Histopathology 2020, 76, 25–36. DOI: 10.1111/his.

14016

REVIEW

Ovarian germ cell tumour classification: views from the testis

Daniel M Berney,1 Sara Stoneham,2 Rupali Arora,3 Jonathan Shamash4 & Michelle Lockley1
1
Centre for Molecular Oncology, Barts Cancer Institute, Charterhouse Square, Queen Mary University of London,
2
Department of Paediatric and Adolescent Haematology and Oncology, University College Hospitals London,
3
Department of Histopathology, University College Hospitals London, and 4Department of Medical Oncology,
Bartshealth NHS Trust, St Bartholomew’s Hospital, London, UK

Date of submission 31 July 2019

Accepted for publication 6 October 2019

Berney D M, Stoneham S, Arora R, Shamash J & Lockley M

(2020) Histopathology 76, 25–36. https://doi.org/10.1111/his.14016
Ovarian germ cell tumour classification: views from the testis

The classification of ovarian germ cell tumours has
remained unchanged for many years, while there have
been considerable changes in the testicular classifica-
tion. In recent years there has been concern about the
overtreatment of clinical stage 1 testicular germ cell
tumours with increasing use of surveillance for low-
risk disease. We outline here the current classification
of germ cell tumours of the ovary with particular
regard to treatment and outcome and highlight some
areas which may cause confusion, particularly
Keywords: dysgerminoma, germ cell tumour, Immature teratoma, neuroepithelium, ovary
pertaining to immature teratomas and mixed germ cell
tumours. We suggest that some minor changes to the
classification, evidenced by a recent retrospective series
by some of the authors, may lead to less adjuvant
chemotherapy for immature teratomas and may obvi-
ate the need for the grading of immature teratomas, by
aligning with testicular experience in pure post-puber-
tal teratomas. Adoption of this will require retrospec-
tive and prospective re-evaluation, but may avoid
long-term patient morbidity.

Introduction therapy of an essentially benign entity, which shows

Malignant germ cell tumours arise most frequently in
the testis. Their extremely diverse morphology has
meant that classification into distinct pathogenetic
entities with differing behaviours has proved difficult
and has resulted in many revisions in classification
and differences of opinion in terminology. The confu-
sion in terminology in particular has led to dangers
of both over- and undertreatment of the disease. For
example, the word ‘teratoma’ has been applied to
both benign and highly malignant entities. Also, the
essentially benign ‘spermatocytic seminoma’1,2 has
led to occasional overtreatment with adjuvant
Address for correspondence: D M Berney, Department of Molecular
Oncology, Barts Cancer Institute, Queen Mary University of Lon-
don, John Vane Building, Charterhouse Square, London ECIM 6BQ,
UK. e-mail: daniel.berney@nhs.net
© 2019 John Wiley & Sons Ltd.
a poor response to therapy even after rare metas-
tases.3 The difficulties are compounded by the rarity
of testicular germ cell tumours and the potential for
misdiagnosis by less specialised pathologists.4,5
In 2016, there was a radical revision of the testicu-
lar germ cell classification to try to address some of
these problems.6 The crucial division was between
those germ cell tumours derived from germ cell neo-
plasia in situ (GCNIS) and those not derived from
GCNIS (Figure 1). The new name, GCNIS, has replaced
previous terminology, which was divisive and was
slightly misrepresentative of the location of the preneo-
plastic germ cells.7 The tumours not derived from
GCNIS include the renamed spermatocytic tumour and
the new prepubertal-type teratoma, which consists of
those pure teratomas arising in childhood and the
increasing recognition of these in adults, which posed
no risk of metastasis, as well as prepubertal yolk sac
26 D M Berney et al.

Seminoma
Embryonal
carcinoma

Sarcomatoid
GCNIS-derived Yolk sac tumor YST/sarcoma
NOS

Choriocarcinoma
Trophoblastic
Germ cell Other
tumors trophoblastic
tumors
Teratoma,
postpubertal-
type Somatic
malignancy

