Kidney Cancer Journal | Volume 9, June 2025

Papillary renal cell carcinoma (pRCC) represents the second most common renal cell carcinoma. Diagnosis of pRCC has been challenged by emergence of several novel renal tumor entities with papillary morphology. Some of these have been found to constitute independent entities with specific molecular drivers, e.g. fumarate hydratase deficient renal cell carcinoma or TFE3-rearranged or TFEB-altered RCC. Others are still considered emerging entities, such as papillary renal neoplasm with reverse polarity associated with KRAS mutations and biphasic hyalinizing psammomatous RCC associated with NF2 mutations. The recognition of these entities has changed the spectrum of “true” pRCC, and subclassification into type 1 and type 2 is no longer recommended. With the discovery of novel entities with specific diagnostic molecular traits, it is expected that the spectrum of pRCC is becoming increasingly narrow. This will potentially allow for a better prediction of prognosis and treatment response of pRCC. In this review we discuss recent developments in the diagnosis of renal tumors with papillary morphology, including emerging/provisional papillary renal tumor entities. The evolution of renal tumor classification has improved our understanding of biologic behavior and molecular background of pRCC with consequences on histopathological and molecular pathological approaches.

The incidence and prevalence of chronic kidney disease (CKD) and end stage renal disease (ESRD) are on the rise causing significant health issues associated with hemodialysis, peritoneal dialysis and kidney transplantation. Moreover, all CKD patients have dramatically higher risk than the general population of developing kidney tumors with  5% incidence of renal cell carcinoma. This review highlights the spectrum of precursor lesions, most common benign and malignant neoplasia in patients with CKD and ESRD, focusing on pathogenesis, morphologic and immunophenotypic findings.

Renal tumors associated with familial syndromes, characterized by germline mutations in specific genes such as VHL, MET, FLCN, TSC1, TSC2, FH, and SDHB, offer critical insights into renal cell carcinoma tumorigenesis and necessitate tailored genetic counseling, screening, and surveillance. Each syndrome exhibits unique clinical manifestations, impacting treatment strategies and long-term patient management. This review summarizes recent advances in the clinicopathologic, immunohistochemical, and molecular characteristics of both established and emerging familial renal cell carcinoma syndromes. Key syndromes include von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis renal cell carcinoma, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, hereditary paraganglioma-pheochromocytoma syndrome, BAP1 tumor predisposition syndrome, and PTEN hamartoma tumor syndrome. The review emphasizes the importance of pathological assessment in diagnosing these syndromes, especially in cases where clinical presentations are insufficient to raise specific suspicions. Understanding these familial syndromes is crucial for accurate diagnosis, effective patient management, and the development of surveillance programs to improve outcomes for patients and their families.

SMARCB1-deficient renal medullary carcinoma is one of the most aggressive forms of kidney cancer and mainly affects individuals with sickle hemoglobinopathies. Herein, we have sought to provide a contemporary update regarding our understanding of this entity. Recent studies have improved our understanding of the pathophysiology of this tumor including potential modifiable risk factors, putative cell of origin, and mechanisms of SMARCB1 loss. Furthermore, mechanisms of oncogenesis based on the SMARCB1-deficient phenotype continue to be elucidated. These tumors are classified as SMARCB1-deficient renal medullary carcinoma, and SMARCB1-deficient medullary-like renal cell carcinoma based on the presence of sickle hemoglobinopathies, and established subtypes of renal cell carcinoma with secondary SMARCB1 loss continue to be identified. Current diagnostic algorithms help in separating the above-mentioned tumors from morphologic mimics which include collecting duct carcinoma, upper tract urothelial carcinoma, FH-deficient, and ALK-rearranged renal cell carcinoma which have different natural histories and therapeutic implications. Finally, there is an unmet need to develop better treatment regimens for patients with renal medullary carcinoma given its aggressive clinical course and several agents continue to be evaluated in addition to standard-of-care platinum-based cytotoxic chemotherapy.

