Cancer Treatment Reviews 56 (2017) 47–57

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Cancer Treatment Reviews

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Controversy

Classification systems in Gestational trophoblastic neoplasia - Sentiment

or evidenced based?
V.L. Parker a,⇑, A.A. Pacey a, J.E. Palmer b, J.A. Tidy b,c, M.C. Winter c, B.W. Hancock d
a
Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, The University of Sheffield, Level 4, The Jessop Wing, Tree Root Walk,
Sheffield, S10 2SF, United Kingdom
b
Department of Gynaecological Oncology, G18, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom
c
Sheffield Centre for Trophoblastic Disease, Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Whitham Road, Sheffield S10 2SJ, United Kingdom
d
Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: The classification system for Gestational trophoblastic neoplasia (GTN) has proved a controversial topic
Received 30 December 2016 for over 100 years. Numerous systems simultaneously existed in different countries, with three main
Received in revised form 7 April 2017 rival classifications gaining popularity, namely histological, anatomical and clinical prognostic systems.
Accepted 8 April 2017
Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide con-
sensus on the optimal classification system, largely due to a lack of high quality data proving the merit of
one system over another. Remarkably, a validated, prospectively tested classification system is yet to be
Keywords:
conducted.
Gestational trophoblastic disease
Gestational trophoblastic neoplasia
Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO
Classification classification system, and its ability to identify patients most likely to develop primary chemotherapy
System resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby
Prognosis one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6.
Evidence This review aims to examine the historical basis of the GTN classification systems and critically
appraise the evidence on which they were based. This culminates in a critique of the current FIGO/
WHO prognostic system and discussion surrounding clinical preference versus evidence based practice.
Ó 2017 Elsevier Ltd. All rights reserved.

Introduction
The main factor that has driven the development of a classifica-
tion system for GTN is to identify, at the point of diagnosis, which
patients will not respond to single-agent chemotherapy treatment.
This is extremely important to guide subsequent management, and
ensure that patients are treated with the most appropriate first line
regimen, highlighting those who are likely to need more intensive
therapy [1]. However, the classification of GTN has historically pro-
ven highly controversial, and prior to the combination of the FIGO
and WHO classification system in 2000, multiple classification sys-
tems were used throughout the world [2]. Each comprised differ-
ent combinations of prognostic risk factors for GTN (e.g. maternal
age, blood group, smoking status) and attributed varying weighting
to their clinical significance in terms of remission or primary cure.
This variability renders attempts to compare the merit of each clas-
sification system extremely difficult, if not impossible, as depend-
⇑ Corresponding author.
E-mail address: v.parker@sheffield.ac.uk (V.L. Parker).
ing on country of diagnosis, patients with the same risk factors
would have a different prognostic assessment and receive different
chemotherapy regimens (i.e. some would receive single-agent low-
risk treatment whereas others would have high-risk combination
chemotherapy). Therefore, it is not possible to compare time to pri-
mary remission, the percentage of patients cured by primary
chemotherapy, and rates of relapse with any accuracy or validity.
Even today, despite attempts to standardise the classification sys-
tem worldwide, countries such as Japan continue to develop and
utilise their own [3].
One of the main difficulties in generating a unifying classifica-
tion system arises from the fact that GTN incorporates three dis-
tinct pathological diagnoses: (i) post-molar GTN; (ii)
choriocarcinoma; and (iii) Placental Site- (PSTT) and Epithelioid
Trophoblastic Tumour (ETT). These heterogeneous subtypes differ
in terms of incidence, clinical presentation and prognostic risk fac-
tors including antecedent pregnancy and interval, pathological,
immunohistochemical and genetic characteristics [4]. Accommo-
dating these differences within a single classification system is
extremely difficult, and one of the reasons why the current FIGO/

