The 2016 WHO Classification of Renal Neoplasia contains significant changes from the 2004 classification. Key changes include: 1) Renal tumor subtypes are now defined based on features such as cytoplasmic appearance, architecture, anatomical location, associated diseases, and molecular alterations. 2) Multilocular cystic renal cell carcinoma is now termed "multilocular cystic renal neoplasm of low malignant potential" based on its indolent behavior. 3) Papillary renal cell carcinoma subtypes (type 1 and 2) are still recognized but type 2 is heterogeneous and oncocytic variants are not a distinct entity. Papillary adenomas are now defined as ≤1.5 cm. Several

2. The 2016 WHO Classification of Renal Neoplasia - An Update
("Adapted from Eur Urol 2016; In Press")
Holger Moch, MD
Department of Pathology, University Hospital Zurich, Switzerland
The new “Blue Book” of the 2016 World Health Organization (WHO) classification of
urogenital tumors contains significant changes, which were discussed at the WHO Consensus
Conference in March 2015 in Zurich, Switzerland [1]. The Vancouver consensus conference
of the International Society of Urological Pathology (ISUP) provided the basis for much of
the 2016 WHO renal tumor classification [2]. The revision of the 2004 WHO renal tumor
classification was performed by a large group of uropathologists under consideration of new
knowledge on pathology, epidemiology and genetics [3, 4]. This review will summarize the
most important changes of the new WHO classification, including changes from existing renal
tumor types, novel renal tumors, provisional/emerging tumor entities and the WHO/ISUP
grading system for renal tumors.
Important changes from existing WHO-tumor types
1. The new 2016 WHO-classification refers to subtypes that have been named on the
basis of predominant cytoplasmic features (e.g. clear cell and chromophobe RCC’s),
architectural features (e.g. papillary RCC), anatomical location of tumors (e.g.
collecting duct and renal medullary carcinomas), correlation with a specific renal
disease background (e.g. acquired cystic disease-associated renal cell carcinomas) as
well as molecular alterations pathognomonic for RCC subtypes (e.g. MIT family
translocation carcinomas and Succinate Dehydrogenase-deficient renal carcinomas) or
familial predisposition syndromes (e.g. hereditary leiomyomatosis and RCC (HLRCC)
syndrome-associated RCC). In contrast to the 2004 WHO classification, familial
forms of RCC, which also occur in a sporadic form (e.g. clear cell RCC in VHL
syndrome patients or chromophobe RCC in patients with Birt-Hogg-Dubé syndrome)
are now discussed with the corresponding sporadic tumor types in joint chapters.
2. Multiple publications report no recurrence or metastasis in patients with multilocular
cystic renal cell carcinoma [5]. Multilocular cystic renal neoplasm of low malignant
potential, therefore, is now the WHO-recommended term for this lesion. Such tumors
are defined as tumors composed entirely of numerous cysts with low grade tumor cells

3. (WHO/ISUP grade 1 or 2). The cysts are ligned by a single layer of tumor cells with
abundant clear cytoplasm. The septa contain at the maximum groups of clear cells but
without expansile growth.
3. The entity of papillary renal cell carcinoma has traditionally been subdivided into two
types: type 1 and type 2 papillary renal cell carcinomas [6, 7]. It has been accepted
that a subset of tumors have mixed histology. Recent molecular studies suggest that
type 2 papillary renal cell carcinomas may not constitute a single well-defined entity,
but rather individual subgroups with a different molecular background [8]. Papillary
renal cell carcinomas with eosinophilic (oncocytic) cytoplasm and oncocytoma-like
low-grade nuclei have been called oncocytic papillary renal cell carcinomas. Since
tumors with this morphology have not yet been fully characterized, they are not
considered an own WHO entity. The Vancouver consensus conference has
recommended to diagnose such tumors as type 2 PRCC for the time being [2].
4. Papillary adenomas have been defined until 2015 as tumors measuring ≤ 0,5 cm. The
WHO 2016 classification defines papillary adenomas as unencapsulated tumors with
papillary or tubular architecture, low WHO/ISUP grade and a diameter ≤1.5 cm. The
decision to increase the size cut-off was due to available data that unencapsulated
grade 1-2 tumors have no capacity to metastasize [9]. However, it is emphasized 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 defined papillary adenomas with ≤ 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 (e.g. small renal papillary tumors detected in transplanted
kidneys).
5. Mixed epithelial and stromal tumors (MEST) encompass a spectrum of tumors ranging
from predominantly cystic tumors (adult cystic nephromas) to tumors that are more
solid. Adult cystic nephroma was previously classified along with pediatric 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 tumor subcommittee

