EUROPEAN UROLOGY 70 (2016) 93–105

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Platinum Priority – Guidelines

Editorial by Rodolfo Montironi, Liang Cheng, Marina Scarpelli and Antonio Lopez-Beltran on pp. 120–123 of
this issue

The 2016 WHO Classification of Tumours of the Urinary System

and Male Genital Organs—Part A: Renal, Penile, and Testicular
Tumours

Holger Moch a,*, Antonio L. Cubilla b, Peter A. Humphrey c,

Victor E. Reuter d, Thomas M. Ulbright e
a
Department of Pathology, University Hospital Zurich, Zurich, Switzerland; b Instituto de Patologı´a e Investigación, Facultad de Ciencias Médicas, Universidad
c d
Nacional de Asunción, San Lorenzo, Paraguay; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Department of
e
Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Indiana University Health
Partners, Indiana University School of Medicine, Indianapolis, IN, USA

Article info Abstract

Article history: The fourth edition of the World Health Organization (WHO) classification of urogenital
Accepted February 4, 2016 tumours (WHO ‘‘blue book’’), published in 2016, contains significant revisions. These
revisions were performed after consideration by a large international group of pathol-
Associate Editor: ogists with special expertise in this area. A subgroup of these persons met at the WHO
James Catto Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This
review summarizes the most significant differences between the newly published
classification and the prior version for renal, penile, and testicular tumours. Newly
Keywords: recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell
WHO classification carcinoma (RCC) syndrome–associated RCC, succinate dehydrogenase–deficient RCC,
Male genital organs tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC.
The WHO/International Society of Urological Pathology renal tumour grading system
Urogenital tract was recommended, and the definition of renal papillary adenoma was modified. The
new WHO classification of penile squamous cell carcinomas is based on the presence of
human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia
in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of
invasive germ cell tumours, and testicular germ cell tumours are now separated into two
fundamentally different groups: those derived from GCNIS and those unrelated to
GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and
placed within the group of non–GCNIS-related tumours in the 2016 WHO classification.
Patient summary: The 2016 World Health Organization (WHO) classification contains
new renal tumour entities. The classification of penile squamous cell carcinomas is
based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is
the WHO-recommended term for precursor lesions of invasive germ cell tumours.
# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Pathology, University Hospital Zurich, Schmelzbergstrasse

12, CH-8091 Zurich, Switzerland. Tel. +41 442552500; Fax: +41 442553194.
E-mail address: holger.moch@usz.ch (H. Moch).