http://dx.doi.org/10.1016/j.ctrv.2017.04.004
0305-7372/Ó 2017 Elsevier Ltd. All rights reserved.
48 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57
WHO scoring system is not validated for use in patients diagnosed
with PSTT and ETT.
Despite difficulties concerning sample size given the rare nature
of GTN, the literature on which classification systems and current
management of GTN patients are based is frequently of low
methodological quality and reproducibility. Conducting robust
clinical trials that are not skewed by bias is problematic, an issue
which was identified by the latest Cochrane review investigating
first line chemotherapy in low-risk GTN, highlighting that the find-
ings of several studies were influenced by selection, detection or
reporting bias [5]. Further problems arise given that worldwide
there is little standardisation in the management of GTN, with dif-
ferent centres using varying chemotherapy regimens, doses and
administration schedules. Given the extremely high cure rate in
trophoblastic disease, conducting clinical trials is also fraught with
ethical dilemmas and anxiety in changing proven chemotherapeu-
tic regimens, reducing the enthusiasm of clinicians and patients
alike to engage in such research. These problems contributed to
the early closure of a recent Gynecologic Oncology Group trial
(GOG275) in low-risk GTN.
Furthermore, with the advent of national centralised registries
for GTN patients, it has become increasingly evident that the cur-
rent FIGO/WHO classification system is imperfect, with a signifi-
cant proportion of patients being resistant to primary
chemotherapy, which occurs in 25–35% patients classified as
low-risk (WHO score  6) and 70–80% of those with a WHO score
of 5 or 6 [1,5–14]. Suggested predictors of resistance to single-
agent chemotherapy include a high pre-treatment hCG level [15],
metastatic disease at diagnosis [8,16] and a histological diagnosis
of choriocarcinoma [17]. However, within the low-risk group, a
more robust system is required to more accurately identify the
25–35% patients who are likely to require second line or more
intensive treatment, after failing to respond to first line single-
agent chemotherapy. This would enable tailored and more accu-
rate counselling of patients from the outset, and potentially medi-
ate the damaging psychological consequences to both the patient
and their family of ‘failing’ to respond to treatment. Ultimately, this
may also influence the selection of chemotherapy regimen (single-
agent versus multi-agent) offered to patients as first line treat-
ment. Based upon this, several authors have called for a revision
of the current FIGO/WHO classification system to more accurately
predict from the outset, which patients will be resistant to primary
chemotherapy to enable targeted, more efficacious treatment
[9,18–20].
Anatomical, histological and clinical classifications
Histological classification
Historically, the classification system for GTN has taken three
rival approaches; an anatomical, histological or clinical prognostic
score, with different research groups maintaining that each is
superior to the other. The first histological classification of GTN
dates back to Sänger in 1893 [21], who described the condition
as a uterine sarcoma, subdivided into three morphological groups:
(a) decidual sarcoma with chorionic elements (diffuse ulcer-
ated, nodular non-ulcerated and mixed nodular-ulcerative
sub-types);
(b) decidual sarcoma with chorionic elements following hyda-
tidiform mole; and
(c) interstitial, destructive hydatidiform mole.
Subsequently in 1895, Marchand pioneered the introduction of
a histological classification that was also guided by prognostic fea-
tures; dividing patients into typical and atypical forms depending
upon their clinical behaviour and outcome [22]. However, a com-
peting system was born fifteen years later when Ewing classified
patients according to their histological sub-type: syncytial
endometritis, chorioadenoma destruens (invasive mole) and chori-
ocarcinoma [23], which formed the basis of the histological GTN
subgroups used in current practice.
The main difficulty with a histological classification system was
that it could not be used prospectively to predict prognosis and
guide management, which led to significant delays in patient care
and management. Furthermore, it required primary surgical man-
agement (hysterectomy), which was not routinely practiced or
indeed indicated in such young women who wished to conserve
their fertility. Increasing observational data also suggested that
tumour type and the degree of trophoblast differentiation was
not significantly associated with prognostic outcome and
chemotherapeutic response [18,24]. It is clear that these histolog-
ical classification systems were entirely based upon individual
clinicians’ experience, with no robust validation studies on large
patient populations.
Despite these concerns, several years later in the 1960s, Japan
developed a morphological classification system for GTN [18,25].
Compared to previous histological classifications, this system more
closely approximates the GTN sub-types that are used in current
practice. However, if the histological diagnosis was unavailable,
patients were classified as having a ‘clinically invasive mole’ or
‘clinical choriocarcinoma’ using a choriocarcinoma risk score
developed in 1982, of which is still used today (Table 1).
Anatomical classification
Inspired by the classification of other malignancies, a Beijing
group developed an anatomical staging system endorsed by FIGO
in 1982, which divided patients into Stage I-IV. Stage I involved
disease confined to the uterine corpus, whereas stage IV was
defined by distant metastases (Table 2) [26]. This system was soon
refuted as patient prognosis was found to vary considerably within
each stage, indicating that other factors were more influential
[18,24]. Despite this, some units in China still use this classification
system, highlighting the inconsistency with which GTN patients
are risk stratified and managed, and the dominance of clinical pref-
erence and individual units’ experience rather than evidence based
data.
Clinical classification
Evidence gradually mounted that clinical factors strongly influ-
enced GTN prognosis, such as the presence of metastases or large
tumour bulk. Following a conference in 1965, The International
Union Against Cancer (UICC) produced the first combined anatom-
ical and clinical classification system, including clinical factors
such as the presence of metastases, antecedent pregnancy and his-
tory of previous treatment (Table 3) [16]. This followed a study in
1965, which was one of the first papers to identify clinical factors
as important prognostic determinants [27]. The study involved a
retrospective, single unit review of fifty patients with metastatic
GTN who were sequentially treated with methotrexate and dacti-
nomycin, of which 74% (thirty-seven out of fifty) achieved remis-
sion. Irrespective of the histopathological sub-type or duration of
disease, patients with hCG levels <1  106 mouse uterine units
(MUU) had significantly higher remission rates (p < 0.001). Fur-
thermore, an interval of 4 months before starting chemotherapy
was associated with reduced remission rates (p < 0.025), irrespec-
tive of the hCG titre or histopathological diagnosis. The presence
of cerebral metastases was also deemed a negative prognostic indi-
cator. Histological sub-type, age, gravidity, antecedent pregnancy
 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57 49

Table 1
Japanese morphological classification and risk score for trophoblastic disease) [18,25]. Copyright 1982, with permission from John Wiley and Sons.

(a) Morphological Classification for trophoblastic disease

1. Total (or complete) hydatidiform mole
2. Partial hydatidiform mole
3. Invasive (or destructive) hydatidiform mole
4. Choriocarcinoma
5. Persistant trophoblastic disease (a) Post-molar persistantly high hCG level
(b) Clinically invasive (or destructive) mole
(c) Clinical choriocarcinoma
Score 0 1 3 4 5
(b) Japanese Choriocarcinoma Risk Score
Probability of choriocarcinoma (%)
Parameter <50 50–60 70–80 80–90 >90
Preceding pregnancy Hydatidiform mole – Abortion – Delivery
Interval time <6 months – – 6 months to 3 years 3 years
Primary tumour Corpus/parametrium/vagina – Tube/ovary Cervix Extra-pelvic
Metastatic site None/lung/pelvis – – – Extra pelvic (except lung)
Lung metastases
(a) Diameter (mm) <20 – 20–30 – 30
(b) Size Uniform – – Variety in size Variety in size
(c) Number 20 – – – 21
Urinary hCG (mIU/mL) <106 106–107 107 – –
Menstrual cycles Monophasic (irregular) – – Biphasic (regular)

Score 4 = Clinical invasive mole, recommend first line single-agent chemotherapy.

Score 5 = Clinical choriocarcinoma, recommend first line combination chemotherapy.

