimic the dual
villous population of PHM as a result of admixture of large molar villi with smaller,
normal-appearing villi. Presence of fetal tissue, nucleated red blood cells or
gestational membranes from the normal twin may be taken as evidence of PHM. P57
will show ‘divergent pattern’ of p57 (101,102) with an admixture of p57 negative and
positive villi. This is helpful in confirming the suspected morphological diagnosis.
Ploidy will show diploid conception and genotyping will be helpful if two population
of villi are microdissected.

Mosaic moles are rare and present with apparent diffuse placental CHM change
with molar villi intermixed with morphologically normal villi, and a
chromosomally and phenotypically normal infant. They appear to represent true
mosaicism, with androgenic and biparental cell lines derived from the same
sperm. The villi are androgenetic in the molar areas and biparental in the
histologically normal areas [98]. Discordant p57 expression characterizes
androgenetic/biparental mosaic/chimeric conceptions, with discordant expression
in different cell types based on the presence or absence of maternal genetic
material in those particular cells. Discordant p57 implies any
combination/admixture of negative and positive results for villous stromal cells
and cytotrophoblast within individual villi, including positive staining in
cytotrophoblast and negative staining in villous stromal cells, or vice versa
(101,102).

Figure 4.17 Placental Mesenchymal dysplasia showing hydropic and enlarged stem villi with
aneursymal dilatation of vessels. Tertiary villi are normal

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Figure 4.18 Twin Pregnancy with large molar villi (right) and normal tertiary villi (left)

4.9 INVASIVE MOLE

The majority of CHMs remit after evacuation and curettage, but the tendency in
some instances to invade the myometrium resulting in uterine perforation and
extension to adjacent organs is well known and historically approximately 15% of
CHMs behaved in this way [12, 15, and 16]. Histologically the appearance of the
chorionic villi is similar to that of other CHMs, but swelling of villi is less often seen
in deeply implanted invasive moles and histological diagnosis is based on the
excessive trophoblastic proliferation, markedly irregular shape of villi and their
invasive nature (Figure 4.19). Some degree of myometrial trophoblastic invasion is
probably present in most moles; indeed, myometrial invasion is not exclusive to
molar pregnancies. Hertig [12], borrowing the terminology used for myometrial
placentation, classified invasive moles into accreta, increta and percreta. Since
hysterectomy is rarely performed in current practice in the treatment of moles, the
few specimens seen are usually in unmonitored and often unsuspected pregnancies
and, sometimes, are paradoxically percreta moles (the rarest form) presenting as
acute abdomen due to uterine perforation (Figure 4.20) and consisting of a hematoma
with molar villi often implanted on a pelvic organ such as the ovary, tube or broad
ligament, or on a loop of intestine. IM in association with PHM is very rare. All but
one of the IMs in hysterectomy specimens in our archival material are CHMs but rare
invasive triploid PHMs requiring hysterectomy have been reported [83,103] and we
have seen a PHM which required three curettages, the last under ultrasound control,
for removal of deeply implanted myometrial villi.

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 Pathology

Figure 4.19 Fundal unsuspected invasive mole.

Figure 4.20 Invasive CHM in myometrial vessels. There is abundant excess trophoblast
and hydrops is conspicuous.

4.9 MOLAR METASTASES

CHMs can spread locally to the cervix, vaginal wall and vulva
[58,104,105] but with modern chemotherapy this does not imply a worse
prognosis [58]. In the past, up to 10% of patients with CHM had
radiological lung opacities which were interpreted as metastases [106]
and this was confirmed histologically in some cases [107,108]. With
early diagnosis and early chemotherapy, the number of patients with
metastases has been reduced and disease is usually limited to the uterus
and parametrial tissues. Exceptionally, tissue from CHMs has been found
in other sites, including brain, retroperitoneum and inguinal lymph nodes
[15]. In pre-chemotherapy days lung metastases sometimes regressed
after evacuation or eradication of the mole [109], but the appearance or
persistence of metastases long after evacuation of a CHM may indicate
GTN or CC. We have not seen tissue from PHMs outside the uterus.

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 Pathology

Figure 4.21 Invasive CHM in lung parenchyma presenting as haemothorax (a). Molar villi
and trophoblast are seen plugging a bronchial blood vessel (b).

4.10 ECTOPIC MOLES

There is a tendency to overdiagnose tubal moles due to the presence of

extensive trophoblast proliferation which may be associated with
abnormal implantation at this site. [110, 111]. Burton et al (2001) noted
only 3 of 20 cases referred as ectopic moles were confirmed on review
and similarly, this is our experience, [112, 113] most referred cases
turning out to be non-molar specimens with abundant polar trophoblast in
early gestation. It appears that tubal moles are considerably rarer than
tubal CC and we have found no reliable reports of tubal mole followed by
CC, although GTN after tubal pregnancy does occur [114,115].