Not GCNIS-derived

Spermatocytic
tumor
Spermatocytic
tumor with
sarcoma
YST, prepubertal
type

Teratoma,
prepubertal type

Figure 1. Classification of testicular germ cell tumours (from Williamson et al.6)

tumour (YST).8 A mixed prepubertal-type yolk sac and
teratoma was also recognised. This morphological and
pathogenetic classification also aligns extremely well
with the molecular biology of the disease. Isochromo-
some 12p is a hallmark of GCNIS-related tumours of
the testis, but usually absent from non-GCNIS related
tumours.9,10
The new classification therefore has the benefits of
aligning treatment with nomenclature and also
molecular pathogenesis. Localised GCNIS-related
tumours can either be treated with adjuvant treat-
ment or followed-up with serial scans and serum
markers, while those not derived from GCNIS can be
strongly reassured and follow-up minimised, with
reductions in, or even removing the need for, radio-
logical follow-up.
Germ cell tumours at other sites, however, do not fit
into this categorisation in any easy manner. The
malignant forms are extremely rare, although it should
be remembered that once mature teratomas are
included, germ cell tumours are much more common
in the ovary than the testis. In many centres, malig-
nant germ cell tumours may not be seen by an oncolo-
gist specialising in the more common malignant
testicular germ cell tumours. They have a completely
different biology and genetics from the much more
common epithelial ovarian malignancies, and treat-
ment aligns much more closely with that for testicular
germ cell tumours. We believe that these patients are
better treated in a specialist germ cell treatment centre.
The current classification of extra-testicular germ
cell tumours is variable and relies upon systems which
predate the 2016 classification. However, it is impossi-
ble to directly align testicular germ cell tumours with
their counterparts elsewhere. There has been no identi-
fication of GCNIS at other sites, although gonadoblas-
toma, an alternative premalignant lesion, is well
recognised mainly in dysgenetic gonads in patients
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

with disorders of sexual development.11,12 Secondly,
there are testicular entities such as spermatocytic
tumour which have not been reported at other sites
and, equally, ovarian tumours which do not have a
direct testicular equivalent.
Ovarian germ cell tumour classification is a particu-
lar issue in terms of how patients are managed.
Prospective clinical trials are extremely challenging for
testicular GCTs: they have an estimated yearly inci-
dence of 7–8 in 100 000, although this is very vari-
able in both geography and ethnicity, and has risen
significantly in the past 50 years.13,14 However, once
the benign ‘dermoid cysts’ are excluded, the incidence
in women has been reported as 0.338 in 100 000, and
therefore 5% of the incidence in men.15 Ovarian GCTs
appear to show less geographical variation.16 Gather-
ing data requires multi-institutional collaboration and
considerable work. In any such effort it will be essential
that pathological data and classification in different
centres are comparable and consistent.
Previously, their treatment has also often been dif-
ferent in the paediatric and adult cohorts, with signifi-
cantly less treatment in the paediatric age range,
while adults are offered more adjuvant chemother-
apy.17–19 Many studies have comprehensively exam-
ined the pathogenesis and aetiology of the multitude of
germ cell tumours.10,20,21 In this paper we do not wish
to concentrate on this approach, but to examine treat-
ment and outcome in a practicable way by examining
the classification of ovarian germ cell tumours in the
hope of better aligning it with the testicular classifica-
tion. The aim of this study has been to approach the
difficulties with the current classification, and the pos-
sibility that it may lead to inappropriate treatment. We
suggest a revision to align more closely with the testic-
ular classification and particularly to prevent
overtreatment. It will also take into account the cur-
rent testicular criteria used for high-risk disease and
hopefully prevent current confusion in grading.
The classification of ovarian germ cell
tumours
The current classification of ovarian GCTs can be
seen in Table 1.22 It has not been changed substan-
tially for a quarter of a century. In many ways, it
aligns better with previous testicular classifications
than the current one, and each entity will be dis-
cussed in detail. One interesting categorisation of
germ cell tumours which has been proposed is from
the Rotterdam group under Oosterhuis and Looi-
jenga21 (Table 2). It embraces germ cell tumours at
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.
Ovarian germ cell tumour classification 27
all sites and is a careful attempt to align pathogenesis
with type of tumour. It is reflected in the current tes-
ticular classification, as GCNIS-related tumours are
Type 2 and non-GCNIS-related are Types 1 and 3.
Thus, a Type 1 germ cell tumour includes prepuber-
tal-type testicular teratoma and prepubertal-type YST;
a Type 2 GCT includes adult testicular tumours
derived from GCNIS. A Type 3 teratoma is synony-
mous with spermatocytic tumour. Type 4 germ cell
tumours are equivalent to ovarian ‘dermoid cysts’. It
makes some excellent points about the widespread
nature of tumours with germ cell differentiation. It
also makes the point that not all germ cell tumours
are necessarily derived from germ cells in the pres-
ence of Type 6 tumours.23
Although ambitious and elegant, a caveat with this
system is that the types are not descriptive, and it
has to be absolutely remembered which type is asso-
ciated with which descriptor. This is challenging to
Table 1. 2014 Classification of ovarian germ cell tumours
Dysgerminoma
Yolk sac tumour (primitive endodermal tumour)
Embryonal carcinoma
Polyembryoma
Non-gestational choriocarcinoma
Teratomas
Immature
Mature
Solid
Cystic
With secondary tumour
Monodermal
Struma ovarii
Carcinoid tumour
Neuroectodermal tumours
Sebaceous tumours
Squamous cell carcinoma
Mixed germ cell tumours
Gonadoblastoma
With mixed germ cell tumour
Mixed germ cell sex cord-stromal tumour
28 D M Berney et al.