Table 3
Table 2 The UICC 1967 Classification for GTN [16]. Copyright 1967, with permission from
The Song classification system for GTN [26]. Copyright 1981, with permission from Springer.
Publisher.
A Gestational
Stage Description B Non-gestational
I Disease confined to the uterus I. Clinical diagnosis
II A Disease extends to the adnexa and parametria (1) Non-metastatic
B Disease extends to the vagina (2) Metastatic (a) Local (pelvic)
III A Disease extends to lung and metastases are <3 cm in diameter or (b) Extrapelvic (specify location)
mottling in less than half of one lung (3) Other required (a) Evidence
B Disease extends to lung and metastases are >3 cm in diameter or information (i) Morphological
mottling in more than half of one lung (ii) Non-morphological
IV Disease extends to other organs e.g. brain, liver, kidney and
bowel (b) Antecedent pregnancy – specify duration
(i) Normal
(ii) Abnormal
(iii) Molar
(c) Previous treatment
or history of previous hysterectomy ± oophorectomy did not signif-
(i) Untreated
icantly affect prognosis, yet statistical analysis was not provided (ii) Treated, specify
within the paper. II. Morphological diagnosis
Unfortunately the number of patients receiving each regimen 1. Hydatidiform (a) Non-invasive
was not equally divided (methotrexate n = 38, dactinomycin mole (b) Invasive
2. Choriocarcinoma
n = 14), whilst although the data suggests that the remission rates
3. Uncertain
were higher amongst the group receiving primary dactinomycin 4. Other required (a) Diagnostic basis – specify
(57% compared to 47% for methotrexate) or dactinomycin followed information (i) C = curettage
by methotrexate (60% compared to 47% for methotrexate followed (ii) U = excised uterus
(iii) N = necropsy
by dactinomycin), this was not noted within the paper and statis-
(iv) O = other
tical assessment was not provided. This may have distorted the
interpretation of the importance of clinical prognostic factors, (b) Date of diagnosis (with respect to date of
given that the data was pooled for this analysis, to include all onset of treatment)
remissions irrespective of the treatment administered. The study (c) Subsequent change in morphological diagno-
sis – specify diagnosis as in II.4a
only involved metastatic GTN patients and a single unit’s experi-
ence, which combined with the above discussion, questions the
study validity and generalisability. This is of particular concern
given this paper has been influential in the development of subse- hCG titre, and is still used in Japan today in preference to the
quent prognostic classification systems, including the UICC 1967 FIGO/WHO system [25].
classification for GTN. A recent analysis re-classified 443 GTN patients according to
At the same time, The Japan Society of Obstetrics and Gynecol- the 2000 FIGO/WHO classification, who were initially scored using
ogy developed a rival classification system, which more closely the Japanese Choriocarcinoma system [2,18,25,28]. FIGO low-risk
approximates the modern-day FIGO/WHO prognostic classification and high-risk disease tended to correlate with clinical invasive
system. The system combines anatomical criteria such as tumour mole and clinical choriocarcinoma groups respectively within the
location and metastatic site, with key clinical factors including Japanese system. Regarding drug resistance, primary remission
antecedent pregnancy, interval to commencing treatment and and relapse rates, no significant difference was observed between
50 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57
patients classified as FIGO low-risk and clinical invasive mole on
the Japanese score, or FIGO high-risk and clinical choriocarcinoma.
Significantly higher relapse and resistance rates existed between
the FIGO high-risk and low-risk group (p = 0.001) and Japanese
choriocarcinoma versus invasive mole group (p = 0.001), despite
giving combination chemotherapy to the FIGO high-risk and clini-
cal choriocarcinoma groups. The significant degree of chemother-
apy resistance amongst patients with a FIGO score of 5–6 was
evidenced by a separate sub-group analysis. Out of the fifty-two
patients with a FIGO score of 5 or 6, seventeen were classified as
clinical choriocarcinoma within the Japanese system and received
combination chemotherapy, despite which, 25% patients experi-
enced disease relapse. The remaining thirty-five patients were cat-
egorised as having a clinical invasive mole and were given single-
agent first line treatment according to the Japanese classification,
and had a statistically lower relapse rate of 5.7% (p = 0.001). Inter-
estingly, in patients with a FIGO score of 5–6, the rates of drug
resistance were not significantly different amongst patients with
a clinically invasive mole or choriocarcinoma based upon the Japa-
nese classification system, despite administering combination
chemotherapy to the choriocarcinoma group. This analysis
prompted the authors to recommend using the Japanese classifica-
tion system for patients with a FIGO score of 5–6; to facilitate the
choice of chemotherapeutic agent; minimising unsuccessful treat-
ment and disease relapse [28].
The validity of these conclusions is questionable however, given
the method of re-classifying patients, which involved a significant
proportion of patients given different first line treatment. In the
FIGO/WHO classification, low-risk patients score 0–6 and are given
single-agent chemotherapy, whereas high-risk patients score 7
and are given first line combination chemotherapy. However,
twenty-seven patients (25.7%) in the clinical choriocarcinoma
group had a score <7 and three patients (0.9%) with a clinical inva-
sive mole had a score 7, potentially distorting the findings.
In 1973, the Southeastern Trophoblastic Disease Centre devel-
oped a competing clinical classification that paved the way for
the current WHO classification system, dividing patients into good
and poor prognostic groups based on features such as hCG level at
diagnosis, duration of symptoms, antecedent pregnancy and previ-
ous chemotherapy treatment (Table 4) [29]. This classification sys-
tem was widely adopted throughout the USA. The classification
was based upon a single unit, retrospective (1966–1971) analysis
of eighty-eight patients with metastatic GTN, of which seventy-
one patients (79%) were classified as having ‘good prognosis’ and
seventeen (19%) had ‘poor prognosis’.
Similar to the aforementioned studies [16,18,27], this analysis
only included patients with metastatic disease. It is apparent that
modern day GTN classification systems have been developed from
Table 4
Hammond’s Southeastern Trophoblastic Disease Centre Clinical classification for GTN
[29]. Copyright 1973, with permission from Elsevier.
I Non-metastatic GTN
II Metastatic GTN
A Good Prognosis
1. Urinary hCG <100,000 IU/24 h urine or <40,000 IU/L serum
2. Symptoms present for less than 4 months
3. No brain or liver metastases
4. No prior chemotherapy
5. Pregnancy event is not term delivery (i.e. mole, ectopic or
spontaneous abortion)
B Poor prognosis
1. Urinary hCG >100,000 IU/24 h urine or >40,000 IU/L serum
2. Symptoms present for more than 4 months
3. Brain or liver metastases
4. Prior chemotherapeutic failure
5. Antecedent term pregnancy
a subset of patients that are not comparable to the current patient
population, where the vast majority (75% (Author’s unpublished
data)) do not have metastatic disease at presentation. Overall the
classification is based upon the authors’ findings [30], a study
involving sixty-two patients with metastatic GTN [31] and the
aforementioned 1965 paper, whose methodology we have cri-
tiqued earlier in this review [27]. The clinical risk factors included
in this classification system were entirely based upon relatively
low quality, observational, single unit studies with small patient
numbers and the use of varying treatment regimens, which is
likely to confound the results. The study quality is additionally
reduced by the inclusion of unequally sized prognostic groups
(seventy-one versus seventeen patients). It is likely that PSTT and
ETT patients, not yet characterised at this time, were erroneously
incorporated into these analyses, particularly considering that a
large proportion of these cases present with metastatic disease.
PSTT and ETT should not be included in prognostic classification
systems due to their differing biological behaviour.
A rival and improved system was simultaneously underway in
England in 1976, whereby a seminal paper identified twelve clini-
cal risk factors to formulate the first weighted classification system
(Table 5a), which indicated the relative prognostic importance of
each factor and undoubtedly formed the foundations of today’s
combined FIGO and WHO prognostic classification (Table 5b)
[14,32]. The system was based upon a retrospective analysis of
314 patients treated at a single unit (Charing Cross Hospital, Lon-
don, UK) between 1958 and 1973 and found that chemotherapeu-
tic response was definitively influenced by multiple factors,
including antecedent pregnancy, interval between antecedent
pregnancy and start of chemotherapy, parents’ blood group, mater-
nal age, tumour burden as indicated by hCG level, extent of
mononuclear infiltration in the tumour, patients’ immunological
status, size of the tumour mass and the size and location of metas-
tases [32]. The classification system divided patients into low-,
medium- and high-risk groups, yet its widespread use was limited
due to substantial variations in the score allocated to the same risk
factors by different clinicians, and the fact that risk factors were
often missed out due to a lack of clinical information or unavail-
ability of some tests in developing countries [33]. Critically
appraising this paper, the quality of the results may be reduced
by the retrospective analysis, as prospective data are more accu-
rate to prevent opportunistic analysis of multiple factors. The study
is also limited by its use of data from only one unit, considering
that the numbers in some groups (e.g. race, metastatic sites) were
too small to statistically assess. Furthermore, statistical analyses
were not applied to all risk factors, hence statistical significance
is dubious; whilst in some cases, there was insufficient tissue for
the research centre to validate the histological sub-type and diag-
nosis of GTN.
Nevertheless, this system was adopted by the WHO in 1983,
who simplified the classification system to contain only nine risk
factors and adjusted the attributed weighting to 0–4 compared
with 0–40 [34]. The WHO classification system classified patients
into three prognostic groups to guide chemotherapeutic manage-
ment; score 4 low-risk, 5–7 medium-risk and 8 high-risk. Many
centres worldwide used this system, yet the lack of evidence to
support a specific, unified classification system was again revealed
by the two UK Centres for Trophoblastic Disease (Weston Park
Hospital in Sheffield, UK and Charing Cross Hospital in London,
UK) using slightly different classification systems. Sheffield used
the same nine risk factors but divided patients into only two treat-
ment groups; score 0–7 low-risk, score >7 high-risk.
In 1992, FIGO proposed a final update to the anatomical classi-
fication system, combining anatomical staging with two clinical
risk factors; specifically hCG levels > 100,000U/l and time to diag-
nosis > 6 months [35]. However, through multivariate analyses, it
 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57 51

