01Preface

The rapid advancement in the treatment of renal cancer highlights the importance of integrating various expertise in the decision-making process, particularly in enhancing personalized diagnostic and therapeutic approaches using novel molecular technologies. Previously, the classification of renal cancer was mainly based on morphological characteristics and immunohistochemical profiles. With the increasing application of next-generation sequencing (NGS) and the growing understanding of molecular alterations in renal cancer, there is a significant shift in diagnostic methods from morphology to molecular analysis. Therefore, in addition to morphology-based classification of renal tumors, the fifth edition of the WHO classification of renal tumors includes molecularly defined renal cell carcinomas. Molecularly defined renal cell carcinomas include: TFE3 rearranged renal cell carcinoma (formerly known as Xp11.2 translocation-associated renal cell carcinoma), TFEB rearranged renal cell carcinoma (formerly known as t(6,11) chromosomal translocation renal cell carcinoma), ELOC mutated renal cell carcinoma, FH deficient renal cell carcinoma, succinate dehydrogenase deficient renal cell carcinoma, ALK rearranged renal cell carcinoma, SMARCB1 deficient renal medullary carcinoma (also known as medullary carcinoma). Molecularly defined renal tumors may exhibit significant heterogeneity in morphology, with some renal tumors showing similar morphological changes but different molecularly driven genes, hence cannot be diagnosed solely based on morphology. Conversely, although most of the posterior adrenal adenomas, posterior adrenal fibromas, and posterior adrenal interstitial tumors have BRAF V600E mutation, they are still considered morphologically defined tumors.

Furthermore, characteristic gene alterations have been discovered in newly emerging renal tumor entities, and evidence collection in this regard is ongoing, with key features yet to be determined.^[3]

Molecularly defined renal cell carcinoma and ICD-O codes in the fifth edition of the WHO classification of renal tumors^[1]

02TFE3 rearranged renal cell carcinoma

The TFE3 gene is located on the Xp11.2 locus and its related protein belongs to the MiT subfamily of transcription factors. TFE3 rearrangements occur in approximately 1-4% of adult RCCs, but are more common in pediatric RCCs. This is a rare but often aggressive disease. The fifth edition of the WHO classification of renal tumors renamed and defined TFE3 rearranged renal cell carcinoma, which is defined as renal cell carcinoma with fusion of the TFE3 gene with many different partner genes. Partner genes reported to fuse with the TFE3 gene include ASPSCR1 (ASPL), PRCC, NONO (P54NBB), SFPQ (PSF), RBM10, MED15, CLTC, DVL2, PARP14, KAT6A, NEAT1, MATR3, FUBP1, and EWSR1, with PRCC, ASPSCR1, and SFPQ being the most common fusion genes. Overexpression of TFE3 fusion protein as an aberrant transcription factor can activate the expression of multiple downstream targets, including those typically activated by the MiT family transcription factor MITF (such as melanocyte markers and tissue protease K). The "basic and valuable diagnostic criteria" added in the chapter on TFE3 rearranged renal cell carcinoma include a mixed histological pattern, including papillary structures and psammoma bodies, strong nuclear positivity for TFE3 immunohistochemical staining, and detection of TFE3 gene rearrangement by FISH probe separation or identification of TFE3 gene fusion by RNA sequencing.

03TFE3 rearranged renal cell carcinoma

In the fourth edition of the WHO classification of renal tumors, t(6;11) translocation renal cell carcinoma was included in the MiT family translocation renal cell carcinoma. In recent years, in addition to t(6;11) translocation renal cell carcinoma, there have also been reports of TFEB-amplified renal cell carcinoma. Therefore, the fifth edition of the WHO classification of renal tumors has been renamed "TFEB rearranged renal cell carcinoma", which is defined as renal cell carcinoma containing gene fusions encoding the TFEB transcription factor, usually resulting from t(6;11)(p21;q12) translocation leading to MALAT1-TFEB fusion. TFEB-amplified renal cell carcinoma carries amplification of the TFEB 6p21 locus, leading to overexpression of TFEB protein and its downstream effects. Histologically, TFEB-amplified renal cell carcinoma typically presents as high-grade, poorly differentiated renal cell carcinoma with eosinophilic cytoplasm and papillary structures.