4.11 HYDATIDIFORM MOLES WITH TWIN PREGNANCY

The fact that CHMs can coexist with a twin pregnancy has already
been mentioned as a possible cause of confusion in the ultrasound and
histological diagnosis of PHM and as one of the possible explanations of
the finding of fetal red cells in the vessels of a CHM. Twin molar
pregnancies are now well-reported. The frequency of dizygotic twin
pregnancy in the general population is one in about 110 [116]. CHMs
21
 Pathology

with evidence of a twin, or a second population of non-molar villi

suggestive of a twin, represent about one in 200 histologically confirmed
CHMs. Combinations of PHM with a normal twin are considerably rarer
and we have only seen a handful of examples: one possible reason is that
it may be more difficult to detect morphologically, particularly in early
miscarriages.
The outcome of pregnancies with histologically confirmed CM and
co-twin has been examined in a series of 77 cases at Charing Cross
Hospital. The risk of GTN development was no higher than reported
following singleton CM pregnancies, and furthermore, the risk of GTN
was not different in those cases managed by early elective termination of
pregnancy at diagnosis and those who chose to continue the pregnancy.
However, in such cases in which pregnancy continuation is attempted,
several complications may develop. Almost half of the pregnancies result
in fetal loss before 24 weeks’ gestation, and of the half that reach
potential viability, 25% result in intrauterine death and 40% deliver
severely preterm at <32 weeks’ gestation. In this series, severe pre-
eclampsia was an unusual complication (5%). Therefore, overall, the
incidence of GTN in CHM with a twin is similar to that of CHM in a
singleton pregnancy and the risk of GTN is unaffected by pregnancy
management [117- 123].

Immunohistochemistry in the diagnosis of molar disease

The basis for the diagnosis of CHM and PHM remains detailed
examination of tissue morphology on routine Haematoxylin & Eosin
(H&E) stained sections. Additional special stains may be carried out to
highlight certain aspects of the microanatomy, such as trichrome stains
for collagen, but these have not been shown to provide useful additional
diagnostic information. Immunohistochemical methods may be used to
identify trophoblast and define the hormonal profile of the tissue but, in
contrast to the case with gestational trophoblastic neoplasia, in molar
pregnancy, this does not provide clues to the differential diagnoses.[6]
Immunomarkers of cell proliferation, such as PCNA and Ki67, have also
been examined in this context, and similarly have been reported to be of
little practical use in differentiating between HA, CM and PM. [124, 125]
Recently, the expression of cell cycle control proteins has been examined
and E2F-1 and cyclin E reported to be upregulated in molar tissue [126].
Furthermore, since molar pregnancies are associated with defects in
imprinting (see chapter 2), it has been suggested that abnormal expression
of imprinted gene products could also provide diagnostic information.
Distinguishing between partial moles and complete moles on
morphological features is not usually difficult but occasionally,
particularly in early gestations, the features indicate a molar pregnancy
but determining the type is difficult. The assessment of expression of the
p57KIP2 protein, a cell cycle inhibitor, has proved useful in specialized
centres. p57KIP2 is a strongly paternally imprinted gene, being expressed
predominantly from the maternal allele in most tissues. Hence there is a
lack of p57KIP2 expression in cytotrophoblast and villous mesenchyme in
CHM compared with strong expression in similar cells in both PHM and
HA. [127]. Such immunostaining however, is of no value in
distinguishing between PHM and non-molar miscarriage, which is the
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 Pathology

most difficult morphological differential diagnosis.p57

immunohistochemical analysis is quite useful for recognition of
androgenetic/biparental mosaic/ chimeric conceptions [102].Pitfalls for
p57 staining include occasional p57 positive CHM in cases of retained
maternal chromosome 11 and similarly loss of maternal chromosome 11
resulting in p57 positive PHM. We have also encountered cases of non-
molar p57-negative biparental diploid, with no morphological features of
biparental hydatidiform mole. These have also been reported in a large
series by Banet et al [102]. At present therefore, immunohistochemical
techniques remain an important but minor adjunct to morphological
diagnosis in molar disease.