http://dx.doi.org/10.1016/j.eururo.2016.02.029
0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
94 EUROPEAN UROLOGY 70 (2016) 93–105
1. The new renal tumour classification
The Vancouver consensus conference of the International
Society of Urological Pathology (ISUP) provided the
foundation for much of the 2016 World Health Organization
(WHO) renal tumour classification [1,2] (Fig. 1). The
revision of the 2004 WHO renal tumour classification
was performed after consideration of new knowledge about
pathology, epidemiology, and genetics [3–5].
2. Important changes from existing renal tumour
types
First, the new 2016 WHO classification refers to subtypes
that have been named on the basis of predominant
cytoplasmic features (eg, clear cell and chromophobe renal
cell carcinomas [RCCs]), architectural features (eg, papillary
[(Fig._1)TD$IG]
Fig. 1 – World Health Organization (WHO) classification of tumours of the kidney. Reproduced with permission from the WHO International Agency for
Research on Cancer [1].
WHO = World Health Organization.
RCC), anatomic location of tumours (eg, collecting duct and
renal medullary carcinomas), and correlation with a specific
renal disease background (eg, acquired cystic disease–
associated RCCs) as well as molecular alterations patho-
gnomonic for RCC subtypes (eg, MiT family translocation
carcinomas and succinate dehydrogenase [SDH]–deficient
renal carcinomas) or familial predisposition syndromes (eg,
hereditary leiomyomatosis and RCC [HLRCC] syndrome–
associated RCC). In contrast to the 2004 WHO classification,
familial forms of RCC, which also occur in sporadic form (eg,
clear cell RCC [ccRCC] in patients with von Hippel-Lindau
[VHL] syndrome or chromophobe RCC in patients with Birt-
Hogg-Dubé syndrome) are now discussed with the corre-
sponding sporadic tumour types in joint chapters.
Second, multiple publications report no recurrence
or metastasis in patients with multilocular cystic RCC
[6]. Consequently, multilocular cystic renal neoplasm of low
 EUROPEAN UROLOGY 70 (2016) 93–105
malignant potential is now the WHO-recommended term for
this lesion. Such tumours are defined as tumours composed
entirely of numerous cysts with low-grade tumour cells
(WHO/ISUP grade 1 or 2). The cysts are lined by a single
layer of tumour cells with abundant clear cytoplasm. The
septa contain, at the maximum, groups of clear cells but
without expansile growth.
Third, the entity of papillary RCC has traditionally been
subdivided into type 1 and type 2 papillary RCCs [7,8]. It has
been accepted that a subset of tumours have mixed
histology. Recent molecular studies suggest that type
2 papillary RCCs may constitute not a single well-defined
entity but rather individual subgroups with different
molecular backgrounds [9]. Papillary RCCs with eosinophil-
ic (oncocytic) cytoplasm and oncocytoma-like low-grade
nuclei have been called oncocytic papillary RCCs. Because
tumours with this morphology have not yet been fully
characterized, they are not considered a distinct WHO
entity. The Vancouver consensus conference has recom-
mended diagnosing such tumours as type 2 papillary RCC
for the time being [2].
Fourth, papillary adenomas were defined until 2015 as
tumours measuring 0.5 cm. The WHO 2016 classification
defines papillary adenomas as unencapsulated tumours with
papillary or tubular architecture, low WHO/ISUP grade, and a
diameter 1.5 cm. The decision to increase the cut-off size
was based on available data showing that unencapsulated
grade 1–2 tumours have no capacity to metastasize [10]. It is
emphasized, however, that a diagnosis of papillary adenoma
based on needle biopsy should be made with extreme caution
because the presence of any capsule or grade heterogeneity
may not be visualized. Current protocols, which define
papillary adenomas as 0.5 cm in size, state that the
presence of papillary adenoma in a donor kidney is not a
contraindication for renal transplantation. The new cut-off of