Table 5
Weighted prognostic classification systems.

Score 0 10 20 40
(a) Bagshawe prognostic classification system (1976) [32] Copyright 1976, with permission from John Wiley and Sons
Age (years) <39 39 – –
Parity 1, 2, >4 3 or 4 – –
Antecedent pregnancy Mole Abortion Term –
Histological diagnosis Invasive mole Not known Choriocarcinoma –
Interval (AP to start of chemotherapy) (months) <4 4–7 7–12 >12
hCG (plasma IU/L or urine IU/day) 103–104 <103 104–105 >105
ABO groups (patient  husband) AA O  O, A  O BOA –
O or A  B O  A, B  B AB  O  A
O or A  AB AB  B
Number of metastases None 1–4 4–8 >8
Site of metastases Not detected Spleen Gastrointestinal tract Brain
Lung, vagina Kidney Liver
Largest tumor mass diameter (cm) 3 3–5 5 –
Lymphocytic infiltration of tumour Marked Moderate or unknown Slight –
Immune status Reactive Unknown Unreactive –
Relapse after previous chemotherapy – – Yes –

(b) The Combined FIGO/WHO prognostic classification system (2000) [14] Copyright 2000, with permission from Elsevier
FIGO Anatomical Stage
Stage
I Disease confined to the uterus
II GTN extends outside of the uterus but is limited to the genital structures (adnexae, vagina, broad ligament)
III GTN extends to the lungs, with or without known genital tract involvement
IV All other metastatic sites
Score 0 1 2 4
Modified WHO Prognostic Classification System, as adapted by FIGO
Age (years) <40 40 – –
Antecedent pregnancy Mole Abortion Term –
Interval months from index pregnancy <4 4–6 7–12 >12
Pre-treatment hCG (IU/L) <103 103–104 104–105 >105
Largest tumor size including uterus (cm) <3 3–4 5 –
Site of metastases Lung Spleen, kidney Gastrointestinal Liver, brain
Number of metastases – 1–4 5–8 >8
Previous failed chemotherapy – – Single drug 2 drugs

Score 0–6 = Low-risk, Score 7 = High-risk.