Table 2. The types of germ cell tumour
Germ cell
Tumour type Description
1 Testis: prepubertal type teratomas and
prepubertal yolk sac tumour
Ovary: may form a subset of some ovarian
teratomas and yolk sac tumours
2 Testis: postpubertal type adult teratomas,
seminoma and other non-seminomatous
‘malignant’ germ cell tumours
the testis, spermatocytic tumours (Type 3) are usually
benign, but may metastasise if showing sarcomatoid
change; rare metastasising non-sarcomatoid excep-
tions are known, and even the presence of isochro-
mosome 12p. Immature teratomas (IT) may also
show a spectrum of behaviour, which will be dis-
cussed below. The descriptions will therefore consider
more what a tumour is differentiating towards, rather
than its cell of derivation. The specific types of ovar-
ian germ cell tumour will now be discussed.

Ovary: dysgeminoma and other ‘malignant’

ovarian tumours (yolk sac, embryonal
Dysgerminoma
carcinoma) and possibly ‘immature teratomas’ The main issue with dysgerminoma (Figure 2) is
of the ovary
purely one of nomenclature. This tumour has an
3 Testis: spermatocytic tumour identical morphology, immunochemistry, molecular
features and behaviour to its counterpart in the testis,
Ovary: no counterpart exists
seminoma, and other germ cell sites (germinoma). It
4 Ovarian ‘dermoid cysts’ also known as benign is a historical aberration that we have three names
cystic teratomas. May include some ‘immature for essentially the same tumour in humans and one
teratomas’
that cannot be changed, partly because the use of the
5 Gestational trophoblastic neoplasia name ‘seminoma’ is uncomfortably applied to
females. The differences in name cannot be easily
6 Somatic tumours showing trans-differentiation
to elements with characteristic germ cell
addressed, but there may be a case for using ‘germi-
features noma’, which is gender-neutral, at all sites: a sugges-
tion which will not be well received in the testicular
germ cell community. Also similar to seminomas,
dysgerminomas may show scattered syncytiotro-
those unfamiliar with the spectrum of GCTs. This, we
phoblastic cells leading to a rise in serum human
feel, prevents it from being adopted widely by the
chorionic gonadotrophin (hCG). However, an inte-
clinical community. We suggest that descriptive ter-
grated approach with knowledge of the serum mark-
minologies are best used for these entities. The use of
ers may prevent a misdiagnosis, as an unexplained
typing is ‘cleaner’, but does not provide insight into
rise in alpha feto-protein (AFP) is highly indicative of
behaviour and runs the continued risk of misinterpre-
YST, the solid variety of which may mimic dysgermi-
tation by clinicians if a descriptive morphology is not
noma. Dysgerminomas show the identical PLAP/c-
included. While this pathogenic classification is useful
as a root, in terms of patient treatment it is important
to have a classification which aligns with the use of
differing therapies. These different classifications are
not necessarily mutually exclusive.
Ovarian germ cell tumours also fit uncomfortably
into this classification (as admitted by the authors).
While the ‘benign’ so-called dermoid cysts or mature
teratomas (Type 4) are split off as a separate entity
on good pathogenetic grounds, and Type 2 germ cell
tumours (encompassing dysgerminoma, embryonal
carcinoma and most mixed tumours) are equivalent
to those in the testis, the presence of so-called imma-
ture teratomas straddles Types 1, 2 and 4 and does
not concord with this neat pathogenetic classification.
It should also be remembered that within each type
there is a large spectrum of behaviour. Type 4 ovar- Figure 2. Dysgerminomas show identical morphological features to
ian GCTs can rarely show somatic transformation. In testicular seminoma

© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

 Ovarian germ cell tumour classification 29

KIT/OCT 4 positivity seen in seminomas. The screening and careful discussions concerning fertility
tumours are exquisitely radio- and chemosensitive, options.
and cure is greater than 90% even with advanced-
stage disease.
An important part of examination of any dysgermi- Embryonal carcinoma
noma is identification of any gonadoblastoma (Fig-
These are extremely rare in the ovary in pure form;
ure 3A, B). This alternative ‘in-situ’ tumour occurs
when present they are usually mixed with other ele-
mainly in phenotypical females with gonadal dysgen-
ments and again identical to their testicular counter-
esis and an abnormal karyotype, most of whom have
parts, with CD30 and OCT 4 co-positivity. Embryonal
part or all of a Y chromosome. Identification is very
carcinoma is more aggressive than dysgerminoma/
important, as the other gonad is at risk of neoplastic
seminoma and its identification is important.
transformation and a contralateral gonadectomy is
Although usually easily identified on morphology,
usually indicated, as well as genetic counselling,
immunochemistry is sometimes required.

A
Yolk sac tumour
This type of germ cell tumour is included in both
Types 1 and 2 germ cell tumours, and may even be a
differentiation pattern seen in somatic tumours (Type
6). Its protean nature, with differentiation towards
endodermal-like structures which may range from
mesenchymal, allantoic, glandular and hepatic differ-
entiation, make it challenging but important to recog-
nise (Figure 4). Serum AFP may be extremely helpful.
Immunochemistry for AFP may also be helpful, but
in our experience is patchy, and glypican-324,25
(although less specific) is a superior marker.

B
Non-gestational choriocarcinoma
These extremely rare tumours, similar to the testis,
are usually metastatic at presentation with a very
high serum hCG. The characteristic mixture of
cytotrophoblast and syncytiotrophoblast is required,

Figure 3. A, A low-power view of a gonadoblastoma showing calci-

fication and a mixed population of germ cells and immature sex
cord-stromal cells. Gonadoblastoma is seen more commonly in phe-
notypical women and largely in those with disorders of sexual
development. B, Immunohistochemistry for OCT 4 in a gonadoblas-
toma showing positive germ cells and negative sex cord-stromal Figure 4. A pure yolk sac tumour. These are more common prepu-
cells bertally and most commonly ‘Type 1’ germ cell tumours

© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

30 D M Berney et al.

as scattered syncytiotrophoblast may occur in other somatic transformations in the testis, the diagnosis
malignant types. OCT4 negativity and hCG positivity may be difficult. Methods of assessing somatic transfor-
is usual on immunochemistry. mation are given in the following section.