1.5 cm could have a significant impact on some clinical
situations (eg, small renal papillary tumours detected in
transplanted kidneys).
Fifth, mixed epithelial and stromal tumours (MEST)
encompass a spectrum of tumours including predominantly
cystic tumours (adult cystic nephromas) and tumours that
are more solid. Adult cystic nephroma was previously
classified, along with paediatric cystic nephroma, as a
separate entity from MEST. On the basis of similar age and
sex distributions and a similar histochemical profile, adult
cystic nephroma is now classified within this spectrum of
MEST, and the WHO renal tumour subcommittee recom-
mended using the term mixed epithelial and stromal tumour
family for both entities. In contrast to adult cystic nephroma,
paediatric cystic nephroma is a distinct entity with specific
DICER1 mutations [11].
Sixth, most carcinoids of the kidney have a poor
prognosis, with frequent occurrence of metastasis after
nephrectomy. The renal tumour subcommittee recom-
mended renal carcinoids should be newly designated as
well-differentiated neuroendocrine tumours of the kidney
and simultaneously placed within the group of endocrine
tumours encompassing small cell neuroendocrine carci-
nomas, large cell neuroendocrine carcinomas, and
95
paragangliomas (extrarenal pheochromocytoma). The
term carcinoid of the kidney is obsolete.
3. New renal tumour entities
Over the past decade, several new tumour entities have
emerged; therefore, the WHO working group was entrusted
with the responsibility to decide whether enough molecular
clinical follow-up data and pathologic data justify the
recognition of any new distinct tumour entity within the
classification system. The newly recognized epithelial renal
tumours in the 2016 WHO classification are HLRCC-
associated RCC, SDH-deficient RCC, tubulocystic RCC,
acquired cystic RCC, and clear cell papillary RCC. Paediatric
cystic nephroma represents a new entity in the group of
nephroblastic and cystic tumours occurring mainly in
children (as described under ‘‘Important changes’’).
3.1. Hereditary leiomyomatosis and renal cell carcinoma (RCC)
syndrome–associated RCC
HLRCC-associated RCCs are rare tumours occurring in the
setting of nonrenal leiomyomatosis and demonstrate
germline fumarate hydratase mutations [12]. The tumours
have papillary architecture with abundant eosinophilic
cytoplasm, large nuclei, and very prominent nucleoli with
perinucleolar clearing. The prognosis of these tumours is
poor [13].
3.2. Succinate dehydrogenase–deficient renal cell carcinoma
SDH-deficient RCC is composed of vacuolated eosinophilic
or clear cells [14,15]. Immunohistochemistry is a useful tool
for their diagnosis because there is a loss of expression of
SDHB, a marker of dysfunction of mitochondrial complex II
(Fig. 2). It presents mainly in young adults, and most
patients have germline mutations in an SDH gene [15]. Most
tumours are solid, with a brown, sometimes red, cut surface.
The most distinctive feature is the presence of cytoplasmic
vacuoles. There are sometimes flocculent inclusions. Most
SDH-deficient RCC has good prognosis. In cases with
sarcomatoid differentiation and necrosis, the prognosis is
less favourable.
3.3. Tubulocystic renal cell carcinoma
Tubulocystic RCC is a dominantly cystic renal epithelial
neoplasm. Macroscopically, it is composed of multiple small
to medium-sized cysts and has a spongy cut surface. The
nuclei are enlarged with WHO/ISUP grade 3 nucleoli. The
cytoplasm has abundant eosinophilic and oncocytoma-
like aspects. Only 4 of 70 reported cases showed metastasis
to bone, liver, and lymph nodes [16–19].
3.4. Acquired cystic disease–associated renal cell carcinoma
Acquired cystic disease–associated RCC occurs in the
kidneys of end-stage renal disease and acquired cystic
kidney disease [20]. Histologically, these tumours show a
96 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._2)TD$IG] [(Fig._3)TD$IG]