4. recommended to use the term “mixed epithelial and stromal tumor family” for both
entities. In contrast to adult cystic nephroma, pediatric cystic nephroma is a distinct
entity with specific DICER-1 mutations [10].
6. Most carcinoids of the kidney have a poor prognosis with frequent occurrence of
metastasis after nephrectomy. The renal tumor subcommittee recommended “renal
carcinoids” should be newly designated as well differentiated neuroendocrine tumors
of the kidney and simultaneously placed within the group of endocrine tumors
encompassing also small cell neuroendocrine carcinomas, large cell neuroendocrine
carcinomas as well as paragangliomas (extrarenal pheochromocytoma). The term
carcinoid of the kidney obsolete.
New tumor entities
Over the last decade several new tumor entities have emerged. Therefore, the WHO working
group was entrusted with the responsibility to decide, if enough molecular, clinical follow-up
data and pathological data justify the recognition as a new distinct tumor entity within the
classification system. The newly recognized epithelial renal tumors in the 2016 WHO
classification are HLRCC-associated RCC, SDHB-deficient RCC, tubulocystic RCC,
acquired cystic RCC and clear cell papillary RCC. Pediatric cystic nephroma represents a new
entity in the group of nephroblastic and cystic tumours occurring mainly in children (see
above).
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated RCC are rare
tumors occurring in the setting of non-renal leiomyomatosis and demonstrate germline
Fumarate hydratase (FH) mutations [11]. The tumors have papillary architecture with
abundant eosinophilic cytoplasm, large nuclei and very prominent nucleoli with perinucleolar
clearing. The prognosis of these tumors is poor [12].
Succinate dehydrogenase (SDH)-deficient RCC is composed of vacuolated eosinophilic or
clear cells [13, 14]. Immunohistochemistry is a useful tool for their diagnosis, because there is
a loss of SDHB expression, a marker of dysfunction of mitochondrial complex II. It presents
mainly in young adults and most patients have germline mutations in a SDH gene [14]. Most
tumors are solid, with a brown, sometimes red cut surface. The most distinctive feature is the
presence of cytoplasmic vacuoles. There are sometimes flocculent inclusions. The majority of
SDH-deficient RCC have a good prognosis. In cases with sarcomatoid differentiation and
necrosis, the prognosis is less favourable.

5. Tubulocystic RCC is a dominantly cystic renal epithelial neoplasm. Macroscopically, they are
composed of multiple small to medium sized cysts and have 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 [15-18].
Acquired cystic disease associated RCC occurs in the kidneys of end-stage renal disease and
acquired cystic kidney disease [19]. Histologically, they show a broad spectrum with a
cribriform/microcystic/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 tumors have an indolent behavior.
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 alignement away
from the basement membrane [19]. They account for up to 5% of all resected renal tumors
and arise sporadically, in end-stage renal disease and von Hippel-Lindau syndrome [20, 21].
Some of these tumors were previously referred as renal angioadenomatous tumors. The tumor
cells have a characteristic diffuse CK7 positivity and a carbonic anhydrase IX positivity in a
cup-like distribution. CD10 is negative or only focally positive. According to current
knowledge, these tumors have an indolent behaviour.
Emerging / provisional renal tumor 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, others are still kept
as emerging. The WHO classification noted that although these entities appear to be distinct,
these are rare tumors, which are not yet fully characterized by morphology,
immunohistochemistry and molecular studies. Therefore, further reports are needed to refine
their diagnostic criteria and established clinical outcomes. SDH-deficient RCC was regarded
as emerging entity in the Vancouver classification but is now considered to be an established
entity. RCC in neuroblastoma survivors was included in the 2004 WHO-classification [22],
but it is now recognized that some of these tumors represent MiT-family translocation RCCs
[23]. Others are difficult to classify based on the published pathological details. Therefore, it
was decided to remove this entity from the 2016 WHO classification, despite they appear to
be a distinct variant, which for the purpose of the current classification is considered an
emerging entity. Very few thyroid-like follicular RCCs have been described [24, 25]. Most of
these tumors have indolent behavior. Less than 10 RCCs associated with ALK-gene
rearrangements have been reported in the literature [26-28]. Some of them are medullary