4.12 PROGNOSIS OF MOLES

No immortal cell lines or long-term growth in nude mice have yet

been achieved with trophoblast of moles [128], whereas this can be
readily done with CCs. This supports the view that the excessive
trophoblastic proliferation in moles intrinsically lacks the features of
malignancy in most cases. Nevertheless, molar trophoblast can continue
to grow and invade, needing active intervention to preserve the uterus or
to avoid a catastrophic hemorrhage. Exceptionally, molar trophoblast can
survive for long periods and the immediately preceding pregnancy of a
CC may not be the genetically causative one, the tumour genetically
deriving from the previous CHM. [129,130]; however, the vast majority
(>95%) of complications due to persistent or invasive moles occur in the
six months following a molar evacuation [131-132]. The reported
incidence of CHMs needing treatment varies according to the criteria for
diagnosis of GTN and to whether PHMs and HAs have been reliably
excluded in the series. Around 8% of all moles require treatment
[86,131,132], including around 15% following CHM and 0.5% following
PHM. Figures of up to 30% reported from the USA [134,135] are a
consequence of less stringent diagnostic criteria for GTN and many such
patients would not have been treated in the UK. A higher incidence of
GTN was initially suggested in heterozygous (dispermic) moles
[135,136], which comprise about 20% of CHMs [28], but this has not
been supported by more recent studies [26,28,137]. The lack of
relationship between the amounts of trophoblast in the sample and the
incidence of GTN has already been discussed. Although as a group
CHMs with higher hyperdiploid fractions may have higher incidences of
GTN [67] this does not predict outcome in individual patients. Neoplastic
transformation of a mole is recognized when villous stroma is no longer
formed but nothing is known of the factors which control this change in
behavior. In the past, approximately 3% of CHMs became CCs [11, 12].
Because of early chemotherapy in CHM, the figure now is probably
lower, but the real incidence is not known, since histological confirmation
in GTN is nowadays seldom available, the patients being treated with
chemotherapy on the basis of their hCG levels.
The incidence of GTN after PHM is considerably lower than after
CHM. High incidences of 18% and 20% [90, 138] include many diploid
PHMs which undoubtedly were misdiagnosed CHMs. Using American

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 Pathology

criteria for diagnosis of GTN, 5.5% of patients with PHMs were treated
in the New England Trophoblastic Disease Center [139]. Using UK
criteria, GTN follows about 0.5% of histologically reviewed PHMs [6]
[140]. The incidence of CC after PHM is not known but histologically
and genetically confirmed cases are well-reported. We have not observed
more trophoblast in PHMs which develop GTN than in PHMs which do
not, but trophoblastic excess in PHM can be very focal and the potential
for sampling error is great.

Despite numerous small studies suggesting a range of morphological

features and immunohistochemical findings being associated with
adverse outcome, recent blinded data indicates that there are no features
or immunoprofiles, present at diagnosis of CHM that can reliably predict
those cases at increased risk of developing GTN and requiring
chemotherapy (57)

4.13 CHORIOCARCINOMA

This is a malignant neoplasm of trophoblast with differentiation

towards the phenotype of villous cytotrophoblast and syncytiotrophoblast
(Figure 4.22). Occurring primarily in patients of reproductive age, rare
cases of gestational choriocarcinoma have been reported in post
menopausal patients after long latency (141). It can occur after CHM,
PHM or non-molar pregnancy but the incidence of CC after CHM (about
1 in 50) is about a thousand times greater than after a normal pregnancy
(about 1 in 50,000). The proportion of CCs preceded by moles in
reported series varies between 39% and 78%, but this is probably an
underestimate due to under-recognition of early complete moles in the
historical literature [4]. It is generally assumed that the immediate
antecedent pregnancy is responsible for the tumour and although in most
cases it may be so, it is not necessarily the case [129,130]. As in the case
of hydatidiform mole, there are remarkable differences in the incidence of
CC in various parts of the world [4, 28,142].
These are not always explained by an increase in preceding moles but a
serious epidemiological study of the problem is hindered by variations in
the way in which the information is recorded, bias in the selection of
reported cases and the very success of therapy, which all too often
nowadays precludes us from knowing the true nature of the trophoblastic
disease treated.
Vaginal bleeding and marked elevation of serum human chorionic
gonadotropin (hCG) are the characteristic clinical findings; however some
cases may present with a metastatic disease and subsequent diagnosis of
the primary tumour. In rare cases the primary tumour cannot be
discovered and is assumed to have undergone spontaneous regression.
Macroscopically uterine CC typically appears as bulky, destructive,
single to multiple dark red, shaggy masses with extensive hemorrhage,
and variable amount of necrosis. The lesion may line the uterine cavity or
is deep within the myometrium (Figure 4.22, 4.23). Microscopically,
tumour shows an expansile/ pushing border with characteristic bilaminar
pattern reminiscent of pre-villous trophoblast. The neoplastic cells are an
admixture of of syncytiotrophoblast, intermediate trophoblast and

24
 Pathology

cytotrophoblast. The biphasic pattern (Figure 4.24) is easily identifiable

but in some cases most of the tumour is either predominantly
syncytiotrophoblastic (Figure 4.25) or predominantly cytotrophoblastic
(Figure 4.26, 4.27). This monomorphic variant may be difficult to
diagnose and requires a careful search for second component. The viable
tumour is frequently seen only at the periphery of the nodule and within
vascular spaces in adjacent myometrium and as a rule no intrinsic
vasculature can be demonstrated. Blood–lakes, pseudovascular channels
and geographic necrosis is therefore a frequent accompaniment. A direct
relationship between the intensity of the surrounding inflammatory
reaction and a better prognosis has been demonstrated [143] and some
relationship between the degree of anaplasia and prognosis has been
suggested [144]; these studies have less relevance today because of the
good therapeutic response seen in most patients.
Some predominantly cytotrophoblastic tumours secrete smaller
amounts of hCG [145]. This is not surprising, since synthesis of hCG
occurs mainly in syncytiotrophoblast. Some hPL is usually demonstrable
in syncytiotrophoblast but, unlike placental site trophoblast, villous
cytotrophoblast does not contain significant amounts of hPL. The
morphology of CC can be markedly changed after chemotherapy, and
when therapy-resistant metastases are removed they are often composed
of bizarre mononuclear cells [146] which probably represent therapy-
resistant clones. These atypical CCs are sometimes difficult to
differentiate from PSTT and ETT but unlike PSTT and ETT, they form
hemorrhagic nodules, readily infiltrate vessels, have a high mitotic rate
and express more hCG than hPL or PLAP [147].