Fig. 2 – (A) Succinate dehydrogenase–deficient renal cell carcinoma

composed of vacuolated cells. (B) Immunohistochemically, there is a
loss of SDHB expression (with positivity in normal tubular cells).

broad spectrum with a cribriform, microcystic, or sieve-

like architecture. They have an eosinophilic and/or clear
cytoplasm and prominent nucleoli. Calcium oxalate crystal
deposition is common. CK7 is typically not expressed. Most
tumours have indolent behaviour.

3.5. Clear cell papillary renal cell carcinoma

Clear cell papillary RCC is a renal epithelial neoplasm

composed of low-grade clear epithelial cells arranged in
tubules and papillae with a predominantly linear nuclear
alignment away from the basement membrane [20]. They
account for up to 5% of all resected renal tumours and arise
sporadically in end-stage renal disease and VHL syndrome
[21,22]. Some of these tumours were previously referred to
as renal angioadenomatous tumours. The tumour cells have
characteristic diffuse CK7 positivity and carbonic anhydrase
IX positivity in a cuplike distribution. CD10 is negative or
only focally positive (Fig. 3). According to current knowl-
edge, these tumours have indolent behaviour.
4. Emerging or provisional renal tumour entities
The 2013 ISUP Vancouver classification identified a
category of emerging or provisional new entities. Some of
these emerging entities have been accepted by the WHO,
Fig. 3 – (A) Clear cell papillary renal cell carcinoma is a renal epithelial
neoplasm composed of low-grade clear epithelial cells arranged in
tubules and papillae with a predominantly linear nuclear alignment. (B)
The tumour cells have a characteristic diffuse CK7 positivity.
and others were kept as emerging. The WHO classification
noted that although these entities appear to be distinct, they
are rare tumours that are not yet fully characterized by
morphology, immunohistochemistry, and molecular stud-
ies. Consequently, further reports are needed to refine their
diagnostic criteria and established clinical outcomes.
SDH-deficient RCC was regarded as an emerging entity in
the Vancouver classification but now is considered to be an
established entity. RCC in neuroblastoma survivors was
included in the 2004 WHO classification [23]; however, it is
now recognized that some of these tumours represent MiT
 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._4)TD$IG]
Fig. 4 – World Health Organization/International Society of Urological
Pathology grading system for clear cell renal cell carcinoma and
papillary renal cell carcinoma [34].
family translocation RCCs [24], and others are difficult to
classify based on the published pathologic details. Conse-
quently, it was decided to remove this entity from the
2016 WHO classification, although it may be distinct, and to
continue to consider it as an emerging entity. Very few
thyroid-like follicular RCCs have been described [25,26]. Most
of these tumours have indolent behaviour. Fewer than 10
RCCs associated with ALK gene rearrangements have been
reported in the literature [27–29]; some are medullary-
based tumours. Recently, reports of RCC associated with
prominent angioleiomyomatous stroma have been pub-
lished. It is unclear if the renal angiomyoadenomatous
tumour represents a variant of ccRCC or clear cell papillary
RCC [30]. Some tumours were sporadic, and others were
associated with tuberous sclerosis [31]. A recent report
identified TCEB1 gene mutations in tumours with this
morphology [32].
5. Grading of renal tumours
Many grading systems have been proposed for renal cell
neoplasia. The Fuhrman system was the most frequently
used grading system in RCC but should not be applied for
chromophobe RCC [33]. Furthermore, the Fuhrman system
has not been validated for most of the new subtypes of renal