Mature teratoma Immature teratomas

By far the most common ovarian germ cell tumour,
It is in this area that most of the problems with the
these tumours are benign unless a somatic transfor-
classification arise when compared with testicular
mation occurs, which is extremely rare. Any mature
tumour classification. The concept of immaturity in
tissue type is allowed. Although the terms ‘dermoid
testicular germ cell neoplasia has been abandoned in
cyst’ and ‘mature cystic teratoma’ have been used,
the last two iterations of the World Health Organisa-
we prefer the current designation of ‘mature ter-
tion (WHO) system. This was because postpubertal-
atoma’, as all three germ layers are represented. The
type teratomas with immaturity (including primitive
presence of neuroepithelium is used in the diagnosis
neural elements) behave in exactly the same manner
and grading of immature teratoma. However, it has
as those without these elements, and agonising over
been suggested by some that the presence of rare
the level of immaturity of an organoid mix of tissue
microscopic foci of neuroepithelium is associated with
was not necessary. These tumours require follow-up,
an excellent outcome,26,27 and that therefore ‘small
but are given no adjuvant treatment. When a great
microscopic foci’ can be ignored.27 We agree that
deal of overgrowth of one type occurs, the possibility
they have an excellent prognosis, but think that such
of somatic transformation is raised. However, while
tumours should always be classed as ‘immature ter-
somatic transformation in distant metastatic sites (for
atomas’ if immature neuroepithelium is seen. This
instance, in a retroperitoneal lymph node dissection
point, as we will emphasise in many areas of the clas-
after treatment) is associated with a dismal progno-
sification, is that advice to ‘ignore’ small areas of a
sis, when somatic transformation is seen solely in the
different morphology results in vague cut-offs
testis with no evidence of distant spread the progno-
between different entities, and variation in diagnosis
sis appears to be good. The only time immaturity
between different pathologists will increase. This has
becomes important is when differentiation of a post-
the risk of inappropriate classification and therapy.
pubertal-type from a prepubertal-type teratoma is
Apart from the primitive neuroepithelium, which
necessary, as immature elements, GCNIS and atrophy
will be dealt with in the section on IT below, there
are exclusion criteria for a prepubertal-type teratoma
remains the classification of both monodermal ter-
diagnosis.
atomas and somatic-type malignancies arising in a
In ovarian germ cell pathology, there appears to be
mature teratoma.
a different entity which sits uncomfortably in the
Monodermal teratomas may show a huge range of
‘typing’ classification outlined above, with variable
morphologies, including epidermoid cysts, neural
amounts of primitive neuro-epithelial tissue (Figures
tumours and struma ovarii, with thyroid-type epithe-
5A, B and 6). This entity causes some issues in terms
lium.28,29 In some cases, such as pure thyroid tissue,
of diagnosis and treatment. First, there appears to be
malignancy cannot be easily predicted from the mor-
disparity about the other elements allowed in an
phology.
immature teratoma. As mentioned above, some sug-
gest that tiny amounts of immature neuroepithelium
can be disregarded and the tumour diagnosed as a
Somatic transformation in a mature
mature teratoma. It is also stated in the WHO classifi-
teratoma
cation and other publications that small amounts of
Somatic transformation in these tumours is well recog- both YST or even embryonal carcinoma could be
nised in a variety of tumours, such as well-differenti- included in the diagnosis of immature teratoma:
ated neuroendocrine tumours,30 squamous cell ‘Endodermal structures are less common. . . the most
carcinomas31 and many other rarer transformations, primitive component of immature teratoma is in the
which can be of epithelial32 or soft tissue derivation.33 form of embryoid bodies constituted by yolk sac
These rarities should be dealt with on an individualised epithelium and a germ disk whose epithelium resem-
basis, but all require overgrowth of the organoid mixed bles that of embryonal carcinoma (tumours domi-
nature of the mature teratoma by a single element. In nantly composed of embryoid bodies have been
many cases this will be straightforward, but similar to termed ‘polyembryoma’).22
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