6. based tumors. Recently, reports of RCC associated with prominent angioleiomyomatous
stroma have been published. One term was renal angiomyoadenomatous tumor. If they
represent variants of clear cell RCC or clear cell papillary RCC has to be shown [29]. Some
tumors occurred sporadically and some are associated with tuberous sclerosis [30]. A recent
report identified TCEB1-gene mutations in tumors with this morphology [31].
Grading of renal tumors
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 [32]. Further, the Fuhrman system has not been validated for most of the new subtypes
of renal carcinoma. For these reasons, the 4-tiered WHO/International Society of Urological
Pathology grading system is recommended by the WHO [33]. For grade 1 to 3 tumors, the
system defines tumor grade on the basis of nucleolar prominence. Grade 4 is defined by the
presence of pronounced nuclear pleomorphism, tumor giant cells, and/or rhabdoid and/or
sarcomatoid differentiation. This grading system has been validated for clear cell RCC and
papillary RCC. It has not yet been validated for other tumor types due to the small numbers of
reported cases.
Selection of important future issues
1. The VHL tumor suppressor protein pVHL functions as a tumor suppressor via HIF-
dependent regulation in most clear cell RCC. However, the chromosome 3p locus
contains up to seven potential ccRCC tumor 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].
2. The identification of novel therapeutic agents that are effective against RCC cells that
harbor specific genetic alterations is an important ongoing research topic [34]. This
includes also emerging immunotherapies targeting immune checkpoints and tumor
associated antigens in patients with RCC [35]. In contrast to other solid tumors (e.g.
melanoma or lung cancer), there are at present no predictive molecular biomarkers
suitable for routine use [36]. The use of such biomarker has to consider the
considerable genetic intratumoral heterogeneity with the parallel evolution of multiple
tumor clones [37, 38].

7. 3. There has been a remarkable expansion of knowledge on the genetics of renal cancer
in the last years. This has led to a greater understanding of the molecular pathogenesis
of renal cancer [39]. Such knowledge will be incorporated in a future WHO
classification and clarify the position of some emerging renal tumor entities (e.g.
TCEB1 mutated RCC; angiomyoadenomatous RCC) or subgroups of papillary RCC
[8, 29, 31].
4. The novel WHO/ISUP grading system has been validated for clear cell RCC and
papillary RCC, but not for other tumor types [33]. Several grading schemes have been
proposed for chromophobe RCC to predict its behavioral outcome [40-43]. It is
important to have an internationally accepted chromophobe RCC grading system in
the near future.
References:
[1] Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO Classification of Tumours of the
Urinary System and Male Genital Organs. Lyon: IARC; 2016.
[2] Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International
Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. The
American journal of surgical pathology. 2013;37:1469-89.
[3] Moch H. Kidney Cancer. In: Stewart BW, Wild CP, editors. World Cancer Report 2014.
Lyon: World Health Organization International Agency for Research on Cancer (IARC);
2014. p. 2-9.
[4] Frew IJ, Moch H. A clearer view of the molecular complexity of clear cell renal cell
carcinoma. Annu Rev Pathol Mech Dis 2015;10:263-89.
[5] Eble JN, Bonsib SM. Extensively cystic renal neoplasms: cystic nephroma, cystic partially
differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma
of renal pelvis. Semin Diagn Pathol. 1998;15:2-20.
[6] Delahunt B, Eble J. Papillary renal cell carcinoma: a clinicopathologic and
immunohistochemical study of 105 tumors. Mod Pathol. 1997;10:537-44.
[7] Jiang F, Richter J, Schraml P, Bubendorf L, Gasser T, Mihatsch M, et al. Chromosomal
imbalances in papillary renal cell carcinoma: Genetic differences between histologic subtypes.
Am J Pathol. 1998;153:1467-73.
[8] Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, et al.
Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. The New
England journal of medicine. 2015.

