presentation of renal clear cell carcinoma

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Renal clear cell cancer.

Rahul D. Arora ; Faten Limaiem .

Affiliations

Last Update: January 1, 2023 .

• Continuing Education Activity

Clear cell renal cancer is the most common type of kidney cancer, comprising 80 percent of all malignant tumors found within the kidney. It is known as the internist tumor and is well known to cause a wide spectrum of paraneoplastic manifestations to mimic other tumors and benign conditions. This activity describes the evaluation and management of this aggressive tumor, while also trying to highlight the role of the interprofessional team in the comprehensive management of the patient.

• Review the histopathological findings of clear cell renal cancer.
• Summarize the role of history taking, physical examination, radiological investigations in the evaluation and management of clear cell renal cancer.
• Outline the options available in the management of clear cell renal cancer.
• Review interprofessional team strategies for improving care coordination and communication to advance patient-related outcomes in clear cell renal carcinoma.
• Introduction

Renal cell carcinoma, of which clear cell carcinoma is the most common histological subtype (80 to 90 percent), comprises 90 percent of all Kidney tumors. [1]  Traditional morphological classification of these tumors divides them into three main subtypes – clear cell, papillary, and chromophobe subtypes. [2]  Clear cell and papillary cell cancer originate from the proximal tubular cells, while chromophobe cell cancers originate from the intercalated cells. [2]  The percentage of distant metastases in these various subtypes varies from 15 percent in clear cell carcinoma to 3 percent in papillary and 4 percent in chromophobe cell cancers. [3]  

The cancer-specific 10-year survival ranges from 71 percent in clear cell cancer to 91 percent in papillary cancer, 88 percent in chromophobe cancer, and 33 percent in collecting duct cancers. [4]  As is expected, diagnosis at an earlier stage offers a relatively higher chance of cure. The goals of the management of advanced RCC emphasize a focus upon improvement in the quality of life parameters. [5]

Clear cell tumors have the propensity to spread hematogenous, with direct extension into the major vessels – namely the renal veins and the inferior vena cava. [6]  Lung, bone, brain, liver, lymph nodes, liver, and adrenal glands form the main sites of dissemination. [7]  Lytic bony metastases, which might become sclerotic with treatment, can be present. [8]  Clear cell carcinoma is considered uniformly metastatic, irrespective of the tumor size. [9]

Obesity, hypertension, and cigarette smoking remain the leading potentially modifiable risk factors involved in the pathogenesis. [10]  An increase in BMI of 5 kg/meter square, central adiposity, waist-hip ratio ranging between 0.86 and 2.88, increase in body weight between 18 and 35 years of age have been positively associated with the development of RCC in various subpopulations. [11]

Chronic kidney disease, renal transplantation, hemodialysis, acquired cystic kidney disease, a history of previous renal cell carcinoma, and co-existing diabetes mellitus have been recognized as potential risk factors associated with an increase in incidence in renal cell carcinoma in population-based studies. [12]

Studies exploring the effects of moderate alcohol consumption, physical activity, and socioeconomic status on the incidence have led to conflicting outcomes, and it is generally agreed that the effect of these interventions on the etiopathogenesis of renal cell carcinoma needs to be explored further. [13] [14] [15]

While most of the cases of clear cell carcinoma are sporadic, 2 to 3% of the cases are related to genetic alterations in the von Hippel landau gene, chromatin remodeling genes/epigenetic regulators (Polybromo 1, BRCA protein 1, and SET D1), and genetic alterations in pathways that disrupt signal transduction involving the PI3K/Akt/mTOR pathway.  [16] [17]  PTEN deficiency is usually associated with a more aggressive phenotype. [18]  While angiomyolipoma is the most common renal neoplasm seen in patients with tuberous sclerosis, clear cell tumors may be seen rarely. [19]  Clear cell tumors can also be seen in a small minority of patients with Birt Hogg Dube syndrome, who have been otherwise shown to develop hybrid oncocytic- chromophobe tumor and oncocytomas. [20] [21]

• Epidemiology

It is estimated that 295,000 cases are diagnosed annually, and 134,000 cases recorded worldwide. [22] [23] [24]  The new cases in the United States in 2018 was estimated to be 65340, with 14970 annual deaths. [25]  The male to female ratio is close to 2 to 1. [26]  RCC ranked twentieth in the list of cancers, grouped in order of the number of years lost. in descending order, among both sexes in 2017 (compared to the nineteenth position in the same list in 2007). [27]

The mean age at diagnosis is 64 years, and an earlier age of diagnosis should prompt a search for an underlying genetic predisposition (syndrome). [28]  An increasing incidence has been attributed to an increase in rates of obesity. [29]  Declining mortality rates have been shown to correlate with an improvement in treatment options. [30]

Among European countries, the rates of renal cell carcinoma are highest in the Czech Republic. [31]  Renal cell carcinoma accounts for 2.6 % of all cancer deaths in men and 2.1 percent of all cancer deaths in women. [32]  SEER data from 2012 point towards a 5-year cancer-free survival rate were 91.7 % for localized disease, as compared to 64.2 and 12.3 percent respectively, for those with regional spread and distant metastasis. [32]

• Pathophysiology

The genetic silencing of the 3p25 genetic locus, which houses the Von Hippel landau tumor suppressor gene through various mechanisms that involve a point mutation, insertion, deletion, and epigenetic silencing (via promoter methylation), is the most frequently identified driving event in clear cell carcinoma. [33] [34]  VHL is part of the E3 ligase complex responsible for the proteasome-mediated degradation of Hypoxia-inducible factors 1 alpha and 2 alpha by taking part in the ubiquitination of these molecules. [35]  The accumulation of hypoxia-inducible proteins in an environment that is sufficiently oxygenated leads to an overexpression of genes involved in apoptosis, glycolysis, and angiogenesis. [36]

Despite this underlying mechanism, which might lead one to attribute oncogenesis in clear cell carcinoma to a mutation in the VHL tumor suppressor gene only, it is essential to understand that this single event does not have the potential to lead to oncogenesis, as is evidenced by the long latent period, that precedes the development of tumors. [17]  The primary pathway to be targeted in clear cell renal cancers includes the VEGF pathway due to VHL tumor suppressor gene loss located on the short arm of chromosome 3; however other secondary targets may consist of mTOR c1, MET, and IL-8. [37]