Figure 4.22 Choriocarcinoma grows by invading maternal vessels and viable tumour is
usually only found at the periphery of a hemorrhagic mass. Reduced from natural size.

25
 Pathology

Figure 4.23 Choriocarcinoma with a circumscribed haemorrhagic and necrotic mass in

lower uterine segment.

Figure 4.24 The typical form of choriocarcinoma forms cyto- and syncytiotrophoblast
similar to that of villous trophoblast. X180.

Figure 4.25 Predominantly syncytiotrophoblastic choriocarcinoma in endometrial

curettings.

26
 Pathology

Figure 4.26 Some choriocarcinomas are predominantly cytotrophoblastic and secrete

less hCG but retain a predominantly intravascular mode of invasion; unlike placental site
tumor they contain little hPL, are composed of cells with less dense cytoplasm and have
numerous mitoses.

Figure 4.27 Monophasic choriocarcinoma mimicing poorly differentiated

choriocarcinoma

CC metastasizes readily and it is not uncommon to find secondary

nodules in the cervix or vagina on presentation. The lungs, brain and liver

are the distant organs more often involved and sometimes metastases

dominate the clinical picture and patients may rarely present with

intracerebral hemorrhage or with acute cor pulmonale due to extensive

intravascular lung disease [148,149]. Unexplained intracerebral

hemorrhage or acute cor pulmonale in a woman of childbearing age

should prompt suspicions of CC. Failure to consider this possibility has

led in the past to CC developing in immunosuppressed organ recipients

[150]. Melena or hematuria from metastases to intestine or kidney are

27
 Pathology

less common [149]. In contrast, lymph nodes are rarely the site of

metastasis and the finding of a tumor with apparent trophoblastic

differentiation in lymph nodes without evidence of a gestational primary

should raise doubts about the gestational origin of the tumor, which could

be of germ cell origin or a carcinoma with trophoblastic metaplasia. CC

following a normal term pregnancy is presumably the result of the

development of an intraplacental choriocarcinoma (Figure 4.28) but the

primary tumor may be microscopical and may not be detected, since

pathological examination of apparently normal placentae in normal births

is seldom carried out. Origin from specific pregnancies can nevertheless

be demonstrated genetically [125]. It should be remembered that

placental CC can metastasize to the child as well as the mother [151-153].

A common problem is the differential diagnosis between CC and

trophoblast from an early pregnancy or that of a mole. Curettage in an

early pregnancy may yield abundant sheets and fragments of pleomorphic

trophoblast. As a rule, normal young trophoblast is less pleomorphic than

that of CC and its polar arrangement may still be discernible. It is

exceptional to find villi when CC develops except in the context of third

trimester intraplacental CC. The presence of villi and abundant

trophoblast in endometrial curettings is suggestive of a recent miscarriage

rather than CC, which has in the past been overdiagnosed by pathologists

[154], but in a few cases residual degenerate villi may often be seen

[145]. However, the pleomorphic trophoblast from a mole, particularly a

CHM, can be morphologically indistinguishable from that of CC,

although it has a different biological behavior. Selective sampling of a

28
 Pathology

second curettage after evacuation of a CHM may yield trophoblast

without villous stroma, when a diagnosis of persistent trophoblast should

be made and its significance judged together with clinical ultrasound and

serological data. As a rule, the longer the period between evacuation of a

known pregnancy and the finding of trophoblast in curettings, the more

likely its pathological significance provided a new pregnancy can be

ruled out [154].

An additional diagnostic difficulty may be differentiating a true

gestational choriocarcinoma from non-gestational germ cell tumour or
rare choriocarcinomatous differentiation in a somatic malignancy. This
can only be achieved with certainty using molecular genotyping of
microdissected tumour and non-tumour tissue (see genetics chapter)

4.14 ECTOPIC CHORIOCARCINOMA

Primary CC of the fallopian tube is rare but well-described [110].

