The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth

Abstract

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic “type 1 versus type 2” classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.

Long Non-Coding RNAs as Novel Biomarkers in the Clinical Management of Papillary Renal Cell Carcinoma Patients: A Promise or a Pledge?

“…Traditional morphologic subdivision into type 1 and type 2 is not always feasible, and the morphologic criterion remains controversial because of the lack of molecular and biochemical evidence [38]. In the last 20-30 years, our knowledge of the molecular abnormalities featured in pRCCs has grown, leading to a deeper understanding of the morphological and biological spectrum of renal tumors with papillary growth pattern [40]. As a matter of fact, the 2021 GUPS update on renal neoplasia stated that pRCC subtyping is no longer recommended because of the subjectivity in applying the histologic criteria, overlapping features among subtypes, and lack of clinical benefit.…”

“…With regard to pRCC, some renal entities are bound to pRCC due to their similar microscopic appearance and/or molecular features, for instance, clear cell tubulopapillary RCC, tubulocystic-RCC, and mucinous tubular and spindle carcinoma [41,42]. After the publication of the most recent WHO classification in 2016, provisional or emerging tumor entities with papillary growth were described, including papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC [40].…”

Kidney Cancer Models for Pre-Clinical Drug Discovery: Challenges and Opportunities

“…There is a remarkable and still emerging diversification in the classification of papillary RCC that goes beyond the “classical” type 1 and type 2 subtypes ( 13 ). Emerging variants of papillary renal tumors are for example, papillary renal neoplasm with reversed polarity, biphasic squamoid/alveolar RCC, biphasic hyalinizing psammomatous RCC or thyroid-like follicular RCC ( 14 ). There are also RCCs that are defined by gene translocations such as the MiT family translocation RCCs (harboring TFE3 or TFEB translocations) or ALK -translocated RCCs, which frequently show aggressive growth characteristics ( 14 ).…”

The Role of Circulating Biomarkers in the Oncological Management of Metastatic Renal Cell Carcinoma: Where Do We Stand Now?

“…According to the World Health Organization, there are three major histological subtypes of RCC, all differentiated by histological and molecular genetic changes: clear cell (70%), papillary (10–15%), and chromophobe (4–5%) [ 10 ]. Both clear cell (ccRCC) and papillary (pRCC) cancers originate from the renal proximal tubule, while chromophobe (chRCC) arises from the distal part of the nephron [ 11 ]. Each type of histology displays diverse morphology but also different genetics and behavior.…”

“…The remaining 10% of renal tumors include a variety of uncommon, sporadic, familial carcinomas and a group of unclassified carcinomas [ 12 ]. Briefly, minor histological subtypes are: oncocytoma, angiomyolipoma, collecting-duct carcinoma, sarcomatoid RCC, unclassified RCC, multilocular cystic RCC, papillary adenoma, renal medullary carcinoma, translocation carcinoma, mucinous tubular and spindle cell carcinoma, metanephric adenoma, adenofibroma, metanephric stromal tumor, renal epithelial and stromal tumors, and hereditary kidney tumors (Von Hippel–Lindau Syndrome, hereditary pRCC, Birt–Hogg–Dubé Syndrome, hereditary leiomyomatosis, tuberous sclerosis, and constitutional chromosome 3 translocation) [ 11 , 13 , 14 , 15 , 16 ].…”