The presence of mutations in BAP 1 (histone deubiquitinase), PBRM1(involved in chromatin remodeling), SETD2 (histone methyltransferase), and KDM 5C and their association with prognosis has led to a proposal to classify renal cell carcinoma based on molecular pathogenesis. [38]  Activating mutations in the mTOR-RHEB gene are also seen in clear cell tumors. [39]  Both intratumor and intratumoral heterogeneity has been well documented. [40]

• Histopathology

On Gross examination, clear cell carcinomas are solid and yellow cortical based lesions, which are interspersed with cystic changes, hemorrhage, and necrosis in varying amounts. [41]  The yellow color of the tumor has been attributed to the presence of lipids – namely cholesterol, neutral lipids, and phospholipids. [2]  These tumors demonstrate pushing borders in addition to an expansive pattern of growth. [2]  They usually possess a fibrous capsule or a pseudocapsule, though infiltration of the surrounding tissues may also be seen. [2]  The microscopic examination usually shows nests of clear cells with eosinophilic granular cytoplasm, rich in glycogen, and cytoplasm in the background of delicately branching, fine vessels. [22] [42]

Nuclear morphology has been shown to form the basis of grading these tumors, with grading systems showing a gradual evolution from the 1970s to the present. [43]  Fuhrmann’s system, based upon an assessment of nuclear size, nuclear irregularity, and degree of prominence of the nucleoli, is among the most commonly used systems. [44]  This system classifies the tumor into four grades – with grade 4 tumors characterized by the presence of large, pleomorphic, multilobed giant cells with heavy chromatin lumps and the presence of extreme irregular outlines, being considered the most aggressive. [45]  Fuhrmann’s grading system has come in for severe criticisms – foremost among them being the difficulty associated with the simultaneous examination of three morphological features and the absence of guidelines to characterize the tumor when at least one of these features may not be evident. [43] [46]  Poor interobserver variability and difficulty in discerning the outcome, based upon the three pre-defined parameters, has also been mentioned as a valid critique. [47] [44]  

The World Health Organization/ International Society of urological pathology has introduced a grading system that is based on the nucleolar pathology of the tumor. [48]  Nucleolar size assumes importance in the wake of the observation that nucleolar size correlates with ribosomal biogenesis and that nucleolar grade has been often seen to correlate with patient outcomes. [49]

Multilocular cystic RCC is characterized by cystic lesion, lined by a single layer of clear to pale cells, with scant papillae and fibrous component, clearly demarcated from the cortical component by a fibrous capsule and lacking a solid element. [50] [51]

• History and Physical

The typical triad of clinical features associated with renal cell carcinoma comprises flank pain, abdominal mass, and haematuria. [52]  However, there has been a palpable shift towards tumors being diagnosed incidentally, with only around 30 percent of cases diagnosed based on clinical symptoms alone. [22]  Presenting symptoms might be the result of hormones or cytokine-like substances produced by the tumor. [22]  Patients present commonly with acute or chronic flank pain due to obstruction of the urogenital system, invasion of surrounding viscera, or presence of retroperitoneal mass. [22]  Gross haematuria (due to urogenital tract) and a palpable abdominal mass are seen less frequently. [22]  An isolated varicocele due to venous obstruction or thrombosis might be seen in rare cases.

Hypertension, anemia, and cancer anorexia cachexia are the common paraneoplastic conditions observed. [53]  Abnormal production of inflammatory mediators and cytokines is associated with anemia, sarcopenia, and pyrexia. [53]

Hepatitis, rich in a lymphocytic infiltrate with raised Interleukin 6 levels, has been postulated to underlie paraneoplastic hepatic dysfunction (Stauffer syndrome), which is diagnosed by hepatic enzyme elevation in the absence of liver metastases or intrinsic liver disease or cholestasis. [54]  Stauffer syndrome is known to resolve after the resection of the kidney tumor. [54]

Hypercalcemia may be due to direct bone involvement, due to parathormone related peptide, dihydrocholicalciferol derived from the tumor and prostaglandins. [55]

Erythropoietin production by the renal parenchyma or by the surrounding tissue in response to hypoxia may lead to polycythemia. [56]

Anecdotal symptoms attributable to paraneoplastic phenomena include hypoglycemia, neuropathy, myopathy, vascular thrombosis, Cushing syndrome, protein-related enteropathy, gynecomastia, decreased libido, hirsutism, amenorrhoea, necrotizing myopathy, and immune thrombocytopenic purpura. [53] [57]

Although physical assessment has a limited role in diagnosing this condition, the presence of an abdominal mass, lower extremity edema, and new-onset varicocele should prompt a search for a mass lesion in the retroperitoneal region. [58] [59]

The workup of a patient with symptoms of a renal/retroperitoneal mass should include laboratory evaluation, imaging, and biopsy for accurate staging. [60]

Laboratory Evaluation  [60] [22]

Serum creatinine, hemoglobin, total and differential leucocyte counts, total platelet count, neutrophil to lymphocyte ratio, lactate dehydrogenase, C-reactive protein, and corrected calcium should be evaluated.

Radiological Investigations- Role of Imaging  [22] [60] [41] [60]

Ultrasonography can be used to make a presumptive diagnosis of a renal mass. Imaging can characterize the mass, presence of abdominal metastases, invasion of the great vessels, and local spread of the tumor. Renal function, vascularity, and retroperitoneal involvement also need to be assessed in patients planned for surgical resection.

Typical radiological features of clear cell RCC include an exophytic growth pattern, heterogeneity linked to the presence of intra-tumoral heterogeneity or hemorrhage, and presence of enhancement with contrast intake. 

Additional imaging, including Computed tomography scanning of the thorax, abdomen, and pelvis, MRI Brain, and bone scan, may be required for performing a complete metastatic workup. Though a CT scan of the thorax, abdomen, and pelvis is considered mandatory for accurate staging, the use of a CT brain or bone scan is not recommended routinely. A Noncontrast CT scan with a plain MRI abdomen is indicated in those with an allergy to intravenous contrast agent or renal insufficiency. MRI techniques such as diffusion-weighted imaging and perfusion imaging are being explored for further characterization of the lesion.