(Figure 4.28). About 60% of patients presented with acute symptoms
simulating an ectopic pregnancy and the rest had a pelvic mass
indistinguishable from an ovarian tumor. In no case was there evidence of
a preceding ectopic mole but in two instances there were residual
chorionic villi and evidence of a gestational sac, an unusual finding in
uterine CC. In all other aspects (distribution of metastases, mortality,
response to chemotherapy) the tumors behaved like uterine CCs and only
five of 47 patients survived before the advent of chemotherapy; in
contrast 15 of 16 patients given chemotherapy survived. Tubal CC may
also present with metastases [112] and has been described following
fertility treatment [155].
Although cases of gestational CC of the ovary, broad ligament and
peritoneal cavity have been reported [15,156,157,158] reliable evidence
of their gestational rather than germ cell or metaplastic origin can only be
obtained by genetic fingerprinting of the tumor, the patient and the
patient’s partner. Trophoblastic metaplasia and hCG production can occur
in many carcinomas [159] including ovarian and endometrial carcinomas
[160,161]. Histological differentiation from CCs is not always easy, since
they can mimic the pattern of vascular invasion and the bilaminar
structure of villous trophoblast (Figure 4.24). In some cases there is a
second pattern, such as adenocarcinoma, squamous carcinoma or
transitional cell carcinoma which gives away the diagnosis, but in others
tumors are undifferentiated but for the presence of syncytiotrophoblast or
hCG production; suspicions that the tumor may not be gestational should
arise if the tumor is producing little hCG for its bulk, if it has a vascular
stroma on histology and if it is resistant to chemotherapy. Confirmation
29
 Pathology

is now possible by comparing genetic polymorphisms of the tumor with

those of the patient and her partner, and modern techniques can give a
quick answer which can influence clinical decisions [162,163]. The
problem is not just academic since in carcinomas with trophoblastic
metaplasia surgical eradication offers the only hope of a cure.
Carcinomas with trophoblastic metaplasia probably account for the
majority of so-called ‘primary choriocarcinomas’, reported in viscera,
including lungs, breast, stomach, intestine, liver, adrenal, pancreas,
bladder and kidney [159,163-174].(Figure 4.29)

Figure 4.28 Choriocarcinoma in the fallopian tube. Tumor is obliterating the lumen and
invading the wall of fallopian tube. Choriocarcinoma does not have intrinsic vasculature.

30
 Pathology

Figure 4.29 Carcinoma of the colon with trophoblastic metaplasia. The patient was a 64-
year-old woman and in places the tumor was an adenocarcinoma, but in places (see
intravascular tumor in the lamina propria) was differentiating towards trophoblast with hCG
production. X100.

4.15 INTRAPLACENTAL CHORIOCARCINOMA

Gestational choriocarcinoma is a nonvillous trophoblastic neoplasm with the
exception of intraplacental choriocarcinoma. This develops near term in an otherwise
normal pregnancy. Most reported cases have clinical evidence of a maternal and/ or
fetal metastatic disease (175). It is extremely important to recognise this condition and
once the diagnosis is confirmed both the mother and fetus must be thoroughly
evaluated to exclude metastatic disease [151-153].

On gross examination intraplacental CC are non-specific, resembling either placental

infarcts or thrombi and may be missed on initial examination.

On histological examination, the lesion shows focal proliferation of atypical abnormal

villus cytotrophoblast and syncytiotrophoblast filling the intervillous space with
involvement of adjacent villi (Figure 4.30).

Figure 4.30 Choriocarcinoma in third-trimester placenta. The patient developed lung

metastases soon after delivery of a stillborn infant. X100.

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 Pathology

4.16 PLACENTAL SITE TROPHOBLASTIC TUMOR

This is a rare gestational trophoblastic neoplasm, representing

0·2% of UK gestational trophoblastic disease (48). It is believed to be the malignant
counterpart of non-villous implantation site intermediate trophoblast, which infiltrates
the placental site in normal pregnancy. Kurman et al [176] described 12 cases in
which the lesion remained localized and was sometimes eradicated by simple
curettage. They proposed the term ‘trophoblastic pseudotumor’ but within a few years
it was clear that, on occasion, this lesion behaved in a locally aggressive way and
could metastasize [35,37,177,178] and ‘placental site trophoblastic tumor’ [37], is
now the preferred term, which reflects the morphological similarities with placental
site trophoblast. Epithelioid trophoblastic tumour (ETT) is probably a variant of PSTT
in which trophoblastic differentiation more closely resembles the ‘vacuolated’
trophoblast often seen in the chorion of late pregnancy. In these tumours, PLAP rather
than hPL is often the dominant immunoreactant [37,179].
PSTT usually present in the reproductive age group with amenorrhea or irregular
vaginal bleeding months or years after a pregnancy, [35,178,180] and origin from
both moles (including PHM) and normal pregnancy has been demonstrated
genetically [181,182]. Occasionally, the patient may be peri- or post-menopausal
[182-184]. The mean interval from the last pregnancy is three years but a range of
less than two years to over five years were seen in a review of 34 cases at Charing
Cross Hospital [185]. The mean interval tends to be longer, six years, for ETT with
intervals of up to 18 years having been documented.

Figure 4.31 In placental site trophoblastic tumor necrosis is often extensive but unlike
choriocarcinoma hemorrhage is less conspicuous. Reduced from natural size.

The uterus in PSTT is usually enlarged and pregnancy proteins such as hCG, hPL and
ß1-glycoprotein (SP-1) are elevated although hCG is seldom as high as in CC. In rare
instances (less than 10% of reported cases), PSTT may be associated with the
nephrotic syndrome, which has remitted after eradication of the tumor [35,186].
Fibrin and IgM have been found in glomerular intracapillary deposits. A report of
virilization and testosterone production by a PSTT appears exceptional [187].The
disorder should be suspected if hCG concentrations are low for the volume of disease

32
 Pathology

present on imaging and free-β-hCG values are high, but these features are not
diagnostic. Histological analysis is needed to substantiate the diagnosis.

