E U R O P E A N U R O L O G Y 7 0 ( 2 0 1 6 ) 9 3 – 1 0 5

ava i lable at www.sciencedirect .com

journal homepage: www.europeanurology.com

Platinum Priority – GuidelinesEditorial 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 Patologıa e Investigacion, Facultad de Ciencias Medicas, Universidad

Nacional de Asuncion, San Lorenzo, Paraguay; c Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; d Department of

Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; e Department of Pathology and Laboratory Medicine, Indiana University Health

Partners, Indiana University School of Medicine, Indianapolis, IN, USA

Article info

Article history:

Accepted February 4, 2016

Associate Editor:

James Catto

Keywords:

WHO classification

Male genital organs

Urogenital tract

Abstract

The fourth edition of the World Health Organization (WHO) classification of urogenitaltumours (WHO ‘‘blue book’’), published in 2016, contains significant revisions. Theserevisions were performed after consideration by a large international group of pathol-ogists with special expertise in this area. A subgroup of these persons met at the WHOConsensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. Thisreview summarizes the most significant differences between the newly publishedclassification and the prior version for renal, penile, and testicular tumours. Newlyrecognized epithelial renal tumours are hereditary leiomyomatosis and renal cellcarcinoma (RCC) syndrome–associated RCC, succinate dehydrogenase–deficient RCC,tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC.The WHO/International Society of Urological Pathology renal tumour grading systemwas recommended, and the definition of renal papillary adenoma was modified. Thenew WHO classification of penile squamous cell carcinomas is based on the presence ofhuman papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasiain situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions ofinvasive germ cell tumours, and testicular germ cell tumours are now separated into twofundamentally different groups: those derived from GCNIS and those unrelated toGCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour andplaced within the group of non–GCNIS-related tumours in the 2016 WHO classification.Patient summary: The 2016 World Health Organization (WHO) classification containsnew renal tumour entities. The classification of penile squamous cell carcinomas isbased on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis isthe 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, Schmelzbergstrasse12, CH-8091 Zurich, Switzerland. Tel. +41 442552500; Fax: +41 442553194.

och@usz.ch (H. Moch).

E-mail address: holger.m

http://dx.doi.org/10.1016/j.eururo.2016.02.0290302-2838/# 2016 European Association of Urology. Published by Elsevier

B.V. All rights reserved.

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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$FIG]

Fig. 1 – World Health Organization (WHO) classification of tumours of the kidResearch 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-Dube 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

ney. Reproduced with permission from the WHO International Agency for

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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

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

[(Fig._2)TD$FIG]

Fig. 2 – (A) Succinate dehydrogenase–deficient renal cell carcinomacomposed of vacuolated cells. (B) Immunohistochemically, there is aloss of SDHB expression (with positivity in normal tubular cells).

[(Fig._3)TD$FIG]

Fig. 3 – (A) Clear cell papillary renal cell carcinoma is a renal epithelialneoplasm composed of low-grade clear epithelial cells arranged intubules and papillae with a predominantly linear nuclear alignment. (B)The tumour cells have a characteristic diffuse CK7 positivity.

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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,

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

[(Fig._4)TD$FIG]

Fig. 4 – World Health Organization/International Society of UrologicalPathology grading system for clear cell renal cell carcinoma andpapillary renal cell carcinoma [34].

E U R O P E A N U R O L O G Y 7 0 ( 2 0 1 6 ) 9 3 – 1 0 5 97

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

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.

[(Fig._5)TD$FIG]

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

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.

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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).

[(Fig._7)TD$FIG]

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 smallbasaloid cells involving full epithelial thickness. (C) Basaloid PeIN, p16 staining. Note the dense ‘‘on block’’ staining with p16.

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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

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

[(Fig._8)TD$FIG]

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

E U R O P E A N U R O L O G Y 7 0 ( 2 0 1 6 ) 9 3 – 1 0 5100

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

[(Fig._9)TD$FIG]

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.

E U R O P E A N U R O L O G Y 7 0 ( 2 0 1 6 ) 9 3 – 1 0 5 101

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

9 corresponding to the DMRT1 gene, and is never associated[(Fig._10)TD$FIG]

Fig. 10 – (A) An immature testis from a child shows delayed maturationof germ cells, with gonocyte-like cells localized to the central portion ofthe tubules (arrows). (B) The nuclei of the gonocyte-like cells arehighlighted by an immunostain directed against OCT3/4.

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

[(Fig._11)TD$FIG]

Fig. 11 – (A) A focus of placental site trophoblastic tumour showing loose clusters of variably sized mononucleated and occasionally multinucleatedcells in a hyalinized, nonhaemorrhagic background. (B) Epithelioid trophoblastic tumour shows cohesive nests of atypical squamoid cells withadmixed apoptotic cells and deposits of fibrinoid material. (C) Cystic trophoblastic tumour in an untreated testis showing the characteristic vacuolatedtumour cells lining a cystic space.

E U R O P E A N U R O L O G Y 7 0 ( 2 0 1 6 ) 9 3 – 1 0 5102

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$DIFF].

Acknowledgment: The authors thank Dr. Hiroko Ohgaki and Dr. Paul

Kleihues for their engagement in the WHO ‘‘Blue Books’’.

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