carcinoma. For these reasons, the four-tiered WHO/ISUP
grading system is recommended by the WHO [34]. For
grade 1–3 tumours, the system defines tumour grade based
on nucleolar prominence. Grade 4 is defined by the presence
of pronounced nuclear pleomorphism, tumour giant cells,
and/or rhabdoid and/or sarcomatoid differentiation (Fig. 4).
This grading system has been validated for ccRCC and
papillary RCC. It has not yet been validated for other tumour
types because of the small numbers of reported cases.
6. Important future issues in renal tumour
pathology
First, the VHL tumour suppressor protein pVHL functions as
a tumour suppressor via HIF-dependent regulation in most
ccRCC. The chromosome 3p locus, however, contains up to
97
seven potential ccRCC tumour suppressor genes: VHL,
PBRM1, BAP1, SETD2, RASSF1A, TU3A, and DLEC1. The
elucidation of the effects of different combinations of
mutations on the initiation and progression of ccRCC will be
an important future area of research [4].
Second, the identification of novel therapeutic agents
that are effective against RCC cells that harbour specific
genetic alterations is an important ongoing research topic
[35]. This area includes emerging immunotherapies target-
ing immune checkpoints and tumour-associated antigens in
patients with RCC [36]. In contrast to other solid tumours
(eg, melanoma or lung cancer), there are presently no
predictive molecular biomarkers suitable for routine use
[37]. The use of such potential biomarkers must account for
the considerable genetic intratumoural heterogeneity with
the parallel evolution of multiple tumour clones [38,39].
Third, there has been a remarkable expansion of
knowledge about the genetics of renal cancer in recent
years. This has led to greater understanding of the
molecular pathogenesis of renal cancer [40]. Such knowl-
edge will be incorporated into a future WHO classification
and will clarify the position of some emerging renal tumour
entities (eg, TCEB1-mutated RCC and angiomyoadenoma-
tous RCC) or the subgroups of papillary RCC [9,30,32].
Fourth, the novel WHO/ISUP grading system has been
validated for ccRCC and papillary RCC but not for other
tumour types [34]. Several grading schemes have been
proposed for chromophobe RCC to predict its behavioural
outcome [41–44]. It is important to have an internationally
accepted chromophobe RCC grading system in the near
future.
7. The new classification of penile tumours
The vast majority of malignant tumours of the penis are
squamous cell carcinomas (SCCs) originating in the inner
mucosal lining of the glans, coronal sulcus, or foreskin. Most
previous classification schemes were exclusively morphol-
ogy based. The 2016 WHO classification presents a new
classification based on clinicopathologic distinctiveness
and relation to human papillomavirus (HPV) infection
(Fig. 5).
7.1. Non–human papillomavirus–related subtypes
Non–HPV-related subtypes of SCC are mainly SCC of the usual
type (Fig. 6A). Pseudohyperplastic carcinomas [45] and
pseudoglandular carcinomas [46] are also non-HPV related.
Pseudohyperplastic carcinomas [45] occur in patients in the
seventh and eighth decades of life and are associated
with lichen sclerosus. Pseudoglandular carcinomas [46] are
aggressive tumours simulating adenocarcinomas. Verrucous
carcinoma is a nonmetastasizing low-grade neoplasm with
carcinoma cuniculatum as a variant [47]. Carcinoma cunicu-
latum is a rare low-grade tumour with a labyrinthine growth
pattern with no metastatic potential. Other non–HPV-related
subtypes of SCC are papillary [48], adenosquamous [49], and
sarcomatoid SCC, the latter with the worst prognosis among
all penile carcinomas.
98 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._5)TD$IG]