Curettage may yield decidua or myometrium infiltrated by trophoblastic cells with

dense eosinophilic cytoplasm and pleomorphic nuclei (Figure 4.32); they can be
mononuclear or multinucleated and they often form clusters or cords which separate
myometrial muscle fibers. It may be difficult, or even impossible, to differentiate
between an exaggerated placental site reaction and PSTT in endometrial curettings,
since there may be scanty material or this may be extensively necrotic [188]; also less
confluent PSTT at the periphery of the mass may look identical to placental site
reaction [189]. Immunocytochemistry for hCG, hPL, p63, MelCAM and PLAP is
helpful in diagnosis. In general, PSTT contains more positive cells for hPL and
MelCAM than hCG, p63 and PLAP and finding more hCG than hPL in a tumor may
mean that the tumor is not PSTT but predominantly mononuclear CC. These tumors
have an intravascular rather than interstitial mode of infiltration. They tend to form
hemorrhagic masses and metastasize early [147], so that they behave like CC in all
but the fact that they tend to be chemoresistant like PSTT. Sometimes, there are great
variations in the amounts of hCG detected serologically during treatment which are
not always explained by tumor bulk. Ourselves and others have also noted mixed
tumours consisting of morphologic areas representing both PSTT and CC. [17] We
have observed tumors with morphology of PSTT in the uterus and morphology of CC
in the metastases, as well as tumors with areas indistinguishable from PSTT and areas
looking like cytotrophoblastic CC; it is therefore possible that CC and PSTT may not
arise from different progenitor cells, and whether differentiation occurs towards
villous trophoblast or implantation site intermediate trophoblast could depend on
environmental factors, including prior chemotherapy which could select
chemoresistant clones [187]. In favor of this is the fact that a common form of
presentation of PSTT is as a chemoresistant trophoblastic tumor, but there is no doubt
that some PSTTs have their characteristic morphology even when no chemotherapy
has been administered.

Figure 4.32 Placental site trophoblastic tumor infiltrating myometrium. Cells are
predominantly mononuclear and mitoses are rare. Infiltration is predominantly interstitial
and tumors express more hPL than hCG.

33
 Pathology

Figure 4.33 Placental site trophoblastic tumor infiltrating vessels with characterstic eosinophilic
fibrionoid degeneration of vessel wall resembling implantation site

The most problematic differential diagnosis for PSTT includes an exaggerated

placental site reaction. Confluent sheets of predominantly monomorphic cells,
unequivocal mitoses, an elevated Ki67 index, and absence of chorionic villi are all in
favour of PSTT.[17,190,191] Placental site reaction may have more multinucleate
giant cells. The formation of large sheets of trophoblastic cells with some mitotic
activity appears to be a reliable criterion of neoplasia but in many instances it may
only be possible to say that there is persistent placental site trophoblast and judge
whether it is physiological or pathological in the light of clinical, ultrasound and
serological observations.

A second area of difficulty arises in the differential diagnosis of PSTT from

trophoblastic proliferations like placental site nodules (PSN) [34, 192-195]. In our
experience and that of others, regressing lesions often show marked hyalinization or
central necrosis (Figure 4.34) and, occasionally, there is difficulty in demonstrating
cytoplasmic hPL or hCG, although the epithelial nature of the trophoblastic cells can
be demonstrated with immunostains for cytokeratin [147, 192-195]. It has been
proposed that these nodules are derived from chorionic-type intermediate trophoblast
and their immunocytochemistry profile supports this hypothesis.[196] Some of these
regressing nodules express more p63 and PLAP than hPL [193] but as in PSTT this
may be a reflection of their age. As a rule, PSNs are not associated with elevated
urinary or serum hCG but we have seen PSNs persist for years after the last known
pregnancy. Furthermore, we have recently published the largest study reporting
followup and outcome in a series of PSNs with atypia [197] showing that a
proportion of APSN are associated with malignant placental site or epithelioid
trophoblastic tumours (PSTT/ETT).
Placental site trophoblastic tumours must also be distinguished from ETT, epithelioid
leiomyosarcomas and squamous cell carcinomas. Smooth muscle tumours do not
stain for Inhibin alpha, HPL or cytokeratin 18. Squamous cell carcinomas will not
stain for Inhibin alpha and HPL. ETT usually show stronger staining for PLAP and
p63 and weaker staining for HPL. [17]

PSTT forms masses in which necrosis is marked, but hemorrhage is less conspicuous
(Figure 4.31 a). This reflects a lesser tendency to vascular invasion, infiltration being
predominantly interstitial. Necrosis can be very extensive in long-standing tumors
and dystrophic calcification can occur in areas of necrosis [147], tumor surviving
34
 Pathology

only around vessels (Figure 4.33). In our experience these long-standing tumors
express more PLAP than hPL or hCG [147]. There are good descriptions of the
electron microscopy of PSTT and CC [28,198] but this seldom helps in diagnosis.