8. [9] Lohse CM, Gupta S, Cheville JC. Outcome prediction for patients with renal cell
carcinoma. Semin Diagn Pathol. 2015;32:172-83.
[10] Doros LA, Rossi CT, Yang J, Field A, Williams GM, Messinger Y, et al. DICER1
mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.
Modern pathology : an official journal of the United States and Canadian Academy of
Pathology, Inc. 2014;27:1267-80.
[11] Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline
mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and
papillary renal cell cancer. Nat Genet. 2002;30:406-10.
[12] Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of
kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.
The American journal of surgical pathology. 2007;31:1578-85.
[13] Gill AJ, Hes O, Papathomas T, Sedivcova M, Tan PH, Agaimy A, et al. Succinate
Dehydrogenase (SDH)-deficient Renal Carcinoma: A Morphologically Distinct Entity: A
Clinicopathologic Series of 36 Tumors From 27 Patients. The American journal of surgical
pathology. 2014.
[14] Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, et al. Germline
SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008;100:1260-2.
[15] Zhou M, Yang XJ, Lopez JI, Shah RB, Hes O, Shen SS, et al. Renal tubulocystic
carcinoma is closely related to papillary renal cell carcinoma: implications for pathologic
classification. Am J Surg Pathol. 2009;33:1840-9.
[16] Amin MB, MacLennan GT, Gupta R, Grignon D, Paraf F, Vieillefond A, et al.
Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive
rare subtype of renal cell carcinoma. The American journal of surgical pathology.
2009;33:384-92.
[17] Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, et al. Tubulocystic carcinoma of the
kidney: clinicopathologic and molecular characterization. Am J Surg Pathol. 2008;32:177-87.
[18] Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P, et al. Tubulocystic
carcinoma of the kidney: a new entity among renal tumors. Virchows Arch. 2007;451:905-9.
[19] Tickoo SK, Deperalta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young
AN, et al. Spectrum of Epithelial Neoplasms in End-Stage Renal Disease: An Experience
From 66 Tumor-Bearing Kidneys With Emphasis on Histologic Patterns Distinct From Those
in Sporadic Adult Renal Neoplasia. Am J Surg Pathol. 2006;30:141-53.

9. [20] Rohan SM, Xiao Y, Liang Y, Dudas ME, Al-Ahmadie HA, Fine SW, et al. Clear-cell
papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis
on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins.
Modern pathology : an official journal of the United States and Canadian Academy of
Pathology, Inc. 2011;24:1207-20.
[21] Zhou H, Zheng S, Truong LD, Ro JY, Ayala AG, Shen SS. Clear cell papillary renal cell
carcinoma is the fourth most common histologic type of renal cell carcinoma in 290
consecutive nephrectomies for renal cell carcinoma. Human pathology. 2013.
[22] Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell
carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity.
The American journal of surgical pathology. 1999;23:772-80.
[23] Argani P, Lae M, Ballard ET, Amin M, Manivel C, Hutchinson B, et al. Translocation
carcinomas of the kidney after chemotherapy in childhood. Journal of clinical oncology :
official journal of the American Society of Clinical Oncology. 2006;24:1529-34.
[24] Amin MB, Gupta R, Ondrej H, McKenney JK, Michal M, Young AN, et al. Primary
thyroid-like follicular carcinoma of the kidney: report of 6 cases of a histologically distinctive
adult renal epithelial neoplasm. The American journal of surgical pathology. 2009;33:393-
400.
[25] Berens S, Vogt P, Alkadhi H, Berger N, Moch H. [Thyroid-like follicular carcinoma of
the kidney : A separate tumor entity?]. Der Pathologe. 2013.
[26] Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, et al. ALK
alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in
a large series of consecutively treated patients. Modern pathology : an official journal of the
United States and Canadian Academy of Pathology, Inc. 2012;25:1516-25.
[27] Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, et al. Identification of
anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical
screening by the intercalated antibody-enhanced polymer method. Cancer. 2012;118:4427-36.
[28] Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, et al. Renal
cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor
spectrum. Modern pathology : an official journal of the United States and Canadian Academy
of Pathology, Inc. 2011;24:430-42.
[29] Deml KF, Schildhaus HU, Comperat E, von Teichman A, Storz M, Schraml P, et al.
Clear Cell Papillary Renal Cell Carcinoma and Renal Angiomyoadenomatous Tumor: Two