Renal cell carcinoma (RCC) is linked to signature molecular alterations that influence their morphological characteristics and associated clinicopathologic features. This has been fueled by an incremental understanding of the molecular underpinnings of RCC. The current 2022 WHO classification has now incorporated novel diagnostic entities as well as a new category of “molecularly defined renal carcinomas”. This review delves into our current understanding of molecular correlates with the evolving taxonomic classification of RCC. This review’s contents consist of molecularly defined entities with morphological annotations that correspond to distinct morphologies such as clear cell, papillary, and eosinophilic. Thus, we highlight the morphological context, diagnostic algorithm, and the available biomarkers that can assist practicing pathologists in these respective categories and thereby correctly diagnosing these unique tumor entities. Wherever possible a brief summary of the current therapeutics that align with morphological and molecular correlates have been providedas well.

Renal tumors in the pediatric age group are a unique group of tumors that are generally quite distinct from tumors arising in the adult kidney. This review covers benign and malignant renal tumors commonly presenting in the pediatric population. Pertinent clinical, epidemiologic, macroscopic, and microscopic features are included. Key histologic differential diagnoses are addressed. Diagnostic evaluation, including immunohistochemical staining and molecular analysis, is presented.

Renal cell carcinoma (RCC) makes up most adult kidney cancers. The classic presentation is a spherical, well-circumscribed mass, but fewer subtypes present as more infiltrative neoplasms. Both growth patterns can affect tumor staging and prognosis. Accordingly, this review will discuss the current status of staging, grading, and pathologic prognostication in RCC. Typically, the most important prognostic parameter in RCC is tumor stage. Pathologic staging categories (i.e., pT) are influenced by tumor size (pT1-pT2) and invasion of structures including renal sinus, perinephric fat, the renal vein or segmental branches, vena cava, or adjacent organs/structures (≥pT3). This invasion is prognostically important but can prove difficult to diagnose, due to the more common nodular rather than infiltrative pattern of RCC. In clear cell RCC, more than half of tumors over 5 cm and over 90% of tumors over 7 cm invade the renal sinus soft tissue, such that true pT2 clear cell RCC is rare. However, the size to invasion relationship is less clear for other RCC subtypes, some of which become large without invading structures (e.g., papillary RCC, chromophobe RCC), and others of which are infiltrative irrespective of size (e.g., renal medullary carcinoma, FH-deficient RCC). Histologic grading in recent years has evolved to focus mostly on prominence of the nucleolus. Other emerging assessments in RCC include tumor necrosis as a prognostic parameter (predominantly for clear cell RCC), architectural grades in clear cell RCC, and specific growth patterns in papillary RCC, such as microcystic growth. Overall, this review is aimed to serve as a guideline to the staging and grading of RCC in clinical practice, as well as highlight the potential challenges and pitfalls in this crucial interface between clinical management and diagnostic pathology.

Mesenchymal neoplasms of the kidney encompass a wide range of tumor types with heterogeneous clinical, histologic, and molecular features. Given their rarity relative to renal epithelial neoplasms, diagnosis may be challenging. In this review, the clinicopathologic and molecular characteristics of selected mesenchymal neoplasms of the adult kidney are discussed, including benign entities with diverse lines of differentiation (such as juxtaglomerular cell tumor, angiomyolipoma, and anastomosing hemangioma), sarcomas (synovial sarcoma, leiomyosarcoma, Ewing sarcoma), and tumors with variable biologic potential (solitary fibrous tumor). Mesenchymal lesions that may arise in peri-nephric soft tissue (including well differentiated / dedifferentiated liposarcoma and perinephric myxoid pseudotumor of fat) are also highlighted, given their potential to present as a ‘renal’ mass.

Renal tumors (i.e., abnormal growths within the kidney) encompass both benign and malignant entities. The pathologist plays a key role in determining the nature of the growth (i.e., benign or malignant) by evaluating the tumor with a microscope. It is essential to distinguish between these two categories, as malignant tumors possess the potential to spread or metastasize throughout the body, while benign tumors typically follow a less aggressive course and stay limited to the organ. Benign growths may be followed clinically or surgically removed. Excision is often considered if the benign mass, by virtue of its location, is pressing on the bowel or a blood vessel. The removal of a benign growth via surgical excision is typically curative. Therefore, the need for accurate differentiation between benign and malignant renal tumors cannot be emphasized enough as it is imperative for appropriate patient care and management. All this information is recorded and reported in the pathology report. The report is shared with the surgeon, or the primary care physician, who will review and discuss the findings with the patient. In this review we will discuss the histomorphology and challenges in diagnosis of some of the more frequently occurring benign renal neoplasms.