A probable conversion of immature or ‘malignant’ ele-
B ‘embryonic’ elements they contain. IT were graded
Figure 5. A, This typical ovarian ‘immature teratoma’ shows neu-
roepithelium mixed in an organoid fashion with other elements
and glial tissue. Estimation of percentage involvement can be chal-
lenging. This may not be required in the proposed amendments to
the classification. B, High-power view of ‘immature teratoma’ com-
posed of an organoid mix of elements with scattered immature neu-
roepithelium
Microscopic foci of YST in an IT have been reported
with recurrences in children34 but IT itself can recur,
so there is doubt on their preferred classification. The
phenomenon of ‘growing teratoma syndrome’ is a fre-
quent problem clinically when recurrences occur
meaning they cannot be easily classified. The use of
chemotherapy may lead to a paradoxical increase in
the size of tumours, when in fact it represents a
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.
Ovarian germ cell tumour classification 31
ments in the tumour to more differentiated forms.35
This is an area where better alignment with testis
might occur in which any tumour with any amount
of mixed elements is described as a mixed germ cell
tumour with a comment of the percentage of the dif-
ferent elements in the mix. When ‘small elements’
can be disregarded, as mentioned previously, it
becomes an issue for intra-observer variability in the
amount allowed, and the presence or absence of a
particular element is far more likely to be repro-
ducible.
There is also a well-known and widely adopted
grading system for grading immature teratomas. It
should be added that such a grading system should
only be adopted if it has clinicopathological conse-
quences. IT is graded according to the amount of
using a three-tiered system based on the amount of
immature neuroepithelium present,36 and these were
more recently modified.37
The criteria are challenging in conception:
O’Connor et al. suggest that IT with a total amount
of immature tissue not exceeding one low-power field
(940, using a 9 4 objective and a 9 10 eyepiece) on
any one slide are grade 1; those with more than one
but not exceeding three low-power fields on any one
slide are considered grade 2, and those with more
than three low-power fields of immature tissue are
grade 3 (Table 3). In the same article, a two-grade
system was proposed with grade 1 IT classified as low
grade and grades 2 and 3 IT diagnosed as high
grade. The grading system, it was proposed, has clini-
cal significance, as grade 1 tumours confined to the
ovary do not require combination chemotherapy,
whereas higher-grade tumours are treated. Determin-
ing the aggregation of neuro-epithelium in one slide
is challenging, and may depend on the size of section
taken. Anecdotal information suggests that, among
gynaecological pathologists, many do not ‘aggregate’
all immature neuroepithelia on a given slide, but sim-
ply look for discrete foci of any size that are present
in different low-power fields. A similar tumour in the
testis would be assigned to the ‘postpubertal cate-
gory’, and in all probability no adjuvant treatment
given no matter the amount of neuroepithelium seen.
Similarly, in the paediatric community adjuvant
treatment is not routinely offered for any ovarian IT.
Pure immature teratomas in children have been
shown to behave in an excellent manner,38–41 and at
all ages they appear to show fewer DNA copy num-
bers than ‘malignant’ germ cell tumours and align
more with mature teratomas.42,43
32 D M Berney et al.
Figure 6. A second ‘immature teratoma’ with plentiful primitive
neuroepithelium. However, it is mixed with other elements and
shows no overgrowth
Table 3. Grading of ovarian immature teratomas
Grade 1. Tumours with rare foci of immature neuroepithelial
tissue that occupy less than one low-power field in any slide.
Grade 2. Tumours with foci of immature neuroepithelial tissue
that occupy one to three low-power fields in any slide.
Grade 3. Tumours with foci of immature neuroepithelial tissue
that occupy greater than three low-power fields in any slide.
The need for ‘aggregation’ in the grading system
suggests that the vast majority of cases of IT main-
tain an organoid mix of tissue. Indeed, even gross
cases of somatic transformation in the testis, where
the neuroepithelium appears to outgrow and domi-
nate the other tissue elements, are often treated
expectantly.
We also suggest that the label ‘immature’ as it cur-
rently appears to apply to this group is a misnomer,
as it is almost inevitably an issue of the presence of
neuroepithelium. To avoid potential confusion as well
as to be more precise, we would prefer if these were
termed ‘teratoma with neuroepithelium’.
Previous papers have shown that that grade 3 IT
appear to recur and metastasise far more than grades
1 and 2.17,44 However, to our knowledge, these
papers did not take account of mixed elements in IT
nor assessments of somatic transformation as would
have been performed in the testis.
Some of the authors of this review have recently
published a retrospective series of ovarian germ cell
tumours, concentrating on a number of different fac-
tors.45 First, on review, even small areas of other ele-
ments meant assignation to a mixed germ cell
tumour rather than a pure IT. Secondly, within the
grading system of IT, cases where there was clear
overgrowth and expansile obliteration of other ele-
ments was assigned to a category of ‘somatic trans-
formation’.
In short, the study included 138 patients with ‘ma-
lignant’ ovarian GCTs from multiple expert treatment
centres in London. Overall survival was an excellent
93%, and event-free survival (EFS) was 72%. Impor-
tantly there was no difference in histology, stage or
grade in patients aged greater or less than 18 years,
and EFS was not different in these groups. The histo-
logical subtype, as defined by us, powerfully predicted
EFS and although, as expected, neoadjuvant/adjuvant
chemotherapy significantly reduced future relapse/
progression in dysgerminoma, YST and mixed germ
cell tumours it did not appear to make any difference
in IT. Interestingly, there were no radiological
responses to chemotherapy in IT, and pathological IT
grade did not predict EFS with no IT deaths occur-
ring. In the small group of five patients which we
defined as having somatic transformation of a ter-
atoma to primitive neuroectodermal tumour (PNET),
four were diagnosed at diagnosis and one at a subse-
quent relapse. Only one was successfully treated to
complete remission with surgical resection followed
by intensive chemotherapy, and was disease-free
5 years after diagnosis (Figure 7). It is also of note
that there are considerable risks in overtreatment of
ovarian germ cell tumours. Neoadjuvant/adjuvant
chemotherapy caused 27 potentially chronic toxici-
ties, and one patient subsequently died from acute
lymphoblastic leukaemia.
Somatic transformation has been widely used in
testicular germ cell tumours to define when one ele-
ment of a teratoma overgrows the remaining ele-
ments. It appears in the ovary to have been applied
mainly to ovarian mature teratomas but not to the
category of immature teratomas. In the testis, the def-
initions that have been used indicate a lack of the
usual organoid pattern of mixed differentiation that
occur in teratomas of any sort, with overgrowth of
one element in an expansile mass (Figure 8). The
expansile area should be equivalent to an area seen
by a 9 4 objective. Although in use for many itera-
tions of the WHO classification, the latest edition sug-
gests a more precise minimum size of the mass as
5 mm. Somatic transformation thus defined in the
testis is associated with increased recurrences,
relapse-free survival and decreased overall survival.
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.
 Ovarian germ cell tumour classification 33