04ELOC mutated renal cell carcinoma

ELOC (formerly TCEB1) encodes elongin C, a key component of the VHL complex involved in the physiological ubiquitination and inactivation of HIF1a. ELOC mutations frequently occur at the Y79 residue VHL binding site, disrupting the VHL-elongin C complex, leading to stabilization of Hif1a and activation of oncogenic downstream pathways. In a recent study, ELOC and VHL mutations were found to be mutually exclusive. The fifth edition of the WHO classification of renal tumors adds ELOC mutated renal cell carcinoma, which is defined as renal cell carcinoma with mutations in the ELOC (formerly TCEB1) gene located at the 8q21.11 locus. Literature reports a total of about 20 cases, with over 90% of cases occurring in males, with an average age of 60 years. ELOC mutated renal cell carcinoma exhibits diverse morphological features, with tumor cells separated by thick fibromuscular stroma under low magnification. Immunophenotype: Tumor cells consistently express CK7, CAIX (membrane expression), and CD10, while CK (34βE12) is usually not expressed or expressed focally. ELOC mutated renal cell carcinoma is primarily differentiated from clear cell renal cell carcinoma or clear cell papillary renal tumors: unlike most clear cell renal cell carcinomas, ELOC mutated renal cell carcinoma expresses CK7 and lacks VHL gene inactivation; unlike clear cell papillary renal tumors, ELOC mutated renal cell carcinoma lacks obvious perinuclear cytoplasmic vacuoles, and CAIX is not expressed in a cup-like pattern. ELOC mutated renal cell carcinoma overlaps morphologically with renal cell carcinomas associated with mTOR pathway gene mutations. Some scholars classify these tumors as "renal cell carcinomas with smooth muscle-like stroma" and confirm that ELOC mutation is a necessary condition for diagnosing this type of tumor. ELOC mutated renal cell carcinoma is a molecularly driven renal cell carcinoma, so accurate diagnosis cannot be made without molecular testing. Most ELOC mutated renal cell carcinomas have a good prognosis and exhibit indolent biological behavior.

05FH-deficient renal cell carcinoma

FH-deficient renal cell carcinoma is caused by pathogenic mutations in the FH gene leading to loss of function of the corresponding FH protein. Its morphological manifestations are diverse, with the most common types being papillary, followed by solid, cystic, sieve-like/sieve-like, and cystic. Focal eosinophilic nucleoli are a nonspecific but common feature. Many such cases have been described in the past as "unclassified high-grade renal cell carcinoma", "predominantly papillary unclassified renal cell carcinoma", "tubulocystic carcinoma with focal dedifferentiation", "type 2 papillary renal cell carcinoma", or "collecting duct carcinoma", with the morphological spectrum also including cases with low-grade eosinophilic cell morphology, which are prone to misdiagnosis as fumarate hydratase-deficient renal cell carcinoma, but immunohistochemical staining for SDHB is not missing. FH gene mutations include germline and somatic mutations, with FH germline mutations referring to hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma in the fourth edition of the WHO classification of renal tumors. Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is a hereditary disease caused by germline mutations in the fumarate hydratase (FH) gene, which can manifest as skin, uterine leiomyomas, and malignant kidney tumors. Due to its unique clinical, pathological, and molecular features, it became an independent subtype in the 2016 edition of the WHO classification of renal tumors. Systemic mutations in FH may also lead to the development of renal cell carcinoma, which exhibits extremely similar biological behavior to HLRCC caused by FH germline mutations. Therefore, in the 2022 new edition of the WHO classification of renal tumors, renal cell carcinomas caused by FH germline or systemic mutations are collectively referred to as FH-deficient renal cell carcinoma.