Clear cell tumors have also been to have a significantly higher tumor to nontissue uptake and standardized uptake on 18FDG PET scanning. However, the utility of FDG-PET is limited due to false-negative results due to normal physiological excretion by the kidneys. It has shown a greater role in the recurrent setting and re-staging in advanced disease. Dynamic imaging has been shown to predict disease progression and survival in the recurrent setting (post-surgery).

Renal Biopsy  [22] [60] [61] [62]

Renal biopsy is indicated to establish the diagnosis of radiologically indeterminate renal masses, histological examination of incidentally detected masses in whom active surveillance is indicated, before treatment with renal ablative therapies, and help in selecting the most suitable targeted therapy in metastatic lesions.

Though the histological subtype and the Fuhrmann grade can be correctly determined upon a renal biopsy, complications associated with the procedure (infection, bleeding, the formation of arteriovenous fistula) has been shown to occur in a frequency of 0.3-5.3 percent cases. Complications related to the seeding of the biopsy tract have been minimized using modern biopsy techniques; there is an emerging consensus that the biopsy remains substantially underutilized. The argument in favor of such an observation states that while complications such as bleeding and seeding of the tumor tract are rare, the diagnostic accuracy remains high.

Liquid Biopsy  [63]

The circulating tumor cells and tumor DNA study has been shown to have a role in the noninvasive assessment of tumor burden with a fair degree of precision. Other cytological methods that have postulated to have clinical utility in the setting of RCC include exosomal protein profiling, screening of noncoding ribonucleic acid particles in the serum. Circulating tumor DNA has shown the potential to predict response to immune checkpoint inhibitors. These techniques have also been used to study the functional heterogeneity in tumor tissue, by using a combination of genetic and transcriptomic analysis of a single circulating tumor cell or by parallel single-cell epigenetic and transcriptome analysis. Clear cell cancer has also been proposed as a model to understand the cytomorphological and genetic features of malignancy in the circulating cancer cell and the single-cell level.

• Treatment / Management

Localised Disease  [63] [64] [65] [66] [67] [68]

The choice of the operative procedure has shifted from a radical nephrectomy to nephron-sparing strategies with active surveillance and the use of minimally invasive techniques. This shift towards minimally invasive approaches, which limit overtreatment and iatrogenic kidney injury, has been necessitated by diagnosing smaller lesions and the potential for chronic kidney disease (which is known to develop after radical nephrectomy approaches) to impact the patient’s quality of life adversely. Targeted systemic therapies with angiogenesis inhibitors and immune checkpoint inhibitors have been used to manage metastatic, advanced, or surgically inoperable renal cell carcinoma.

Role of Active Surveillance  [69] [70]

The slow median growth rate, as well as a substantial percentage (one fifth) of resected tumor specimens turning out to benign, along with the potential to prevent surgery-related complications, has led to the concept of active surveillance for renal tumors. Active surveillance may also be carried out for larger tumors in those with multiple risk factors and limited life expectancy to determine the rate of tumor growth. Though there has been no consensus on the absolute tumor size and the rate of growth at which a more radical approach needs to be adopted, tumor size of more than 3-4 cm and growth rates exceeding 0.4-0.5 cm have been defined as possible cut-offs. Initial imaging at 3 to 6 months, every six months for the next two years and annually after that, has been recommended for tumors that meet the criteria for active surveillance. 

Minimally Invasive Techniques  [71] [72] [73]

Renal ablative approaches (cryotherapy and radiofrequency ablation) that use the properties of energy to destroy tumor cells have been used to manage small tumors that have been detected incidentally. Potential complications include bleeding, abscess formation, and adverse effects involving the bowel, bladder, spleen, and pancreas. While comparable recurrence-free survival and cancer-specific survival rates have been demonstrated, a lower degree of decline in Glomerular filtration rate has been demonstrated using minimally invasive techniques (radiofrequency ablation), as per the results of a systematic review and meta-analysis. 

Determination of Presurgical CKD Risk and Strategies to Preserve Renal Function Postoperatively  [74] [75]

Cancer is not the commonest cause of death in patients with solitary renal masses. It has been observed that these patients share common risk factors with patients with chronic kidney disease and that cardiovascular events are a common cause of mortality. This has been attributed to common risk factors such as increasing age, male gender, smoking, presence of diabetes mellitus, and hypertension. The presence of albuminuria usually indicates the presence of advanced disease (higher grade or later stage).

It should be emphasized that the goals of management in those with T 1a tumors need to include preservation of renal function, minimizing cardiovascular mortality, and managing chronic kidney disease. Screening of patients for postsurgical CKD can be done by calculation of glomerular filtration rate and measurement of albuminuria. Stringent preoperative control of blood pressure, good glycemic control, and prevention of hypoperfusion and avoidance of nephrotoxic strategies could mitigate renal injury. The determination of differential kidney function by nuclear scintigraphic techniques has been advised. Intrarenal damage due to hypoxia and loss of renal function due to resection might reflect in changes in postoperative GFR.  

Surgery  [76] [77] [78] [79] [80] [81]

Nephron sparing surgery involves removing all tumor tissue, with preservation of as much normal renal parenchyma as possible. It is found to be related to comparable oncological outcomes and better long term cardiovascular outcomes than radical surgery. 

Indications for nephron-sparing surgery include the presence of a single anatomical and functional kidney, hereditary forms of renal cell cancer in those at risk of developing a malignancy in the contralateral kidney in the future, patients who may be prone to develop dysfunction in their functioning kidney in the future or localized tumors with a healthy contralateral kidney, those with bilateral synchronous RCC’s and Von Hippel Lindau syndrome. Partial nephrectomy is also indicated in those with T1 tumors and a normally functioning contralateral kidney, where it has been shown to have equivalent oncological outcomes when compared to radical surgery.

Tumor size, depth, location, and proximity to the hilar vascular structures and pelvicalyceal system are important factors that help in determining the feasibility of nephron-sparing surgery.

Various scoring systems such as the PADUA, RENAL, and C-index have been developed to assess the feasibility of performing a nephron-sparing procedure in selected patients. The application of these scores aids in the improvement of the selection of patients, providing optimum surgical management, reporting of research outcomes, and prediction of treatment outcomes.