100 %
100 %

A B
Log-rank test I VS. II/III/IV: P = 0.026

75 %
75 %
Event-free survival

Event-free survival
50 %
50 %

FIGO stage
Dys

25 %
25 %

I
II IT
III YST
IV MGCT

0%
0%

PNET
0 5 10 15 0 5 10 15
FIGO Stage Time (years) Histology Time (years)
I: 89 60 42 32 20 11 4 3 2 1 1 DYS: 37 32 27 24 15 9 1 0 0 0 0
II: 11 6 6 3 3 1 0 0 0 0 0 IT: 42 24 14 8 4 2 1 1 1 0 0
III: 23 15 11 11 5 2 1 0 0 0 0 YST: 23 16 13 10 6 4 4 2 1 1 1
IV: 15 9 8 5 3 3 2 0 0 0 0 MGCT: 32 17 13 9 6 2 1 0 0 0 0
PNET: 4 1 0 0 0 0 0 0 0 0 0
HR (95% CI) Wald’s P
Age 8-18 1(Ref)
Age 19-39 0.800 (0.385, 1.662) 0.356 0.55
100 %

Age ≥ 40 3.301 (1.257, 8.672) 5.874 0.015

C
100 %

D Log-rank test P = 0.937

75 %
Event-free survival

75 %
Event-free survival
50 %

50 %
25 %

Grade
25 %

Age 1
≤ 18 2
19-39 3
0%

≥ 40
0%

0 5 10 15 0 5 10 15
Time (years) Time (years)
age Grade
-18: 39 25 18 15 9 8 2 0 0 0 0 1: 14 8 5 2 1 0 0 0 0 0 0
19-39: 39 63 47 35 22 9 5 3 2 1 1 2: 15 12 7 5 4 2 1 1 1 1 1
39-76: 39 2 2 1 0 0 0 0 0 0 0 3: 13 6 5 4 1 1 0 0 0 0 0

Figure 7. Kaplan–Meier event-free survival. Event-free survival according to (A) FIGO stage, (B) histological OvGCT subtype, (C) patient age
at diagnosis and (D) grade of immature teratoma. OvGCT, ovarian germ cell tumour; Dys, dysgerminoma; IT, teratoma; YST, yolk sac
tumour; MGCT, mixed germ cell tumour; PNET, primitive neuroectodermal tumour; HR, hazard ratio; CI, confidence interval (from Newton
et al.45)

Although an admittedly small number of cases, these tumours are excluded, over- rather than undertreat-
findings are replicated in this paper. In practice, there ment remains the major concern in ITs in ovarian
is often complete or near-complete overgrowth in our germ cell pathology, and that aligning the classifica-
experience and the cut-off is rarely used. tion more with current testicular practices may help
From this study we have suggested that, once cases in this regard. The roll-out of reduced-toxicity, paedi-
of somatic transformation to PNET and mixed atric-type regimens to adults should be a priority,

© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

34 D M Berney et al.
Figure 8. High-power view showing pure primitive neuroepithe-
lium. This case may represent somatic transformation of an imma-
ture teratoma to primitive neuroectodermal tumour (PNET)
especially for ITs, and that management of IT in the
first instance should be purely surgical. We therefore
suggest the following changes to the classification.
Any such changes would have to be assessed
prospectively, and it will be challenging to achieve
sufficient numbers of cases. However, we feel that
they are likely to cause fewer differences in pathologi-
cal interpretation and will be more easily translated
into outcome data.
Gliomatosis peritonei
An area of germ cell tumour progression which is vir-
tually exclusive to the ovary is dependent on its close
association with the peritoneal cavity. Presumed rup-
ture of the teratoma may occur with dissemination of
mature glial elements, termed ‘gliomatosis peritonei’
(Figure 9). Despite the alarming macroscopic appear-
ances, prognosis remains favourable.46,47
Proposed changes to ovarian germ cell
tumour classification
MIXED TUMOURS
In the testis, any amount of a secondary element will
convert the tumour from a pure subtype to a mixed
subtype with a specification of the percentage of each
element. There is already a mixed germ cell tumour
category in the current WHO classification. We fully
admit that evidence of the behaviour those tumours
with very small percentages of secondary elements is
Figure 9. Mature glial tissue within peritoneal fat, representing
gliomatosis peritonei
not available: unsurprisingly, as they are extremely
rare. However, in the testis we have diagnosed mixed
tumours where the only embryonal carcinoma present
in an otherwise pure seminoma is within vessels. We
contend that the presence or absence of a particular
germ cell element is more reproducible than a particu-
lar percentage estimation for a cut-off between differ-
ent entities. We suggest that mixed germ cell tumours
should always be diagnosed if there is a mixture of
any of dysgerminoma, embryonal carcinoma, chorio-
carcinoma, teratoma and, importantly, YST. Giving
estimated percentages of the different elements will aid
further work to decide on the treatment, especially in
those cases of immature teratoma with a minor ‘ma-
lignant’ element. The future use of micro-RNAs, which
are being developed as serological markers in all germ
cell tumours, may assist in this.48 In the current testic-
ular tumour classification, there is already a specific
mixed category for prepubertal-type teratomas with
YST and teratoma, although these tumours lack
PNET-like elements. A definitive classification includ-
ing pathogenetic data is, at this point, impossible, but
we contend that all mixed tumours should be placed
in this category regardless of the small percentage of
some of the elements.
MARKER STATUS NEEDS TO BE CONSIDERED IN
DIAGNOSIS
Occasionally, testicular tumours are seen where the
marker status is at variance with the histology. The
most common scenario is of an apparent pure
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.

dysgerminoma with a raised AFP (a mildly raised
beta-hCG is often seen in seminomas and dysgermino-
mas due to the presence of syncytiotrophoblastic cells:
this should not cause any concern with modestly
raised serum levels of hCG).
Despite intensive investigation and processing,
occasionally the yolk sac elements which are pre-
sumed to be present cannot be found. Such tumours
are usually treated as non-seminomas. Occasionally,
therefore, the histopathology may need to be over-rid-
den by the marker status. While these tumours
should still be diagnosed on their histological appear-
ance, it is important to remember that the pathologist
needs to ‘curate’ data from not only the morphologi-
cal appearances, but also the serum markers, cytoge-
netics and clinical factors to aid clinicians who may
be less familiar with the more unusual variants in
germ cell tumours.
We suggest that while still diagnosing the case as a
dysgerminoma it would be important to add a com-
ment to the diagnosis to suggest that, in view of the
raised marker levels, a non-dysgerminomatous ele-
ment may be present and the case will need further
discussion prior to treatment.
IMMATURE TERATOMAS
We suggest that IT grading requires close re-evalua-
tion, and may not be as discriminatory as previously
thought. We suggest that it is better termed as ‘ter-
atoma with primitive neuroepithelium’. This will define
them more clearly and separate them from other germ
cell tumours with other kinds of immaturity. In view of
the difficulties in grading, we suggest that once somatic
transformation to PNET and mixed tumours are
removed behaviour may well be even more favourable,
although this will need to be tested in further retro-
spective series and, hopefully, prospectively.
SOMATIC TRANSFORMATION
Assessments of somatic transformation should be
made on immature teratomas similar to that seen in
the testis with use of the criteria given above of over-
growth of other elements and an expansile mass with
no organoid morphology. The presence of any other
‘malignant’ germ cell elements should be exclusion
criteria for their diagnosis.
Conclusions
The changes we suggest to the current WHO classifi-
cation in ovarian germ cell tumours are not radical.
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 25–36.
Ovarian germ cell tumour classification 35
However, we believe it may remove uncertainties for
pathologists in the assessment of tiny foci of disease
and hopefully improve intra-observer error. More
importantly, it may help avoid overtreatment of
tumours which have previously been given
chemotherapy, which appears to have increased
potential toxicity without improving outcome.
Acknowledgements
D. M. B. is supported by Orchid.
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