Towards a new WHO classification of renal cell tumor: what the clinician needs to know-a narrative review

Abstract

In 1952, renal cell carcinomas had been divided into 2 categories-clear cell or granular cell-depending upon their cytoplasmic staining characteristics. In the following years, the inventory of renal epithelial tumors has expanded by the addition of tumors named by their architectural pattern (i.e., papillary RCC, tubulocystic RCC), anatomic location (i.e., collecting duct carcinoma, renal medullary carcinoma), associated diseases (i.e., acquired cystic disease-associated RCCs). With the extensive application of molecular diagnostic techniques, it becomes possible to detect genetic distinctions between various types of renal neoplasm and discover new entities, otherwise misdiagnosed or diagnosed as unclassified RCC. Some tumors such as ALK rearrangement-associated RCC, MiT family translocation renal carcinomas, SDH-deficient renal cancer or FH-deficient RCC, are defined by their molecular characteristics. The most recent World Health Organization (WHO) classification of renal neoplasms account for more than 50 entities and provisional entities. New entities might be included in the upcoming WHO classification. The aim of this review is to summarise and discuss the newly acquired data and evidence on the clinical, pathological, molecular features and on the prognosis of new RCC entities, which will hopefully increase the awareness and the acceptance of these entities among clinicians and improve prognostication for individual patients.

Keywords: Renal cell carcinoma; Von Hippel-Lindau gene (VHL); anaplastic lymphoma kinase (ALK); classification; clear cell RCC; emerging entities; fumarate hydratase (FH); molecular pathology; non-clear cells RCC; succinate dehydrogenase (SDH).

Figure 1

FH-Deficient RCC, at low (2×) (A) and high magnification (20×) (B), with strong and diffuse positivity for 2SC and loss of FH expression (inserts); Succinate Dehydrogenase Deficient Neoplasia (10×) (C) with loss of SDH2 expression (insert); Tubulo-cystic RCC (10×)(D), at low magnification (insert).

Figure 2

Clear cell papillary RCC. Clear cells of low nuclear grade, variable papillary, tubular-acinar and cystic architecture in a fibroleiomyomatous stroma (10×) (A), “cup-shaped” carbonic anhydrase IX staining distribution (20×) (B), strong and diffuse CK7 positivity (20×) (C). Acquired cystic disease-associated renal cell carcinoma (4×) (D), note the oxalate crystals (arrow) at higher magnification (insert); Thyroid like follicular RCC (4×) (E).

Figure 3

ALK Rearrangement-associated RCC (A, 10×) with mucinous background, ALK-IHC membrane expression (B, 10×); HOT (C, 10×) and LOT (D, 10×), with scant and diffuse CK7 expression, respectively (inserts, 20×).

Figure 4

Xp11 translocation RCCs (A, 10×), TFE3 IHC staining (insert); Mucinous tubular spindle cells carcinoma (B, 4×); Renal medullary carcinoma (C, 10×) with loss of SMARCB1 (INI1) expression by IHC (insert); Collecting duct carcinoma (D, 4×).

Figure 5

Eosinophilic solid and cystic RCC at low magnification (A, 2×) and high magnification (B, 20×), CK20 expression (insert); Biphasic squamoid papillary RCC (C, 10×), BCL1 IHC stained the squamoid cells (insert); Papillary renal neoplasm with reverse polarity (D, 40×), positive nuclear staining with GATA 3 (insert).