Robot-assisted partial nephrectomy and open approaches are utilized for complex tumors; laparoscopic approaches should be reserved for low and intermediate-risk categories and smaller tumors. Shorter warm ischemia times, lesser postoperative complications, lower blood losses, and duration of postoperative stay have been observed with RAPN (when compared to LPN approaches).

Although minimal tumor-free margins have been recommended to prevent recurrences, positive tumor margins (irrespective of the technique employed) have been demonstrated in 1 – 6 % cases.

Robotic approaches have been associated with a shorter hospital stay, lower volume of perioperative blood loss, better postoperative pain control, and faster time to recovery.

Most international guidelines recommend a cytoreductive approach in patients known to have tumors limited to the primary site without any significant metastatic spread. A cytoreductive approach may also be the preferred treatment option in patients with metastatic disease who have received multiple systemic targeted approaches earlier.

Radical Nephrectomy   [82]

Radical nephrectomy involves removing the entire kidney, perirenal fat, suprarenal glands, and regional lymph nodes. Adrenal sparing surgery can be attempted in inferior pole tumors less than 5 cm in size. Regional lymph node dissection can be performed in those with lymph node involvement demonstrated on CT scan or on the table (during the procedure). While the open approach remains the gold standard for the treatment of more complex cases, stage 1 and 2 tumors may be treated radically with a traditional laparoscopic approach. The robotic approach has also been positioned as a viable alternative in patients with venous tumor thrombosis.

Adrenalectomy, Venous Thrombectomy and Lymph Node Dissection   [83] [84] [85] [86] [87]

Adrenalectomy, which was considered a mandatory component of radical procedures, can now safely omitted if no macroscopic disease is diagnosed at the time of preoperative workup or surgery. Lymphadenectomy has shown a survival advantage only in intermediate and high-risk patients.

There is no proven role for sentinel node biopsy. Data on the utility of lymphadenectomy in this setting are not definitive. While lymphadenectomy may have a role in the staging of large tumors, there are no guidelines for its use as a salvage procedure. 

Surgical management has been advised in the management of venous thrombosis involving the renal vein and inferior vena cava. Caval thrombectomy may be safely performed along with radical nephrectomy for the management of tumors with thrombus that does not extend beyond the diaphragm. The extent of resection is decided primarily by the extent of the tumor at the time of operation. A minimum modification of the operative procedure may be warranted when the thrombus is confined to the renal vein; however, dissection involving the vena cava, mobilization of the right atrium, opening up of the right atrium, and cardiopulmonary bypass may be necessary with more extensive involvement. Complete vascular control, prevention of tumor embolization, stringent hemodynamic monitoring, and ensuring ready availability of tissues for caval replacement and venous bypass, if required, are strict urological principles, which need to be adhered to while performing surgical nephrectomy and thrombus removal. 

Localized Disease Treatment According to Tumor Stage   [60] [88]

T1 Tumors (less than 7 cm) – Partial nephrectomy is the treatment of choice. A long term cancer-specific survival equivalent to partial nephrectomy has been demonstrated for minimally invasive approaches but at a slightly higher rate of recurrence. Active surveillance is indicated in elderly patients with short life expectancy or significant comorbidities and solid renal tumors measuring less than 40 mm.

T2 Tumors (more than 7 cm): Laparoscopic radical nephrectomy is the preferred treatment option.

T3 and T4 Tumors (Locally Advanced RCC) – Open radical nephrectomy is the treatment of choice, though laparoscopic approaches have been gaining momentum.

Adjuvant Approaches

Adjuvant Treatment  [89]

A pooled analysis of various trials using Sunitinib (S-TRAC, ASSURE), Sorafenib (ASSURE), and pazopanib (PROTECT) in the adjuvant setting have failed to show any benefit in disease-free survival or overall survival in those with intermediate/high-risk local disease or those who have undergone complete resection for localized renal cell carcinoma. It is found that the use of high dose adjuvant treatment in high-risk disease may be associated with favorable disease-free survival, at the risk of incurring higher grade adverse effects.

Neoadjuvant Systemic Targeted Therapy   [90] [91]

Targeting venous tumor thrombi with an attempt to reducing their size and making them amenable for resection is an approach that is yet to find any favor. It has been a purely experimental approach and cannot be recommended outside of a clinical trial setting.

Surveillance After Definitive Treatment   [92]

Solitary Renal Masses

The American urological association recommends surveillance at baseline, abdominal imaging at three to twelve months after partial or radical nephrectomy, annually for three years following partial nephrectomy. Chest imaging is also suggested annually for three years if indicated.

Metastatic Disease

Immunomodulatory Agents   [93] [94] [95]

The immunogenic nature of RCC is supported by the year for three years after the act that spontaneous tumor regression has been reported. The role of the immune system in the pathogenesis is supported by the presence of multiple infiltrates consisting of immune cells. The mechanisms proposed to be underlying the action of these drugs include T cell-mediated immune regression, due to an increase in lymphocyte proliferation, cellular killing mediated by lymphocytes, and killer cells, which have been activated by lymphokines. Immune modulating drugs approved in the treatment of metastatic renal cell carcinoma include aldesleukin and Interleukin 2.

Nephrectomy   [96]

The beneficial effects of surgical extirpation have been attributed to a reduction in the tumor burden, a direct immunomodulatory effect (attributed to the reduction in immunosuppression), and the creation of an inhospitable tumor microenvironment, due to iatrogenic chronic metabolic acidosis.

Targeted Therapy

Sunitinib   [97] [98]

It inhibits multiple receptor tyrosine kinases, including VEGFR 1, 2, 3, PDGRF alpha, beta, c-kit, FLT-3, and RET. It is an orally administered drug with a half-life of 40-80 hours and a bioavailability of 50 percent. A single daily dose of 37.5 mg is administered for four weeks, followed by a drug holiday for two weeks. It is metabolized by the cytochrome 3a4 enzyme system in the liver, the active drug—excreted in the urine and feces. FDA and EMA approved in 2006. Sunitinib was approved in 2007 for use in low, intermediate, and high-risk groups as a first-line treatment option for advanced, metastatic disease.

Sunitinib has also shown benefit as a treatment option after progression on VEGF targeting agents. It has been studied in case of progression following sorafenib, and re-challenge following progression on multiple first-line settings.