Fig. 5 – World Health Organization classification of tumours of the penis. Reproduced with permission from the World Health Organization
International Agency for Research on Cancer [1].
[(Fig._6)TD$IG]

Fig. 6 – (A) Well differentiated squamous cell carcinoma (SCC; usual type), grade I. Multiple well-delineated invasive tumour nests. (B) Basaloid SCC.
Interanastomosing sheets and nests of basaloid tumour. (C) Basaloid SCC, p16 staining. Dense staining of all tumour cells by p16.

7.2. Human papillomavirus–related carcinomas
HPV-related carcinomas are basaloid [50] (Fig. 6B) and warty
(condylomatous) SCC [51]. Basaloid SCC has a high rate of
nodal metastasis, whereas warty (condylomatous) carcino-
mas [51] are rarely associated with regional nodal
metastasis. Other HPV-related SCCs include warty-basaloid
[52] and the rare variants of papillary-basaloid [53] and clear
cell carcinomas [54]. Very unusual HPV-related tumours are
lymphoepithelioma-like [55] and medullary SCC [56].
Penile intraepithelial neoplasia (PeIN) is a precursor lesion
of invasive SCC showing a penile squamous epithelium
characterized by dysplastic changes with an intact basement
membrane. Non–HPV-related PeIN is the so-called differen-
tiated PeIN, whereas basaloid and warty (or mixed basaloid-
warty) PeINs are usually associated with HPV (Fig. 7).
 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._7)TD$IG]
Fig. 7 – Penile intraepithelial neoplasia (PeIN). (A) Differentiated PeIN. There is parakeratosis and elongation of rete ridges. Cells are maturing,
keratinizing; atypical cells predominate at basal layers. Note the changes of lichen sclerosus in lamina propria. (B) Basaloid PeIN. Atypical small
basaloid cells involving full epithelial thickness. (C) Basaloid PeIN, p16 staining. Note the dense ‘‘on block’’ staining with p16.
The three-tiered WHO/ISUP grading system is the
recommended grading system for penile SCC. Well-differ-
entiated carcinomas (grade 1) have cytologic aspects of
normal squamous tissue. The tumour cells grow in an
irregular nesting pattern with little intervening stroma.
Poorly differentiated carcinomas (grade 3) have an irregular
growth of small tumour cell nests, poor keratinization,
polymorphic tumour cells with hyperchromatic nuclei,
frequent mitoses, and marked stromal reaction. The cases
that do not qualify as grade 1 or 3 are grade 2.
8. The new classification of testicular tumours
Some important changes have been made in the WHO
classification of testicular tumours in 2016 compared with
that adopted in 2004 [3]. These revisions were discussed
over the course of several months in 2014 through e-mail
communications and were finalized in Zurich, Switzerland,
in March 2015. The most significant differences between
the newly published classification and the prior version
concern the germ cell tumours (Fig. 8), but other categories
are also affected.
It has been recognized for several decades that the
majority of germ cell tumours arise from progression of an
intratubular malignant germ cell that has the morphologic
and immunohistochemical features of a seminoma cell.
Such cells were usually designated as either carcinoma in
situ (CIS) [57] or intratubular germ cell neoplasia, unclassified
(IGCNU) [58], with those terms receiving preferential use in
Europe and North America, respectively. Some others,
however, have been used, including testicular intraepithelial
neoplasia [59] and gonocytoma in situ [60]. The use of
different terms for the identical lesion has been a source of
some confusion, and neither the two predominant terms
nor any of the previously used alternatives were considered
entirely satisfactory by the testis subcommittee. The main
objection to CIS was that the malignant germ cells to which
it referred were not epithelial (a similar objection applied to
testicular intraepithelial neoplasia), whereas IGCNU, be-
cause it contained the word unclassified, was felt to falsely
convey an element of doubt concerning the nature and
clinical behaviour of the lesion. Germ cell neoplasia in situ
(GCNIS) was proposed as an alternative term, retaining the
in situ nomenclature that correctly conveys the fact that the
99
lesion is a well-established precursor to an invasive germ
cell tumour and simultaneously does away with both the
misleading epithelial-based nomenclature and the use of
the word unclassified. It was recognized that IGCNU, and
specifically the unclassified designation, was originally
adopted to distinguish it from differentiated forms of
intratubular neoplasia [58], most commonly intratubular
seminoma and intratubular embryonal carcinoma. There
was concern that GCNIS did not make this distinction, but
the testis subcommittee made the important point that
GCNIS refers to malignant germ cells that develop in the
spermatogonial niche (Fig. 9), which is the usual in situ
location for germ cells in the early differentiated testis
[61]. All other forms of intratubular neoplasia are no longer
confined to this location but typically fully occupy the
tubular diameter. GCNIS is now the WHO-recommended
term for this precursor lesion, and other forms of
intratubular neoplasia should be referred to by their
differentiated phenotype with the prefix intratubular.
A new emphasis in WHO 2016 is the distinction of GCNIS
from maturation-delayed germ cells, which are a relatively
common feature in the gonads of patients with disorders of
sex development [61–63]. It is believed that maturation-
delayed germ cells likely give rise to GCNIS, but they should
be distinguished from the latter because progression is not
invariable. Unfortunately, both lesions express the usual
markers used for the identification of GCNIS (eg, OCT3/4,
placental alkaline phosphatase, AP-2g). The differentiation
of the two relies on the more diffuse distribution and central
tubular location of maturation-delayed germ cells (Fig. 10)
as well as the lack of expression of KIT ligand (stem cell
factor) in the associated seminiferous tubules, which
contrast with the findings in GCNIS [61,63,64].
The prior version of the WHO classification was purely
morphologically based and divided the germ cell tumours
into those of single or more than one histologic type. In so
doing, quite disparate tumours came to be placed under
similar diagnostic terms. The new approach recognizes that
there are significantly different pathogeneses for testicular
germ cell tumours, despite only subtle or even—in the case
of yolk sac tumour of paediatric and adult types—no
perceptible morphologic differences. The germ cell tumours
are now broadly separated into two fundamentally different
groups: those derived from GCNIS and those unrelated to
100 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._8)TD$IG]

Fig. 8 – World Health Organization classification of germ cell tumours of the testis. Reproduced with permission from the World Health Organization
International Agency for Research on Cancer [1].