was widely accepted that the WHO clinical classification system
more reliably predicted outcome, due to the inclusion of multiple
clinical risk factors influential in the development of GTN
[24,33,36–41].
For several years, there was no worldwide consensus on the
optimal classification system for GTN, largely due to a lack of high
quality data proving the merit of one system over another. In 2000,
the International Society for the Study of Trophoblastic Disease
(ISSTD) gathered the leading experts in GTN and aimed to resolve
the confusion and ambiguity surrounding the various classification
systems, which reflects the weaknesses in them all [33]. The group
decided to combine the FIGO anatomical and WHO clinical prog-
nostic classification system: classifying patients with both meta-
static and non-metastatic disease into only two groups (low-risk
0–6 and high-risk  7), thus culminating in the FIGO 2000 guideli-
nes [2]. The intermediate category was therefore removed; a deci-
sion predominantly based on data from one study, yet many
experts agreed with this decision [14,41]. In addition, the com-
bined system removed blood group as a risk factor due to a lack
of evidence regarding its influence on outcome, with several stud-
ies proving this on both univariate and multivariate analyses
[36,42–45]. Furthermore, blood group details were often lacking
within clinical data and thus ‘missed out’ of the classification pro-
cess. The weighting of risk factors was also changed to 0 to 4, liver
metastases were deemed high-risk, scoring 4, and PSTT and ETT
patients were excluded from the classification system due to the
differing behaviour of these sub-types.
These recommendations were largely based upon six retrospec-
tive studies [38,41,42,45–47] combined with the historical papers
discussed previously, all of which have significant methodological
flaws. Only one paper [41] investigated the impact of the new com-
bined FIGO/WHO classification system by retrospectively re-
scoring 201 patients treated for persistent GTN according to the
original WHO classification system of 1983 [34], revised FIGO sys-
tem of 1992 [35], and the proposed combined FIGO/WHO classifi-
cation. With respect to chemotherapy resistance and outcome, all
classification systems were largely similar, yet the FIGO/WHO clas-
sification system would have caused sixteen patients to receive dif-
ferent treatment. Of concern, four out of eight patients re-classified
as low-risk by the FIGO/WHO system, who were originally classi-
fied as high-risk by the Sheffield system, were resistant to first line
high-risk treatment, three of which were cured by second line
chemotherapy. The paper also referenced unpublished data from
Charing Cross in London, whereby a retrospective re-
classification of 367 patients according to the combined system,
would have changed the initial treatment in only three cases.
The combined system increased the number of low-risk patients
from 40–50% to 86%, which was suggested to minimise patient
exposure to toxic high-risk chemotherapy regimens without com-
promising outcome [41]. Potential criticisms of this study include
the retrospective analysis, yet the study involved a relatively large
sample number considering the rare nature of the condition, and
excluded patients with PSTT or atypical histology, which increased
the accuracy of the results.
The remaining studies on which the ISSTD based their decision
to change the GTN classification system are highly variable in
methodology, treatment administered to patients, and results gen-
erated, questioning the validity and robustness of the data upon
which such fundamental changes were made (Table 6). None of
the studies analysed the proposed impact of the new combined
Table 6
Summary of articles on which ISTTD recommendations to combine the FIGO and WHO prognostic classification systems were based.
Author, Methodology
Year
Kim  Retrospective analysis, 1982–1995
et al.  2 main centres, 2 smaller units
[45]  165 GTN patients treated with EMA/CO first line
(high-risk patients, WHO score  8, n = 96) or
after 1st (n = 61) or 2nd line (n = 8) treatment
failure with a variety of agents including MTX,
MAC, CHAMOCA). FIGO stages Ib to IVc.
 Overall 136 (83.6%) survived, 27 (16.4% died)
Ngan  Retrospective review, 1976–1988, 2 centres
et al.  2 centres
[36]  55 patients with metastatic GTN, all treated
with CHAMOCA, FIGO stages II-IV.
 16 patients received 1st line treatment prior to
this with poor response.
 Overall 39 (71%) survived, 16 (29%) died.
Soper  Retrospective review, 1968–1992, single centre
et al.  454 patients with metastatic and non-meta-
[42] static GTN; 385 for primary therapy, 69 for sec-
ond line treatment.
 Overall 90% survival, 96.3% for those having pri-
mary chemotherapy, 60% for those receiving
second line treatment (p < 0.0001).
 Range of FIGO stages Ia-IVc.
Results-univariate analysis
Significant prognostic determinants:
Tumour age (p = 0.002), initial hCG level
(p = 0.021), metastatic site (p = 0.001), number of
metastatic organs (p = 0.001), unplanned operation
(p = 0.003), gravidity (p = 0.034) and inadequate
previous chemotherapy (p = 0.012)
Other factors within the WHO classification system
were not significant; age (p = 0.242), antecedent
pregnancy (p = 0.086), blood type (p = 0.290),
largest tumour size (p = 0.159) and number of
metastases (p = 0.715).
Significant prognostic determinants:
Interval between antecedent pregnancy and GTN
diagnosis (p = 0.004), urinary hCG at presentation
(p = 0.02), number of metastatic sites (p = 0.046).
WHO score > 8 associated with a higher probability
of death (p = 0.003).
FIGO stage II-III no significant difference in
probability of dying compared to stage IV patients
(p = 1.0).
Other factors within the WHO classification system
were not significant; age (p = 0.32), antecedent
pregnancy (p = 0.13) blood group (p = 1.0), lesion
size (p = 1.0), number of metastases (p = 0.33), site
of metastases (p = 0.48), previous chemotherapy
(p = 0.72).
Significant prognostic determinants:
For all factors, p < 0.0001: Duration of disease, type
of antecedent pregnancy, clinicopathological
diagnosis, anatomic site of highest risk metastases,
number of metastatic sites or foci, maximum
extrauterine tumour size and type of prior therapy.
Maternal age was also significant (p < 0.02)
hCG level, year of diagnosis and type of
chemotherapy used were not significant (p < 0.1).
Results – multivariate analysis
Stepwise-Cox Proportional Hazards Regression,
significant factors related to survival:
Tumour age (p = 0.0029), number of metastatic
organs (p = 0.0002), metastatic site (p = 0.00249),
inadequate previous chemotherapy (p = 0.0312).
Significant factors in the WHO classification system
on stepwise logistic regression:
Tumour age (p = 0.0029), number of metastatic
sites (p = 0.0002).
Cox multiple regression analysis:
Intervals from antecedent pregnancy to diagnosis
and hCG level were the two main factors
significantly related to survival.
Significant prognostic determinants:
Prior therapy (p < 0.004), antecedent pregnancy
(p < 0.05), number of metastatic sites (p < 0.0001)
and duration of disease (p < 0.006)
Clinicopathological diagnosis (p < 0.07) and pre-
treatment hCG level (p < 0.04) were borderline risk
factors, but not independent risk factors when
patients with metastatic disease and primary
therapy were analysed separately.
52
Comments
 Combined analysis of patients who had
failed previous chemotherapy and those
who were treatment naïve.
 Only performed multivariate analysis on
factors significant on univariate analysis.
 Many factors in WHO classification system
were not significant determinants of
prognosis.
 Conclude that the WHO score is not accu-
rate at predicting outcome due to the wide
range of predicted survival probabilities.
 No improvements to prognostic classifica-
tion system suggested.
 Combined analysis of patients who had
V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57
failed previous chemotherapy and those
who were treatment naïve. Type of first
line chemotherapy not described.
 Statistics for multivariate regression not
provided within the paper.
 Concluded that the WHO classification sys-
tem was not precise in predicting patient
prognosis, due to the range of predicted
survival probabilities.
 WHO system deemed more predictive of
outcome than the FIGO classification.
 WHO system contains many factors that
do not significantly influence prognosis.
 Recommend a prospective trial with a sim-
pler classification system including only
significant risk factors highlighted in this
study.
 Compared several classification systems;
 FIGO anatomic system of 1992, WHO clin-
ical prognostic system of 1983 and the his-
torical clinical classification system.
 Patients were divided into primary and
second line therapy for the analysis; all
systems stratified patients into low- or
high-risk groups with equal efficacy with
statistical significance reached.
 Benefits of the more complex WHO system
are unclear.
 However, no comment on whether one
classification system deemed superior to
the others in predicting survival.
 First paper to statistically prove that FIFO
score is associated with outcome.
 Claim no classification system accurately
predicts outcome.
 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57 53

classification system, even by retrospective analysis. Instead, the

means that fewer patients are exposed to

 Suggest that the proposal to combine the

divide patients into two prognostic groups

 Recommend a prospective study to vali-

multivariate analysis as noted only

patients with metastatic choriocarcinoma
mens, with reduced early and late toxicity.