ESMO magnitude of clinical benefit scale ranking of  4.

Sorafenib   [98] [99]

It inhibits multiple receptor tyrosine kinases, including VEGFR 1, 2, 3, PDGFR beta, c-kit, FMS like tyrosine kinase 3, rearranged upon transfection, and rapidly accelerated fibrosarcoma kinase. While c-kit, FLT Kinase 3, and RET are located upon the cell surface, Raf is an intracellular enzyme (common to all receptor tyrosine kinase pathways). REA disruption of the signal transduction, with inhibition of transcription of various proteins, due to inhibition of the intracellular phosphorylation pathways including the Raf/MEF/ERK and the PI3K/m TOR/AKT pathways is also observed. The anti-angiogenic effect of sorafenib is attributed to its effect on angiogenesis and lymphangiogenesis, which is mediated via the VEGFR 1,2 (angiogenesis) and 3 (lymphangiogenesis), respectively. Inhibition of the Platelet-derived growth factor receptor on the surface of the pericytes and smooth muscle cells also contribute to this effect.

Sorafenib is administered orally in a dose of 400 mg twice daily, with an oral bioavailability of 92 percent. More than 9.5 percent of the drug is protein bound to albumin and alpha 1 acid glycoprotein. It is mainly metabolized to an N oxide metabolite by the Cytochrome p 450 enzyme system. The elimination half-life of the molecule is between 20 to 39 hours. Excretion of the glucuronide metabolite occurs via the urinary and the fecal routes.

ESMO magnitude of clinical benefit scale ranking of 4.

Lenvatinib   [98] [100]

Multitargeted receptor tyrosine kinase inhibitor inhibits VEGFR 2, fibroblast growth factor receptor 1, 2, 3, 4, PDGFR alpha, c kit, and RET. FGFR inhibition, which is unique to lenvatinib (compared to sunitinib and sorafenib), provides an additional mechanism of inhibition of angiogenesis. It is administered in oral form in a dose of 24 mg daily, with an oral bioavailability of 90 percent. It has hepatic and renal metabolism and is excreted in the bile. Demethylated (M2) metabolite is mainly excreted via the urinary and fecal routes.

Axitinib   [98] [101] [102] [101]

It is a multitargeted receptor tyrosine kinase inhibitor, which inhibits VEGFR 1, 2, 3, PDGFR alpha and beta, and c-kit—administered orally in a dose of 5 mg twice daily, with a bioavailability of 58 percent. Metabolized, primarily in the liver, has a half-life of 2.5 to 6 hours and excreted in the urine (less than 1 percent). Approved for use in the second-line setting by the FDA and EMA in 2012.

ESMO Magnitude of clinical benefit scale ranking of 4.

Pazopanib   [98] [103]

A multi-target receptor tyrosine kinase inhibitor which inhibits VEGFR, PDGFR, FGFR, and c-kit. Administered orally in a dose of 800 mg per day, with an oral bioavailability of 21.4 percent (13.5 to 38.9 percent). 99.9 percent protein-bound, mostly to albumin and, to a lesser extent, to alpha1 acid glycoprotein. Mainly excreted unchanged through the feces as the parent compound (in an unchanged form). A minor fraction (2.6 percent) is excreted via urine.

ESMO magnitude of clinical benefit scale ranking of 3.

Cabozantinib   [98] [104] [105]

It is a multitargeted receptor tyrosine kinase inhibitor that inhibits VEGF, AXL, and MET kinase receptors. AXL and MET receptors have been postulated to be responsible for resistance to VEGF targeted therapy. Granted FDA and EMA approval for patients with progression on first-line VEGF targeted therapy. The inactivation of the Von Hippel Lindau gene leads to the activation of various angiogenic pathways, which may be blocked specifically by cabozantinib. The substrate of cytochrome P 450 enzyme system 3A4, predominantly metabolized in the liver.

It is administered in a daily oral dose of 140 mg, with a predicted half-life of 55 hours.

Chemotherapy   [106]

The role of cytotoxic chemotherapy remains poorly defined. Cytotoxic chemotherapy is usually indicated in sarcomatoid and collecting ducts variants of RCC. 

Chemotherapy Plus Targeted Therapy   [107]

Targeted agents may also enhance the delivery of cytotoxic chemotherapy to the local site by reversal of the hypoxic tumor micro-environment and normalization of the tumor vasculature. Various agents used in combination with TKI’s, include fluoropyrimidines, gemcitabine, capecitabine, and thalidomide. However, none have demonstrated an unequivocal clinical benefit that would warrant any change in the standard of care.

Metronomic Chemotherapy   [108]

Targeted agents have been used in combination with low dose cytotoxic chemotherapy to reduce the toxic effects of treatment. Metronomic dosing has been used to enhance the anti-angiogenic effect of targeted therapy by preventing the recruitment of endothelial progenitor cells derived from bone marrow to the tumor vasculature. Though this approach to treatment (a combination of weekly gemcitabine, daily capecitabine with sorafenib) has been associated with partial response in 50 percent of patients, however, the findings have not been replicated.

Immunotherapy   [109] [110] [111]

PD – 1 is a type 1 transmembrane glycoprotein, which belongs to the CD28/CTLA-4 family of immune checkpoint inhibitors, whose expression has been shown to increase in response to immune stimulation/antigenic stimulation. Haematopoetic stem cells, T lymphocytes, B – lymphocytes, natural killer cells, dendritic cells, monocytes, and macrophages are known to express PD-1.

Anti PD 1 directed therapy (nivolumab) and immune checkpoint inhibition (anti cytotoxic T lymphocyte antigen 4) in the form of ipilimumab has been found to show beneficial outcomes in renal cell carcinoma. The checkmate 025 trial, a phase 3 trial, which compared nivolumab with everolimus, demonstrated an improvement in overall survival with the use of nivolumab. The patient population in this trial consisted of locally advanced or metastatic renal cell carcinoma, who had progression of disease after treatment with at least one VEGF/VEGFR inhibitor (targeted therapy). A higher rate of long term durable responses and a higher overall response rate was also seen in the nivolumab arm. An improvement in overall survival, response rate, and a complete response rate of 10 percent was observed in intermediate and poor-risk patients in a phase 3 trial with the use of combination treatment with ipilimumab and nivolumab when compared with the sunitinib arm. While patients with intermediate and low-risk profiles had a better response to combination therapy with nivolumab and ipilimumab, those with poor prognosis had a more favorable response with sunitinib.