PSTT can infiltrate extensively and extend into adjacent organs such as the ovary,
parametrium, rectum or bladder. Distant metastases can occur in lungs, peritoneum,
liver, pancreas and brain, and we have observed retroperitoneal and supraclavicular
lymph node metastases in a tumor with long evolution. It appears that mitotic counts
(more than five mitoses per 10 high-power fields) may predict tumors with
metastasizing potential [147,178,199,200,206]; even this may not prove reliable in
some cases and we have seen a tumor with 11 mitoses per 10 high-power fields in
curettings which apparently regressed, the patient refusing hysterectomy and being
delivered of a normal infant two years later [147].

PSTT grows more slowly, metastasise later, and more commonly involve lymph-
nodes,
and produce less hCG than do choriocarcinomas (48). The importance of recognizing
PSTT lies on the one hand in its lesser metastasizing potential, which makes it
amenable to surgery, and on the other in its greater resistance to chemotherapy,
which accounts for therapeutic failures when surgery is no longer able to arrest its
progress. Hysterectomy with sampling of pelvic lymph nodes is the treatment of
choice.Ovaries are conserved unless the patient has a family history of ovarian cancer
or is postmenopausal. Chemotherapy is indicated for patients with metastases or poor
risk factors such as disease presentation beyond 4 years from the antecedent
pregnancy. However, young nulliparous women may strongly desire to preserve
fertility, especially when there seems to be a focal abnormality in the uterus.
Although uterine-sparing surgery is possible, multifocal microscopic uterine disease
can happen and could compromise survival (201- 204). Appropriate counselling is
needed.

Higher mortality, 20% overall in our experience, appears to be linked with lung
metastates and presentation greater than four years from the previous pregnancy.
[185]

Figure 4.34 Regressing placental site nodule. There is often central hyalinisation around
individual cells, and cells may not express any hormones, although they are usually positive
for cytokeratin structural antigens.

4.16.1 EPITHELIOID TROPHOBLASTIC TUMOUR

35
 Pathology

This is the most recently described and rarest trophoblastic tumour that simulates a
carcinoma. It is composed of malignant trophoblast with differentiation towards
intermediate trophoblast phenotype, and is distinct from both CC and PSTT although
mixed tumours with two or three of these phenotypes together have been noted. In
one of the original papers of 14 cases, 5 cases had a focal mixed pattern [37]. It has
been suggested that PSN may be the benign counterpart of ETT and possibly it is this
lesion which progresses to ETT. A rare group of larger ‘atypical’ PSNs, measuring
over 5 mm with more cellularity and a ki67 index between small PSN and ETT exists
[190] and PSN has been reported adjacent to ETT. [196].

ETT, like other GTN, presents in reproductive age females ranging from 15 to 48
(mean, 36) years. Most patients present with abnormal vaginal bleeding occurring 1
to 18 (mean 6) years after a prior gestation, which is usually a full-term delivery
(205)

This tumour presents as a discrete uterine mass. Microscopically, there is a

characteristic nodular, expansive growth pattern rather than the more diffuse,
infiltrative pattern seen with PSTT. The tumor is composed of sheets and nests of
mononuclear trophoblast with clear, eosinophilic and vacuolated cytoplasm
resembling ‘chorionic’ type intermediate trophoblast [17, 37, 207]. There may be
areas of necrosis and dystrophic calcification. The most characteristic distinctions
however, from monomorphic CC or PSTT, are the nodular architecture and the
immunohistochemical profile. ETT usually stain diffusely positive with p63, PLAP
and cytokeratin, whereas hCG and hPL positivity is weak and scattered
[37,181,207,208]. It would seem from the recent literature that ETT is truly a rare
but distinct trophoblastic tumor rather than just a morphological variant of
longstanding PSTT, although the biological behaviour appears similar.

Figure 4.35. A. Characterstic nodular and expansive growth pattern of ETT mimicking
carcinoma B. Calcification and necrosis in an epithelioid trophoblastic tumour

36
 Pathology

Figure 4.36 Predominantly mononuclear cells with pleomorphism and mitoses

The tumour is confined to uterus when diagnosed, in majority of these patients.

Hysterectomy is the treatment of choice for these patients. Metastases and death
occur in about 25% and 10% of patients, respectively. Lung resection of metastatic
ETT has occasionally been used successfully. ETTs are not as responsive to the
chemotherapeutic agents used in treating other GTN types; therefore, drug
combinations of platinum with etoposide and paclitaxel are used in managing
metastatic ETT (205).