failed previous chemotherapy and those

 Authors excluded presence of metastases

 Concluded WHO score was an important

 New FIGO/WHO classification system

predictor of treatment outcome but UICC

aggressive high-risk chemotherapy regi-

modified FIGO/WHO classification and

(low-risk and high-risk) is realistic and

 Combined analysis of patients who had

and clinicopathological diagnosis from

died. This may have confounded the data.

studies jointly analysed patients who had previously failed pri-
mary treatment (often following inadequate regimens at non-
specialist centres) with those who were treatment naïve, despite

date the new classification system.

these being very different GTN groups. This confounded overall
prognostic data and the interpretation of which risk factors influ-

who were treatment naïve.

score had higher v2 score.

enced outcome [36,38,42,45]. The recommended treatment regi-
mens for patients with low- versus high-risk, metastatic versus
non-metastatic disease have changed significantly over time, lead-
ing studies to compile a retrospective group of patients who have
practicable.

had very different treatments, rendering the data incomparable for

analysis of prognostic risk factors. Some studies only recruited
Comments

patients with certain histological sub-types [38] or metastatic

GTN [36], whilst others contained a combination [38,42,45]. As
most GTN papers included patients with metastatic disease, clini-
cians have suggested that the combined classification should only
system, of which 4 were resistant to first line high-

predicted outcome (p < 0.0001), but the UICC score

classified as low-risk by the combined FIGO/WHO

Number of metastases (p < 0.0001), metastases to

8 patients high-risk on the Sheffield system were

Compared the FIGO 1982, WHO 1983, Hammond

and UICC classification system, all 4 significantly
resistant to primary single-agent chemotherapy.

sites outside the lung or vagina (p = 0.0002) and

include these patients. Those with non-metastatic disease could be

combined FIGO/WHO system, of which 3 were
Sixteen patients would have received different

was the strongest overall predictor of survival

over-treated if classified as high-risk [39]. It is not therefore sur-
treatment according to the new FIGO/WHO

previous failed chemotherapy (p = 0.0014).

classification system and high-risk on the
8 patients were low-risk on the Sheffield

prising that these studies each identified different key prognostic

markers on uni- and multivariate analysis (Table 6: Summary of
Significant prognostic determinants:

articles on which ISTTD recommendations to combine the FIGO

Results – multivariate analysis

and WHO prognostic classification systems were based), yet the

studies concurred that there was no evidence that several risk fac-
tors incorporated in the WHO system actually influenced
classification system:

prognosis.
risk chemotherapy.

(highest v2 score).

Remarkably, in the sixteen years since introducing the com-

bined FIGO/WHO classification system, there has never been a
prospective, validation study to test this classification system,
despite the concerns raised by authors regarding the inclusion of
risk factors that do not appear to influence outcome
[18,20,36,38,42,45]. This is particularly pertinent considering that
Charing Cross, FIGO 1992, WHO 1983 and modified

(p = 0.0003), antecedent pregnancy (p = 0.001), site

proportion of low-risk patients (86%) compared to

over time, issues have emerged with the classification system.

of metastases (p < 0.0001), number of metastases
outcome, the classification systems were similar.

clinicopathological classification (p = 0.0001) and

Patients retrospectively scored according to the

Some clinicians believe that it is a mistake not to include hydatid-

With respect to chemotherapy resistance and

46% with WHO system and 51% using FIGO

combined FIGO/WHO classification system.

iform mole patients as Stage 0 within the classification system, to

New combined system generated a higher

hCG level (p = 0.05), duration of disease

(p < 0.0001), number of metastatic sites

facilitate the monitoring of these patients given that 15% of com-

(p < 0.0001), tumour size (p < 0.0001),

previous chemotherapy (p = 0.0005).

Significant prognostic determinants:

plete hydatidiform moles develop GTN [1,13,18].

The optimal management of patients with a FIGO score of 5–6
remains one of the key challenges amongst trophoblastic disease
Results-univariate analysis

specialists worldwide. Since the removal of the intermediate prog-

nostic group a significant proportion of low-risk patients (25–35%)
are resistant to primary, single-agent chemotherapy. Amongst
patients with a WHO score of 6, primary chemotherapy resistance
classification.

can reach 80% [1,5–14,47]. These patients then require second line
or more intensive chemotherapy regimens, with potential adverse
psychological consequences for the patient and her family [13].
In Europe and Northern America, intramuscular methotrexate is
generally favoured for managing low-risk patients with a score of
Overall 198 (99%) survived, 3 patients (1%) died.
Histology: 85% complete hydatidiform mole, 9%

 Overall 363 (93%) cured; 223 (100%) patients

with non-metastatic disease and 139 (83%) with
 391 patients with GTN (invasive mole and

 223 (57%) had non-metastatic disease, 168 (43%)

Retrospective review, 1986–1996, single centre

 Retrospective review, 1969–1988, single centre

5–6, however an alternative therapy is dactinomycin, which is also

used as a salvage regimen following first line methotrexate resis-
tance. In many countries, methotrexate remains the treatment of
choice in low resource areas, particularly considering its feasibility
choriocarcinoma, 6% partial mole.

of administration as a more straightforward outpatient treatment

[5,48]. Dactinomycin requires intravenous administration, likely
hospital admission if being given as a five-day regimen, and is
had metastatic disease.
201 patients with GTN

associated with much higher treatment costs [49]. The recently

metastatic disease.
 Stages I-IV disease

 Stages I-IV disease

updated Cochrane review included a total of 667 women in seven

choriocarcinoma)

randomized control trials to compare the efficacy of methotrexate

with dactinomycin in patients diagnosed with low-risk GTN. The
Methodology

group concluded with a moderate degree of certainty that dactino-

mycin was more likely to lead to primary remission and less likely
to result in treatment failure compared to methotrexate. Evidence
Table 6 (continued)






concerning the comparative side effect profile was more limited,

yet dactinomycin, particularly the five-day regimen, was suggested
Hancock
et al.

et al.
Author,

[41]

[38]
Lurain

to be associated with more adverse side effects [5].