Combination Therapies with Immune Checkpoint Inhibitors

Immune Checkpoint Inhibitors with Anti-Angiogenic Agents [112] [113]

Anti-angiogenic agents have been shown to enhance tumor-related immune suppression by leading to a decrease in immunosuppressive cells such as myeloid-derived stem cells and regulatory T cells, cytokines (TGF beta and IL -10), and decrease in the PD -1 expression on T cells.

The IM Motion 150 study evaluated the role of combination treatment with atezolizumab (anti-PD-L1)  and bevacizumab against a comparator arm consisting of atezolizumab or sunitinib and demonstrated an improvement in progression-free survival and higher overall response rate. A PDL1 expression in excess of 1 percent was used to define PD L1 positivity. A longer PFS and higher ORR were observed in this subset of patients in the atezolizumab monotherapy arm.

The JAVELIN Renal 101 and Keynote 426 have demonstrated improved outcomes in previously untreated patients with advanced RCC with the use of avelumumab and axitinib or pembrolizumab and axitinib when compared to sunitinib alone.

Recognition of potential driver mutations in deciding the choice of the therapeutic option. [114] [115]

VHL and PRBM1 mutant tumors, which are known to be associated with an immune as well as an angiogenic signature, will be expected to benefit from immune checkpoint inhibitor therapy as well as VEGF targeted therapies. Whereas, tumors that possess a loss of BAP 1, which is associated with a decrease in an angiogenic profile, are expected to respond better to immune checkpoint blockade.

Resistance Strategies to Targeted Agents [116] [117]

Vaccines that have been studied in combination with targeted agents include AGS-003, which is a dendritic cell vaccine, prepared with amplified tumor RNA, which has the potential to augment the immune response against the tumor. IMA 901 is another potential vaccine candidate that underwent an evaluation in a phase 3 trial and consists of a combination of HLA class I and ii tumor-associated peptides but did not demonstrate a clinically significant increase in tumor response, which could be expected to translate into a favorable clinical outcome.

Surgery   [7] [118]

Surgery of resectable metastases has been advised for solitary metachronously arising lesions as long as it is possible to obtain an R0 resection. Resection of the primary tumor has also been shown to be beneficial in those with synchronous metastasis, in those with a favorable performant status (Eastern cooperative oncology group 0-1).

Radiotherapy   [119] [120]

Radiotherapy might be an alternative in patients who do not opt for surgery or in those in whom a complete (R0) resection might not be possible. Various approaches that have been employed include stereotactic radiosurgery (stereotactic irradiation delivered over single or multiple sessions) and high dose external beam radiotherapy. Stereotactic irradiation can also be used in the management of bone and brain metastasis.

First-Line Therapy   [60]

Good risk disease - standard care - sunitinib, pazopanib, interferon and bevacizumab, tivozanib. Other options include high dose interleukin 2, bevacizumab, and low dose interferon.

Intermediate risk disease – standard care – nivolumab, and ipilimumab. Optional treatments include sunitinib, pazopanib, cabozantinib, tivozanib, a combination of bevacizumab, and interferon.

Poor risk disease – standard care – nivolumab and ipilimumab, optional treatments include cabozantinib, sunitinib, pazopanib, and temsirolimus. 

Second-Line Treatment   [60]

Treatment options depend upon the initial treatment that was used in the frontline setting, either a tyrosine kinase inhibitor or immunotherapy with a combination of nivolumab and ipilimumab.

If a tyrosine kinase inhibitor was used in the first-line setting, the standard options include nivolumab, cabozantinib. Other optional treatments include axitinib, everolimus, or a combination of lapatinib and everolimus.

If the combination immunotherapy regimen of nivolumab and ipilimumab was used in the frontline setting, the following treatment recommendations need to be considered – Any Tyrosine kinase inhibitor or a combination of lenvatinib and everolimus.

Third Line Treatment   [60]

Treatment options depend upon the drugs used in the first line and the second line setting

Those who have received treatment with first-line TKI and second-line nivolumab should be considered for standard therapy with cabozantinib.

Those who have received treatment with first-line TKI and second-line cabozantinib should be considered for standard treatment with nivolumab.

Those who have received treatment with first-line TKI and second-line TKI should be considered for standard treatment with either nivolumab or cabozantinib.

Those who have received treatment with first-line nivolumab and ipilimumab and second-line TKI should be considered for standard treatment with another TKI or everolimus.

Recent Update [121]

In an update published in February this year, the European society of medical oncology has endorsed the use of combination therapy with pembrolizumab and axitinib as the frontline therapy for treatment naïve advanced disease, based upon the results of the Keynote 426 trials, where this combinatorial therapy was compared with sunitinib, irrespective of the IMDC subgroup and the PD-L1 biomarker status. While the same update also makes a recommendation in favor of the use of ipilimumab and nivolumab in the intermediate and low-risk settings after analysis of the long term survival results (32 months), VEGF targeted tyrosine kinase inhibitor treatment is recommended after progression on PA/IN combinatorial regimens. Targeted therapy is also indicated in situations where the above mentioned combinatorial therapy cannot be used or is contraindicated.

Response Assessment   [60]

Response assessment CT scans are recommended 3 – 6 monthly in those with high risk for the first two years, a yearly CT scan is recommended in high-risk patients. A 2-4 monthly CT scan is recommended for response assessment in those receiving targeted therapy. The beneficial effect of a long term follow up is yet to be demonstrated.

Although the RECIST criteria (response evaluation criteria in solid tumors) have been used to calibrate the response to treatment, its clinical utility in prediction of changes that require dose modification or discontinuation and valid clinical endpoints is still a matter of debate.

Palliative Medicine   [60]

Management of adverse effects of chemotherapy, symptom directed treatment, counseling regarding goals of care, prognostication, management of cancer-associated syndromes (such as complex cancer pain syndromes, malignant bowel obstruction, metastatic spinal cord compression, pathological fractures, hypercalcemia, hyponatremia), medical symptoms in advanced cancer and provision of good end of life care are considered within the ambit of palliative medicine.