10. Variants of a Morphologic, Immunohistochemical, and Genetic Distinct Entity of Renal Cell
Carcinoma. The American journal of surgical pathology. 2015;39:889-901.
[30] Yang P, Cornejo KM, Sadow PM, Cheng L, Wang M, Xiao Y, et al. Renal cell
carcinoma in tuberous sclerosis complex. The American journal of surgical pathology.
2014;38:895-909.
[31] Hakimi AA, Tickoo SK, Jacobsen A, Sarungbam J, Sfakianos JP, Sato Y, et al. TCEB1-
mutated renal cell carcinoma: a distinct genomic and morphological subtype. Modern
pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.
2015;28:845-53.
[32] Delahunt B, Sika-Paotonu D, Bethwaite PB, McCredie MR, Martignoni G, Eble JN, et
al. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. The American
journal of surgical pathology. 2007;31:957-60.
[33] Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J,
et al. The International Society of Urological Pathology (ISUP) grading system for renal cell
carcinoma and other prognostic parameters. The American journal of surgical pathology.
2013;37:1490-504.
[34] Moch H, Montironi R, Lopez-Beltran A, Cheng L, Mischo A. Oncotargets in different
renal cancer subtypes. Curr Drug Targets. 2015;16:125-35.
[35] Kucharczyka J, Matrana MR, Moch H. Emerging immunotargets in metastatic renal cell
carcinoma. Curr Drug Targets. in press.
[36] Tan PH, Cheng L, Rioux-Leclercq N, Merino MJ, Netto G, Reuter VE, et al. Renal
tumors: diagnostic and prognostic biomarkers. The American journal of surgical pathology.
2013;37:1518-31.
[37] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The
New England journal of medicine. 2012;366:883-92.
[38] Gerstung M, Beisel C, Rechsteiner M, Wild P, Schraml P, Moch H, et al. Reliable
detection of subclonal single-nucleotide variants in tumour cell populations. Nat Commun.
2012;3:811.
[39] Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature.
2013;499:43-9.
[40] Finley DS, Shuch B, Said JW, Galliano G, Jeffries RA, Afifi AA, et al. The
chromophobe tumor grading system is the preferred grading scheme for chromophobe renal
cell carcinoma. The Journal of urology. 2011;186:2168-74.

11. [41] Paner GP, Amin MB, Alvarado-Cabrero I, Young AN, Stricker HJ, Moch H, et al. A
novel tumor grading scheme for chromophobe renal cell carcinoma: prognostic utility and
comparison with Fuhrman nuclear grade. The American journal of surgical pathology.
2010;34:1233-40.
[42] Cheville JC, Lohse CM, Sukov WR, Thompson RH, Leibovich BC. Chromophobe renal
cell carcinoma: the impact of tumor grade on outcome. The American journal of surgical
pathology. 2012;36:851-6.
[43] Amin MB, Paner GP, Alvarado-Cabrero I, Young AN, Stricker HJ, Lyles RH, et al.
Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of
conventional pathologic prognostic parameters in 145 cases. The American journal of surgical
pathology. 2008;32:1822-34.