Year

On the other hand, it is equally problematic to administer more

intensive, toxic combination chemotherapy regimens unnecessar-
54 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57
ily to patients who would have been cured by single- agent ther-
apy. Combination treatment is associated with a significant
increase in more serious short-term effects including alopecia
and myelosuppression, whilst long-term side effects include earlier
menopause (brought forward by three years) and a 1.5-fold
increase in the rate of secondary malignancies, particularly leukae-
mia [6,50–55]. Etoposide has been reported to increase the risk of
secondary breast, thyroid, colorectal cancer and melanomas
[55,56]. However, more recent data from Charing Cross in London
involving 1903 patients followed up for an average of 16.9 years,
concluded that the risk of a secondary malignancy was not
increased following single-agent methotrexate or combination
therapy with EMA/CO (etoposide, methotrexate, dactinomycin,
cyclophosphamide, vincristine). In fact, the risk of subsequent
malignancy was equivalent to the general population [55–57].
Despite this, there remains an increased risk of secondary leukae-
mia in patients treated with combination chemotherapy, with 6
cases seen compared with 1.3 expected (Standard Incidence Ratio
4.5, 95% CI 2.0–10.1, p < 0.01), with the risk increasing with higher
alkylating agent and etoposide exposure [57]. For this reason,
efforts are made to limit the duration of therapy to less than six
months [11,54–56].
Combination chemotherapy additionally accelerates the age of
menopause. A recent study found that 13% women treated with
combination chemotherapy (EMA-CO) had reached the menopause
by age 40 years, rising to 36% by age 45 years. The rates of meno-
pause were significantly higher (cumulative risk by age
35 years = 0.09, p < 0.01, cumulative risk by age 40 years = 0.28,
p < 0.05) in women who started treatment aged  30 years, com-
pared to those treated at younger ages (<30 years) [57].
Fortunately, aside from accelerating the menopause, combina-
tion therapy does not otherwise effect fertility and evidence sug-
gests that there is no increase in the rates of congenital
abnormalities, miscarriage, ectopic pregnancy or stillbirth in future
pregnancies compared to the general population [50,58,59]. Given
the potential significant toxicity profile of combination chemother-
apy, it is essential to optimise methods to identify patients most
likely to be resistant to first line chemotherapy, to avoid under-
or over-treatment and adverse short and longer-term
consequences.
As a strategy to reduce the use of multi-agent chemotherapy in
low-risk GTN patients who develop methotrexate resistance, car-
boplatin has recently been proposed as an alternative second line
agent to combination chemotherapy. In this patient group, prior
standard practice at our centre in Sheffield, recommended dactino-
mycin (intravenous bolus at a dose of 1.25 mg/m2 every two
weeks) if the hCG is <300 IU/L or combination chemotherapy (EA
(etoposide/dactinomycin [E:100 mg/m2 given intravenous, days
1–3, A:0.5 mg intravenous, days 1–3], involving a two night hospi-
tal stay for patients every 10-days)) if the hCG level exceeds
300 IU/L at the time of treatment failure [55]. Using carboplatin
AUC6 on a 3-weekly basis, instead of EA combination treatment,
81% (17/21 patients) achieved a complete hCG response, with four
patients needing third line EA. Eleven of the 21 patients (52%) trea-
ted with carboplatin following first line treatment failure had a
FIGO risk score of 5 or 6. Overall carboplatin was well tolerated,
with the main side effect being myelosuppression. The regimen
was suggested as a promising alternative regimen to combination
chemotherapy in patients resistant to first line methotrexate,
avoiding alopecia and in-patient treatment, and minimising expo-
sure to combination regimens that are also associated with an
increased risk of premature menopause and leukaemia [55].
A ‘regression’ back to an intermediate prognostic group may not
necessarily be the answer. However, patients more accurately
identified to be at the highest risk of non-response to single-
agent methotrexate could be offered alternative, most likely
multi-agent, chemotherapy from the outset, which may limit the
psychological consequences of ‘failing’ first line treatment. Ulti-
mately, the aim would be to reduce the need for sequential lines
of chemotherapy and shorten treatment duration. However, in
the UK using the current scoring classifications, and given that
the survival rate in low-risk disease is 100%, the current consensus
is that patients should be treated with the least toxic, single-agent
therapy first line to avoid exposure to more toxic multi-agent reg-
imens if at all possible [1,15,18,60]. Furthermore, it appears that
non-response to first line single-agent chemotherapy does not sig-
nificantly increase the length of treatment [15]. Some clinicians
recommend counselling patients with their treatment options;
allowing them to make an informed choice between first line sin-
gle or combination chemotherapy [17]. Such practice is carried out
at Charing Cross Hospital, where patients with poor prognostic
markers; FIGO score of 5–6 or hCG level > 100,000 IU/L are offered
either low- risk single-agent methotrexate or combination therapy
with EMA/CO [15].
Future perspectives
In light of the issues raised with the current FIGO/WHO scoring
system in more accurately identifying first line chemotherapy
resistance, several novel approaches have been proposed including
hCG regression; hyperglycosylated hCG; ultrasound features;
microRNA and cell free DNA. These will be discussed briefly below.
hCG regression
The pattern and fall of hCG following uterine evacuation has
been proposed as a useful indicator for predicting the development
of GTN, but also for the early identification of first line, single-agent
chemotherapy resistance. By comparing the regression of hCG in
benign moles whose hCG levels spontaneously resolve, to those
who ultimately develop GTN, linear regression lines and area under
the curve calculations have been generated to predict over half of
GTN patients with a high specificity (97.5%) [61]. Crucially, these
calculations can identify GTN earlier than is currently possible.
Further preliminary work on the regression of hCG has revealed
that hCG measurements before the fourth and sixth course of
single-agent chemotherapy (approximately seven weeks into
treatment) can accurately identify primary treatment resistance
[62]. Studying 800 patients with low-risk GTN, a modeled kinetic
parameter called hCGres can be calculated after only three cycles
of methotrexate to identify patients with chemotherapy resistance.
The study purported hCGres with a cut off value of 420.44 IU/L as a
more accurate predictor of methotrexate resistance than other fac-
tors [63], and was recently validated in 210 patients by the Gyne-
cologic Oncology Group-174 Phase III trial (GOG-174) having a
sensitivity of 88.9% and specificity of 73.1% [64]. Further prospec-
tive validation is now required.
Hyperglycosylated hCG (hCG-H)
Lawrence Cole has pioneered the role of hCG-H, recommending
its use as a highly sensitive and specific tumour marker that can
differentiate between pre-malignant and malignant disease and
predict the need for chemotherapy. Cole describes two distinct
clinical entities of ‘quiescent’ and ‘minimally aggressive GTD’. ‘Qui-
escent’ GTD is characterised by the absence of hyperglycosylated
hCG, representing a group of pre-malignant cases who will ulti-
mately transform, whereas ‘minimally aggressive GTD’ is an in-
between state between highly aggressive disease (with a high pro-