Specialized palliative medicine might include a dissection of various ethical dimensions of decisions concerning continuation and cessation of treatment, nutrition, and hydration in advanced cancer, provision of palliative sedation in the management of refractory symptoms, and end of life care.

Discussions pertaining to organ donation and withdrawal of treatment (provision of passive euthanasia) should also be considered the domain of specialized palliative medicine.

In the setting of the SARS Cov -2 pandemic, telemedicine and counseling of families of patients who are expected to have a limited life expectancy and may not be put on artificial ventilation also become the valid agenda of a palliative medicine consultation-liaison.  

Management of metastasis to the central nervous system:

Brain Metastasis   [122]

Recursive partitioning analysis and graded prognostic assessment are used to prognosticate patients with brain metastasis. Available treatment options include the use of stereotactic brain radiotherapy, whole-brain radiotherapy, and supportive management in the form of decompressive medical therapy using mannitol, glycerol, or carbonic anhydrase inhibitors such as acetazolamide. Corticosteroids, tapered according to the symptoms, also form an important component of medical decompressive therapy.

Metastatic Spinal Cord Compression   [123] [124]

Various prognostication systems include the ASIA, and the Frankel scoring systems, are used to assess the severity of involvement. Treatment modalities include long course, short course external beam radiotherapy, bone-targeted agents, and corticosteroids. Surgical treatment might also be considered for patients with a single level metastasis or the presence of a bony fragment impinging upon the cord.

Metastatic Bone Disease [125]

External beam radiotherapy and the use of bone-targeted agents have been recommended for palliation of symptoms and prevention of skeletal-related events (with an increase in time to first skeletal-related event). The Mirels scoring system is used to calculate the risk of development of a pathological fracture.

Among the bone-targeted agents used bisphosphonates and a monoclonal antibody against the RANKL (receptor activator of nuclear factor kappa beta ligand), denosumab has been used. While zoledronic acid is the most commonly used bisphosphonate, used in a frequency ranging from monthly (in those with prior history of skeletal-related events) to three monthly, denosumab can be used in dosing of 120 mg monthly subcutaneously.

Emerging and Future Immunotherapy Targets

Several combinatorial strategies have been proposed to have shown promise in the development of future therapeutic strategies against tumors that show resistance to currently available strategies. The Ang/Tie 2 pathway is thought to be responsible for basal angiogenesis and vascular stability following vascular endothelial growth factor blockade. [126]  Inhibitors such as trebananib, which block this novel pathway, may have a role in combination with VEGF blockade. [127]  ALK 1 inhibitors such as dalantercept, may have a role in interfering with the formation of the vascular bed. [128]  Dual mTOR c1/c2 inhibitors may be a potential therapeutic option since the existing therapies only target them on the TOR c1 pathway. [129]

Inhibitors targeting hypoxia-inducible factor 2 and aberrant glycolysis, aberrant glutamine, and tryptophan metabolisms such as CB 839 (glutamine metabolism) indoleamine 2.3 dioxygenase inhibitor, are being developed with an intent to lead to potential additional benefit. [130] [131]  It has been suggested that the relationship between the tumor and it’s immune micro-environment needs to be studied further, with the intent to developing beneficial combinatorial therapy options.

Other approaches being studied include personalized vaccination, targeted radiotherapy to enhance immune responses, cytoreductive surgery following systemic therapy, and immunotherapy or targeted therapy in the neoadjuvant setting. [132] [133]  Several molecules that are being investigated as potential targets include chemokine receptors, lymphocyte activation gene – 3, OX -40 (CD 134), B and T lymphocyte attenuator (BTLA), and V-domain containing immunoglobulin containing suppressor of T – lymphocytes activation, soluble. [134]

• Differential Diagnosis

Abscess, metastasis from a distant primary lesion, metastatic melanoma, renal cyst, renal infarction, sarcoma, renal angiomyolipoma, renal oncocytoma, and lymphoma form close differentials of a renal mass. [41]

Chromophobe renal cell carcinoma, oncocytoma, clear cell tubulopapillary carcinoma, multilocular cystic renal cell carcinoma, adenoma, and MIT family transitional renal cell carcinomas are close histopathological differentials. [135] [136] [135]

Renal Angiomyolipoma  [137] [19]

The most common benign renal tumor, mostly sporadic, may be associated with tuberous sclerosis and lymphangioleiomyomatosis. Those with tuberous sclerosis have a larger size, are bilateral, multicentric, and symptomatic. These are mostly seen in females in the middle age. Usually asymptomatic, though, larger tumors may be associated with an increased propensity to cause hemorrhage. The presence of macroscopic fat is pathognomonic, though 15 -30 percent of tumors associated with tuberous sclerosis may be lipid deficient. On MRI, low T2 intensity is shared by lipid poor AML and clear cell renal carcinoma. Compared to hypovascular clear cell tumors, AML’s are usually hypervascular. Larger tumor size, calcification, and intratumoral necrosis favor a diagnosis of renal cell carcinoma.

Another clear cell mimic seen in these patients with tuberous sclerosis is AML with epithelioid features.

Renal Oncocytomas  [138]

It is the second most common renal benign tumor after AML. There remains a strong body of opinion that oncocytoma cannot be reliably distinguished from renal cell carcinoma based on radiological features alone, although parameters such as corticomedullary phase TCR, nephrogenic phase TCR higher than a corticomedullary phase TCR, CT de-enhancement characteristics have been proposed as features capable of characterizing this tumor.

Renal Lymphomas  [139]

The presence of a cystic component, vascular extension into the renal vein or inferior vena cava, and calcification are features considered to be atypical for lymphoma and point towards a diagnosis of renal cell carcinoma.