06Succinate dehydrogenase-deficient renal cell carcinoma

Among SDH-deficient tumors, SDHB gene mutations are the most common (75%), and the lifetime risk of such renal tumors is estimated to be 14%. Succinate dehydrogenase-deficient renal cell carcinoma is a newly added renal tumor type in the fourth edition of the WHO classification of renal tumors. In the fifth edition of the WHO classification of renal tumors, it is classified as a molecularly defined renal cell carcinoma, with the definition and morphological description being essentially consistent with that of the

07ALK Rearranged Renal Cell Carcinoma

ALK rearranged renal cell carcinoma is a subtype of renal cell carcinoma newly added in the fifth edition of the WHO classification. It is a rare subtype of renal cell carcinoma. ALK rearranged renal cell carcinoma is composed of polygonal tumor cells with abundant eosinophilic cytoplasm, and the cytoplasm of tumor cells shows marked vacuolization. Chromosomal translocation leads to fusion of the ALK gene located on chromosome 2p3. Currently, about 40 cases have been reported, ranging in age from 3 to 85 years. VCL-ALK fusion renal cell carcinoma often occurs in young patients with sickle cell characteristics. The tumor usually has clear boundaries, composed of polygonal tumor cells with abundant eosinophilic cytoplasm and marked vacuolization. This type of tumor is considered the eighth variant of sickle cell kidney disease. Renal cell carcinomas with ALK fusion with genes such as TPM3, ML4, STRN, and HOOK1 exhibit various morphologies, which may include cytoplasmic vacuolation, papillary structures, sieve-like structures, intracellular or extracellular mucinous matrix, mucinous tubules, spindle cell-like morphology, and may also have psammoma bodies or rhabdoid morphology. Immunophenotype: tumor cells are ALK-positive, SMARCB1 (also known as INI1, SNF5, or BAF47) is not deleted, TFE3 is often positive but without TFE3 gene rearrangement, melanocyte markers HMB45 and Melan A are both negative. The basic diagnostic criteria for ALK rearranged renal cell carcinoma are the detection of ALK gene rearrangement by FISH or sequencing methods, and the diagnostic criteria worth obtaining are patients with sickle cell characteristics.

08SMARCB1-Deficient Renal Medullary Carcinoma

The SMARCB1 (also known as INI1, SNF5, or BAF47) gene is located on human chromosome 22q11.23, encoding a subunit of the SWI/SNF complex, which is involved in the regulation of chromatin structure and gene expression. SMARCB1 gene mutations drive aberrant gene expression programs, thereby promoting tumor cell proliferation and metastasis. Most commonly, chromosomal translocation or deletion of SMARCB1 leads to its inactivation. SMARCB1-deficient renal medullary carcinoma is a type of renal tumor already present in the fourth edition of the WHO renal tumor classification, named renal medullary carcinoma in the fourth edition. SMARCB1-deficient renal medullary carcinoma refers to a high-grade adenocarcinoma originating from the renal medulla with loss of SMARCB1 (INI1), primarily occurring in young patients with sickle cell anemia. Some unclassified renal cell carcinomas with medullary carcinoma phenotype may exhibit complete loss of SMARCB1 but without sickle cell characteristics or sickle cell anemia; these tumors are considered a subtype of SMARCB1-deficient renal medullary carcinoma in the fifth edition. The basic diagnostic criteria for SMARCB1-deficient renal medullary carcinoma: high-grade adenocarcinoma with evidence of hemoglobinopathy in laboratory/clinical findings. SMARCB1-deficient renal medullary carcinoma is highly invasive, with poor prognosis, and over 90% of patients have lymph node or distant metastases (most commonly to the lungs and liver) at the time of diagnosis.

09Prospects

Molecular alterations are increasingly used for the classification of renal cell carcinomas, especially in challenging cases involving small biopsies, atypical high-grade tumors, and metastatic tumors of unknown origin. However, these alterations are often not limited to a single type of renal cell carcinoma, and a definitive diagnosis may require the use of specially designed NGS panel analysis for mutations, copy number abnormalities, and translocations. The emerging field of precision medicine prioritizes adjusting patient and treatment approaches based on the genomic characteristics of patients.

References:

1. Interpretation of the main changes in the fifth edition of the new WHO classification of renal tumors

2.Virchows Arch. 2024 Feb;484(2):323-337.

3. Consensus on clinical diagnosis and treatment of fumarate hydratase-deficient renal cell carcinoma

4.Asian J Surg 2021 Apr;44(4):692-693.5.Chin Ne

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