GCNIS (Fig. 8). It is apparent, however, that the latter group
is heterogeneous. In contrast, the former group shows a
number of basic similarities despite varied morphologies
and, to some extent, behaviours. The GCNIS-derived
tumours have comparable epidemiologic associations and
usually occur in a background of perturbed testicular
development that has recognizable morphologic features:
impaired spermatogenesis, tubular shrinkage, peritubular
sclerosis, immature Sertoli cells, interstitial widening,
hyalinized tubules, and microlithiasis [65,66]. They share
the finding of amplification of genetic material from the
short arm of chromosome 12, often in the form of
isochromosome 12p, and represent progression from
GCNIS, often through at least a transient stage of seminoma
that may be intratubular.
In making this separation among the germ cell tumours,
it was necessary to remove entities from the GCNIS-derived
group and to introduce changes in nomenclature. The testis
subcommittee recommended that the entity known as
spermatocytic seminoma be newly designated as
spermatocytic tumour and simultaneously placed within
the non-GCNIS related tumours (Fig. 8) because its lack of
association with GCNIS and different molecular features are
well established, and it shows no relationship with
seminoma or any other neoplasm in the GCNIS-derived
group [67–72]. Because teratomas and yolk sac tumours
may develop from GCNIS or apart from it, it was
recommended that the GCNIS-derived entities be designat-
ed as postpubertal type and the non–GCNIS-related ones be
designated as prepubertal type (Fig. 8) because the former
 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._9)TD$IG]
Fig. 9 – (A) Germ cell neoplasia in situ showing confinement of the lesional cells to the base of a seminiferous tubule, the ‘‘spermatogonial niche.’’ In
(B) intratubular seminoma and (C) intratubular embryonal carcinoma, the neoplastic cells have expanded beyond the tubular base and, as shown,
typically occupy most of the tubule.
usually develops in adults and the latter in children. It is
recognized, however, that the prepubertal-type tumours
may, rarely, occur in postpubertal patients [73,74], and the
postpubertal-type tumours may occur in paediatric patients
who have disorders of sex development [75,76]. The evidence
for making these changes is abundant. Spermatocytic tumour
lacks not only association with GCNIS but also 12p
amplification, shows a unique amplification of chromosome
[(Fig._10)TD$IG]9 corresponding to the DMRT1 gene, and is never associated
Fig. 10 – (A) An immature testis from a child shows delayed maturation
of germ cells, with gonocyte-like cells localized to the central portion of
the tubules (arrows). (B) The nuclei of the gonocyte-like cells are
highlighted by an immunostain directed against OCT3/4.
101
with other forms of germ cell tumour. In addition to lacking
GCNIS [77,78], prepubertal-type teratoma and yolk sac
tumour also lack 12p amplification and do not occur in
malformed testes [79]. The prepubertal-type teratomas show
no genetic abnormalities, whereas the prepubertal-type yolk
sac tumours show characteristic gains and losses of portions
of several chromosomes that differ from those frequently
occurring in the GCNIS-derived tumours [79]. Although there
are no apparent differences in tumour morphology between
the prepubertal and postpubertal forms of yolk sac tumour,
the prepubertal teratomas—in contrast to the postpubertal
ones—lack any cytologic atypia and are more frequently
organoid with prominent components of smooth muscle and
ciliated and squamous epithelium [73]. The benign behav-
iour of the prepubertal-type teratomas [73,80] contrasts with
that of the postpubertal type [81,82], and the prepubertal-
type yolk sac tumours behave less aggressively than the
postpubertal-type tumours, with a significantly lower
frequency of relapse on surveillance of clinical stage I
patients and of lymphatic-based metastases [83–85].
An additional change that naturally follows the recogni-
tion of the prepubertal-type teratomas is placement of
dermoid cyst, epidermoid cyst, and carcinoid tumour (well-
differentiated neuroendocrine tumour) as specialized forms
of prepubertal-type teratomas (Fig. 8). This is supported by
the absence of GCNIS and 12p amplification in association
with these entities, consistently so for the first two and in the
majority of cases for carcinoid tumour [73,78,86,87],
although some contradictory information in the literature
suggests the possibility of a dual pathogenesis for carcinoid
tumour [88,89]. Additional work is required to resolve this
question.
In the prior WHO classification, the trophoblastic
tumours were divided into choriocarcinoma and nonchor-
iocarcinomatous trophoblastic tumours, the latter repre-