4.16.2 DIFFERENTIAL DIAGNOSIS OF TROPHOBLASTIC TUMOURS

In cases with morphological findings of a predominantly monomorphic, apparently

trophoblastic tumour the differential diagnoses include monomorphic (or post-
chemotherapy) CC, PSTT, ETT and non-gestational malignancy with trophoblastic
differentiation. The important features of each lesion are previously described but it
should be emphasied that on small biopsy material it may not be possible to establish
the diagnosis with certainty on morphological or immunohistochemical grounds
alone. The most important distinction is between non-gestational carcinoma with
trophoblastic differentiation and GTN, since the response to appropriate
chemotherapy is markedly different and in such cases DNA analysis of the tumor may
provide valuable information in determining with certainty the gestational or non-
gestational nature of the lesion. [129]

4.17 Placental Site Nodule (PSN) and Atypical Placental Site Nodule (APSN)

PSNs occur in the reproductive age group and represent the remnants of a previous,
sometimes unrecognized, pregnancy and its extravillous trophoblast. The antecedent
pregnancy has been reported to have occurred as many as 108 months before the
diagnosis (209-212). Many patients have a history of therapeutic abortion and
cesarean section, and a significant number have a history of a tubal ligation (210).

These lesions are usually incidental findings at hysterectomy or in biopsy specimens

of endometrium, lower uterine segment, and cervix (210-214), with rare cases
occurring in Fallopian tube, broad ligament and ovary (209, 215-217). Less
commonly, patients may be symptomatic, presenting with abnormal uterine bleeding,
recurrent pregnancy loss, abnormal cervical smear results or infertility (17, 209, 212).
37
 Pathology

Macroscopically, PSN appear as single or occasionally multiple, yellow to tan

nodules or plaque ranging from 1 to 14 mm (average 2.1). Histological examination
reveals small, well-circumscribed nodules composed of intermediate trophoblast of
chorionic type with central hyalinisation (Figure 4.37). The trophoblastic cells mainly
singly dispersed or arranged in small clusters and cords and rarely as diffuse sheets.
They have abundant and eosinophilic to clear cytoplasm, relatively small uniform
nuclei and a few having large, irregular, and hyperchromatic nuclei. Multinucleated
cells are occasionally present. Mitotic figures are rare or absent.

Figure 4.37 Typical placental site nodule—(A) Small, circumscribed hyalinized nodules
with rim of intermediate trophoblast. (B) Paucicellular lesion with minimal cytologic atypia,
degenerating and shrunken nuclei (inset with low Ki-67 labeling index).

It is now recognised that rare lesions may be encountered with histopathological

features intermediate between typical PSN and PSTT/ETT, represented by the term
Atypical Placental Site Nodule (APSN).

There are no well-established objective histological criteria to definitively distinguish

APSN as an entity, other than general agreement that they represent lesions which
appear ‘atypical’ to histopathologists experienced in this area. The lesions are
generally larger in size than typical PSN (which rarely exceed 4mm), with higher
cellularity, more cohesive nests and cords of viable trophoblastic cells and increased
proliferation compared to typical PSNs but exact criteria for distinguishing typical
from atypical for these variables have not been established (17, 217-218).

Despite this proposed description, the clinical significance of APSN remained

uncertain, since only rare cases had been reported, and they were thought to behave in
a benign fashion (42, 219). However, recent data demonstrates the apparent
transformation of PSN, through APSN to malignant ETT and PSTT (220) and ETT
(221). The largest series on APSN (197) reported that 15% of histologically confirmed
APSN were associated with malignant PSTT and ETT, either concurrently with the
APSN diagnosis or subsequently.

38
 Pathology

Figure 4.38. Atypical placental site nodule—(A). Circumscribed nodule with higher cellularity (B). Cells
with cytologic and nuclear atypia and necrosis within center of nodule (inset with higher Ki-67 labeling
index)

Cells in APSN usually exhibit positivity with anti-cytokeratin antibodies and may be
variably positive for inhibin, bHCG, human placental lactogen, mel-Cam (CD146),
epithelial membrane antigen and placental alkaline phosphatase (18, 210, and 212).
The trophoblastic cells in PSNs exhibit low proliferative activity with a Ki-67
labeling index of about 5%, similar to that in the intermediate trophoblastic cells in
the chorion laeve (210).

The diagnosis of APSN should therefore prompt thorough radiologic investigations to

exclude an underlying mass lesion, and these patients should be clinically followed up
in view of the association with malignant GTD (PSTT/ETT).

4.18 PATHOLOGICAL LESIONS ASSOCIATED WITH TROPHOBLASTIC

TUMORS

The increased pelvic and uterine vascularity associated with moles and CC is well
known and sometimes persists even after hCG has returned to normal. It may be a
source of life-threatening hemorrhage, which may need either hysterectomy or
uterine artery embolization when the uterus needs to be preserved. Luteal ovarian
cysts used to accompany hydatidiform mole and CC in a variable number of patients
and an incidence of 94% in one report is quoted by Park [15], although they are
rarely seen in current practice. Luteinization of granulosa and theca cells may occur
throughout both ovaries but its intensity varies in different patients and does not
appear related to hCG levels in serum. Rupture can occur [222] and needle aspiration
of the cysts has been recommended to prevent this. It is important not to confuse
these ovarian lesions with metastatic CC

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