portion of hCG-H in the total hCG count) and quiescent disease. In
minimally aggressive GTD, hCG-H levels are typically < 40% of total
 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57
hCG, representing a gradually progressive condition that is charac-
terised by slow hCG doubling times and is believed to represent
the group who are resistant to primary chemotherapy [65–67].
However, Cole’s work has been critiqued by numerous trophoblas-
tic disease experts worldwide, who feel the conclusions are mis-
leading due to absent clinical data and inadequate follow up.
Prospective or validation upon a larger patient population is rec-
ommended prior to the introduction of this marker into routine
clinical practice [68–70].
Ultrasound features
The ultrasonographic features of trophoblastic disease have
recently been suggested as a marker for the early differentiation
between benign and malignant disease and a predictor of first-
line chemotherapy resistance. Significant differences were identi-
fied between healthy controls and patients diagnosed with tro-
phoblastic disease (benign and malignant subtypes), using
ultrasound parameters including the resistance (RI), flow (FI), pul-
satility (PI), vascularisation (VI) and vascularisation-flow indices
(VFI). Moreover, low RI, high VI, FI and VFI appeared to characterise
malignant compared to benign trophoblastic disease, while the VI,
FI and VFI fell concurrently with hCG levels in keeping with an
effective chemotherapeutic response [71]. Ultrasound has addi-
tionally been used to denote chemotherapy response and disease
resistance amongst patients with low-risk, stage I GTN. Reduced
echogenicity of myometrial lesions, decrease in Doppler signal or
size were indicative of a radiological response to chemotherapy.
In three cases of methotrexate resistance as denoted by a refrac-
tory hCG response, ultrasound features could be successfully used
to guide ongoing therapy, recommending that methotrexate
should be continued in the presence of an ultrasound response.
All three of these patients achieved a complete response and
avoided unnecessary combination chemotherapy [72]. Finally, a
group from Charing Cross has investigated the role of Doppler
ultrasound, specifically uterine artery pulsatility index (UAPI) in
predicting first line chemotherapy resistance. UAPI is inversely
proportional to the vascularity of the tumour; therefore a larger
uterine tumour with more vascular, abnormal angiogenesis would
have a lower UAPI. Specifically, patients with a FIGO score of 5–6
have been studied; identifying vascular uterine tumours with a
UAPI  1 to be an independent risk factor for resistance to first line
methotrexate [11,73,74]. Specifically, in patients with a UAPI  1
and a FIGO score of 5 or 6, 81% and 100% respectively were resis-
tant to first line methotrexate. Pending the outcome of a larger val-
idation study, the group advocates a role for UAPI in guiding
clinical management; suggesting that patients with a FIGO score
of 5–6 and a UAPI  1 should be offered first line combination
chemotherapy, due to the very high rates of methotrexate resis-
tance [74].
Biomarkers
The most novel and exciting future direction for GTN is the
identification of reliable biomarkers to predict disease resistance
or even malignant conversion much earlier than is currently possi-
ble. Currently, the role of microRNA and cell free DNA is under
exploration.
microRNA is one of the most rapidly expanding scientific fields
and is certainly an area for further investigation with respect to
trophoblastic disease. In a small patient cohort, specific circulating
microRNAs (hsa-miR-520b, hsa-miR-520f and hsa-miR-520c-3p)
have been identified in patients diagnosed with complete hydatid-
iform moles that either spontaneously resolve or develop into GTN
55
[75,76]. These biomarkers may ultimately prove useful as an
adjunct to hCG in the monitoring of GTN and chemotherapeutic
response. In addition, using formalin foxed trophoblastic tissues,
a specific microRNA (miR-21) has been found to be significantly
upregulated in patients with hydatidiform moles compared to nor-
mal, healthy placentas. Using quantitative real time PCR and Wes-
tern Blotting, miR-21 had an important role in the dysregulation of
normal cellular mechanisms in choriocarcinoma, and therefore
plays a role in the aggressive nature of this condition [77].
Currently, there is one published article detailing the role of
plasma derived cell free DNA (cfDNA) in diagnosing trophoblastic
disease. Circulating tumour DNA was successfully identified in
twelve out of twenty GTN patients, with potential future applica-
tions for earlier diagnosis. Furthermore, circulating tumour DNA
proved helpful to confirm cases of GTN in patients of diagnostic
uncertainty/inconclusive histology [78].
Discussion
Critically appraising the criteria by which prognostic risk factors
have historically been included within the classification systems
leaves significant questions regarding the accuracy and reliability
of the currently used FIGO/WHO classification system. Researchers
from different countries have developed their own classification
systems based on individual, single unit experience, involving rel-
atively small patient numbers and observational data with little
scientific rigor. Key statistics are often absent or involve wide con-
fidence intervals, raising questions regarding the reliability and
precision of the findings. Conclusions are often based on factors
that ‘appear’ to be significant, reliant only upon the clinician’s clin-
ical experience. Remarkably, despite being in existence for over a
decade, the currently adopted FIGO/WHO classification system
has never been tested prospectively. There is no statistical proof
that the included risk factors do indeed influence prognosis, and
no evidence base for the attributed weighting to each risk factor.
Put simply, it seems that clinicians have continued to use this sys-
tem based on sentiment and familiarity, rather than true evidenced
based medicine.
Worldwide, GTN continues to be managed in small hospitals by
clinicians who have limited experience of the condition. Therefore,
one of the major challenges to introducing a new classification sys-
tem will arise from its global dissemination and widespread adop-
tion. Potential dissemination strategies include adoption of the
updated classification system by the International Society for the
Study of Trophoblastic Diseases (ISSTD) and the European Organi-
sation for Treatment of Trophoblastic Diseases (EOTTD). In addi-
tion, FIGO and WHO should distribute knowledge, standardise
management and generate comparable data suitable for multi-
centre clinical trials. Moreover, it is known that outcome and sur-
vival rate is much higher amongst patients treated by specialist,
experienced clinicians in designated centres, highlighting the
importance of a globally adopted system [79].
The need for an updated classification system is particularly
pertinent given the high rates of primary chemotherapy resistance
amongst low-risk patients scoring 5 or 6, who subsequently need a
change in systemic therapy to potentially more intensive
chemotherapy regimens, which has a significant physical and psy-
chological impact upon these women and their families. In addi-
tion, a prognostic classification system is urgently needed for
patients diagnosed with PSTT and ETT who are currently excluded
from the FIGO/WHO system due to the differing tumour character-
istics and behaviour [13]. There are several exciting approaches
under investigation that may prove useful as an adjunct, or even
as an improved prognostic marker, in future practice. Based upon
56 V.L. Parker et al. / Cancer Treatment Reviews 56 (2017) 47–57

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