Introduction to updates in kidney tumor classification,morphology,and molecular alterations in Kidney Cancer

The classification of renal tumors has undergone significant evolution over the past 30 years, from the first edition of the World Health Organization (WHO) Classification of Tumors to the current 5th edition (published in 2022).^1–5 The primary focus of these updates has been to better reflect the advances in molecular biology, histopathology, and clinical outcomes, as well as to improve the precision in the diagnosis and treatment of renal tumors.

Historically, the classification of kidney tumors was based on histological features. In the first and second editions of the WHO, classification was relatively simple and based mainly on morphologic/histopathologic appearances (i.e., how the tumor looks down a microscope). These editions primarily focused on 1) a few kidney tumor subtypes which still remain the more common forms of renal cell carcinoma (RCC) (e.g., clear cell, papillary and chromophobe RCC); 2) pediatric tumors (e.g., Wilms tumor), and 3) benign renal neoplasms (e.g., adenomas and oncocytoma). However, many renal tumors with different biologic properties can look similar down the microscope and over time it became clear that there were more than ‘just a handful’ of renal tumor subtypes (Figure 1). Accordingly, over the years, and reflected in the third and fourth editions of the WHO (Figure 2), the use of special stains (e.g., immunohistochemistry, which identifies specific proteins within tumor cells) and genetic studies (e.g., cytogenetics, which evaluates for chromosome alterations within tumor cells) have not only led to a better understanding of the pathophysiology of renal tumors, but these techniques or ‘ancillary studies’ have helped pathologists to diagnose more specific kidney tumor subtypes (Figure 1). The most recent classification of the WHO (5th edition) (Figure 3) has incorporated cutting-edge molecular and genomic information (e.g., next generation sequencing, which identifies specific gene mutations within tumor cells), as reflecting and expanding significant advances in our understanding of renal tumor genetics. This contemporary version of the WHO represents the most comprehensive and precise renal tumor classification to date,^1,6 and specifically recognizes in more detail multiple RCCs with a familial (i.e., hereditary) association, which is not only important for an individual patient but for family members as well. Emerging and less well understood entities that are still under investigation as described in the WHO and the pathology literature.^1,7

Figure 1.

Molecularly confirmed renal cell carcinomas. Note the varying degree of clear cell cytology and papillary architecture in the distinct subtypes of renal cell carcinoma. (a) Clear cell renal cell carcinoma. (b) Chromophobe renal cell carcinoma. (c) TFE3 (Xp11.2) rearranged renal cell carcinoma. (d) Papillary renal cell carcinoma. E) Fumarate hydratase-deficient renal cell carcinoma. (f) ELOC (TCEB1)-mutated renal cell carcinoma. (all images 400x).

Figure 2.

A summarized overview of the previous classification of adult renal tumors, as originally described in the first through the fourth versions of the World Health Organization (WHO) classification of adult renal tumors.

Figure 3.

A summarized overview of the current (2022) classification of adult renal tumors, as described in the 5^th edition of the World Health Organization (WHO) classification of adult renal tumors.

Although the comprehensive understanding of genetic and molecular alterations in renal tumors has allowed for more specific diagnoses, better targeting of therapeutic options, and a clearer understanding of clinical outcomes, it has also made the landscape of renal neoplasia more difficult conceptually for non-specialized physicians as well as patients, many of whom want a deeper understanding of the disease they are fighting. It was for this reason that Kidney Cancer and I felt a single special edition on kidney tumors, from the pathologic perspective, would be beneficial. Accordingly, this edition of the journal provides a comprehensive overview of the latest updates in kidney tumor classification, emphasizing the integration of morphology, ancillary studies, and molecular alterations in adult and pediatric tumors. The differential diagnosis of renal tumors (i.e., the consideration of one tumor subtype versus another during the diagnostic work up) is also provided. These review articles are approached based on cytologic (e.g., clear cell), architectural (e.g., papillary), clinical associations (e.g., acquired cystic disease, familial syndromes, sickle cell trait), age (adult versus pediatric), and molecular (e.g., genetic) alterations. Additional reviews on staging and grading of RCC, mesenchymal (i.e., non-epithelial) and benign renal neoplasms are also included. As you read these articles, you will notice that the discussion of specific tumor types will be mentioned in multiple reviews, reflecting the complexity of renal tumor diagnostics and classification.

It has been a pleasure to work with Kidney Cancer on this special pathology edition, and I am incredibly grateful to my pathology colleagues who have taken the time to write this excellent and detailed set of reviews. Ultimately, it is my hope that these manuscripts will be useful to a broad audience, including pathologists and non-pathology clinical colleagues with varying levels of training and experience, as well as researchers who study kidney cancer; but most importantly, I hope these reviews provide a good resource to patients who may be trying to better understand their medical situation. Like all of medicine, the comprehension of kidney neoplasia has been and continues to be an evolving field of study, and as we continue to better understand the pathophysiology behind renal tumors, we hope to also transform clinical practice and improve treatment options.