sented by placental-site trophoblastic tumour (PSTT).
So-called monophasic choriocarcinoma was also discussed
in the nonchoriocarcinomatous trophoblastic tumours cate-
gory. The current classification, however, does not separately
recognize monophasic choriocarcinoma but considers it
a morphologic variant of choriocarcinoma. In addition, the
nonchoriocarcinomatous trophoblastic tumour group has
been expanded, recognizing not only PSTT but also epitheli-
oid trophoblastic tumour (ETT) and cystic trophoblastic
102 EUROPEAN UROLOGY 70 (2016) 93–105
[(Fig._1)TD$IG]
Fig. 11 – (A) A focus of placental site trophoblastic tumour showing loose clusters of variably sized mononucleated and occasionally multinucleated
cells in a hyalinized, nonhaemorrhagic background. (B) Epithelioid trophoblastic tumour shows cohesive nests of atypical squamoid cells with
admixed apoptotic cells and deposits of fibrinoid material. (C) Cystic trophoblastic tumour in an untreated testis showing the characteristic vacuolated
tumour cells lining a cystic space.
tumour (CTT) (Figs. 8 and 11) [90,91]. Although these entities
have most frequently been reported in metastatic sites after
chemotherapy, their de novo development in the testis is
now established. The PSTT consists of intermediate tropho-
blast cells that are positive for human placental lactogen
(HPL) and negative for p63. They are usually loosely cohesive
and tend to invade the walls of blood vessels, provoking a
fibrinoid reaction. ETT has a more cohesive arrangement of
squamoid cells, typically displaying apoptotic and fibrinoid
material within cell nests, usually lacks vascular invasion,
and is HPL negative and p63 positive. CTT consists of
frequently vacuolated trophoblast cells that line gaping
spaces that may contain eosinophilic material. Based on the
available evidence, these lesions are less aggressive than
choriocarcinoma, but the data are limited.
In the sex cord–stromal tumours, the sclerosing Sertoli
cell tumour [92,93] is no longer separately classified. These
tumours are now considered to be morphologic variants of
Sertoli cell tumour, not otherwise specified (NOS), based on the
occurrence of CTNNB1 gene mutations and nuclear b-catenin
staining in a similar proportion of both [94–96]. Nonetheless,
it is recommended to continue to use this term for those
Sertoli cell tumours, NOS, that have a hypocellular fibrous
stroma in excess of 50% of the tumour based on their overall
better prognosis than more cellular tumours. Intratubular
large cell hyalinizing Sertoli cell tumour [97] has been added
to the classification as a distinct entity associated with the
Peutz-Jeghers syndrome and as having a characteristic
mutation of the STK11 gene. Myoid gonadal stromal tumour
[98–100] is considered an emerging entity characterized by
fusiform cells arranged in short fascicles that coexpress S-100
protein and smooth muscle actin.
Gonadoblastoma [101–103] is now recognized as the
only entity in the mixed germ cell–sex cord–stromal
category, with the unclassified form of germ cell–sex
cord–stromal tumour considered not sufficiently estab-
lished by the available evidence [104,105]. There is
additional emphasis on the recognition of ‘‘undifferentiated
gonadal tissue’’ as a frequent finding that accompanies
gonadoblastoma and is its likely precursor [106,107].
In contrast to the prior classification, there is no
recognized benign mesothelioma category. The well-differ-
entiated papillary mesothelioma was considered by the
testis subcommittee to be a variant of mesothelioma that
tends to behave indolently, but the members noted that
progression has been identified in other sites by morpho-
logically identical tumours [108,109]. In addition, cystic
mesothelioma, which had also been placed in the benign
mesothelioma category, was regarded as either a non-
neoplastic condition (mesothelial cysts) [110] or a variant of
conventional mesothelioma.
Author contributions: Holger Moch had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Moch, Cubilla, Humphrey, Reuter, Ulbright.
Acquisition of data: Moch, Cubilla, Humphrey, Reuter, Ulbright.
Analysis and interpretation of data: Moch, Cubilla, Humphrey, Reuter,
Ulbright.
Drafting of the manuscript: Moch, Cubilla, Humphrey, Reuter, Ulbright.
Critical revision of the manuscript for important intellectual content: Moch,
Cubilla, Humphrey, Reuter, Ulbright.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Moch, Cubilla, Humphrey, Reuter, Ulbright.
Other (specify): None.
Financial disclosures: Holger Moch certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: None[1_TD$IF].
Acknowledgment: The authors thank Dr. Hiroko Ohgaki and Dr. Paul
Kleihues for their engagement in the WHO ‘‘Blue Books’’.
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