The American Joint Committee on Cancer staging/UICC classification system is used for staging. [140]

While the stage, size, necrosis score is used in localized RCC, the Memorial Sloane Kettering score or the Motzer score is the standard prognostication system used in advanced/metastatic cancer. [141]

The new targeted therapies have led to the up-gradation of these criteria and the development of the international metastatic RCC database consortium criteria or the Heng score, which consists of the Karnofsky performance score (lower than 80 percent), hemoglobin (lower than normal lower limit), time from diagnosis to treatment (less than one year), corrected calcium (higher than 10 mg per dl), platelets and neutrophils (both higher than the normal upper limit). [142] [143]

Inflammatory Markers  [144] [145] [146]

Increasing evidence is supporting the role of inflammation in determining prognosis in renal cell carcinoma. Local immune responses and systemic inflammation have been shown to play a central role in the initiation, maintenance, and progression of the cancer process. The pathogenic role of neutrophils, lymphocytes, and monocytes in promoting intravasation of tumor cells, thereby promoting angiogenesis and allowing the propagation of distant metastasis, associated with a poorer outcome, has also been recognized. The degree of systemic inflammation can be assessed by measuring the C – reactive protein levels (which has the drawback of not having a specific cut off value) and ratios involving various blood components, including the neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR) and measures such as the prognostic nutritional index (PNI), systemic immune inflammation index (SIII) and systemic inflammation response index (SIRI). An NLR more than equal to 4 has been associated with poor outcomes.

Laboratory Parameters  [147] [22]

Variables that have been used to determine response to targeted therapy include hematological (serum hemoglobin, absolute neutrophil count, platelet count), biochemical (serum corrected calcium), functional parameters (Karnofsky performance status), and time from time of diagnosis to beginning of treatment. Morphological features that are known to predict survival include the size of the tumor, stage at presentation, degree of vascular invasion, the extent of tumoral necrosis, and grade. Biomarkers proposed to guide individualized treatment include clinical parameters such as blood pressure, endogenous substances such as proteins present in the plasma, and pathobiological features such as specific mutations.   Failure to obtain a clinically beneficial response with radiotherapy, metastasis at multiple sites, sarcomatoid differentiation, neutrophilia, thrombocytosis, and elevated alkaline phosphatase has also been identified as potential prognostic factors from various studies. High serum interleukin 6 levels above 35 pg/ml and adverse prognosis on the modified Glasgow prognostic score also correlates with poor survival.

Nomograms  [148] [149]

Among the various nomograms which have been used to decide upon the modality of treatment, the following deserve mention – the university of California Los Angeles (UCLA) integrated staging system and stage, size, grade, necrosis (SSGN) score which integrate the clinical TNM stage and Fuhrmann grade, among other variables. The Memorial Sloane – Kettering cancer center score, which comprises of the following parameters – Karnofsky performance status, history of prior nephrectomy, lactate dehydrogenase levels, hemoglobin level, and serum calcium levels has been used to predict survival in those with advanced disease who have undergone treatment with immunotherapy or chemotherapy.

Motzer Score  [150]

Prognostic assessment in metastatic RCC includes the Motzer score, which requires estimation of laboratory parameters such as hemoglobin, total leucocytes, platelet counts, lactate dehydrogenase, and corrected calcium levels. While the survival for those with a favorable risk profile has been estimated to be 43.2 months, those with intermediate and unfavorable risk profiles have a survival corresponding to 22.5 and 7.8 months, respectively.

Clinical Features  [151] [152] [151]

Hypertension is associated with improved progression-free survival and overall survival in those receiving targeted therapy with multi-target tyrosine kinase inhibitors.

Histopathological Features  [153] [50]

The histopathological prognostic features which have been validated by the International Society of urological pathology and WHO classification of RCC include histological subtype of the tumor, the ISUP nucleolar grade (in preference to the Fuhrmann grade), sarcomatoid or rhabdoid differentiation that defines a stage 4 tumor (nonclear cell RCC), presence of necrosis, presence of microscopic vascular invasion, pathological tumor, node, metastasis staging, and description of the nonneoplastic renal tissue. Among morphological features, large size, intralesional necrosis, renal vein thrombosis, retroperitoneal collateral vessels, and interruption of the tumor capsule have been associated with high tumor grade.

The presence of sarcomatoid change and extensive necrosis is usually associated with a poor prognosis. While most clear cell carcinomas are not associated with an intense inflammatory response, those that show a dense lymphocytic or neutrophil rich infiltrate are usually associated with a poor prognosis . Cystic change in clear cell RCC has been associated with a favorable prognosis.

Multilocular clear cell RCC has been associated with an indolent course and uniformly excellent survival. Nodal invasion usually points towards a poor cancer-specific survival, nearing 20 to 30 percent after three years of surgery.

Radiological Features  [154]

CT perfusion might also be useful in prognosticating the tumor as a higher microvascular density has been associated with a better outcome.

Genetic Markers  [155]

There has been a move towards studying genetic markers, with the potential to impact treatment in the metastatic setting. RECORD 3 trial, a randomized phase 2 trial in the metastatic setting, which compared sunitinib with everolimus in the showed that BAP 1 mutations have the potential to impact progression-free survival. Molecular profiling based upon BAP1 and PBRM1 or KDM5C has been advised, with the potential to impact clinical outcomes. Activation mutations of m TOR and biallelic inactivation of TSC1 and TSC2 have been identified as potential biomarkers for assessing long term response in case-based mTOR inhibitor outlier studies.

Immune Markers  [156]

PD-L1 expression, which has been associated with increased aggressiveness and increased lymphocyte density in the tumor microenvironment, have also been identified with potential prognostic factors that might be used to determine responses to immune checkpoint inhibitor therapy.

The potential disadvantage with the use of PD-L1 lies in the heterogeneous expression of this biomarker between the primary tumor and the metastatic sites.

• Complications

Complications of Surgery

Radical Nephrectomy

Common complications reported with radical nephrectomy include hemorrhage, wound infection, seroma, wound disruption, seroma, pneumothorax, sepsis, ileus, cardiac failure, renal events, peritonitis, perihepatic collection. [157]

Complications According to the Site of Metastasis

Metastatic bone disease may present with skeletal-related events such as pathological fractures, hypercalcemia, metastatic extradural spinal cord compression. [158]

Intracranial metastases may present with altered sensorium, signs of raised intracranial tension such as headache, blurring of vision, early morning nausea, and vomiting. Physical examination may demonstrate papilledema (on Ophthalmoscopy)  [159] .

Specific Side Effects of VEGF Targeted Therapy  [160]

The median time to onset of hypertension in a study of 1120 patients treated with multitargeted receptor tyrosine kinase inhibitors was 29 days after the initiation of therapy. Pre-existing hypertension, a body mass index above 25 and age more than 60 years, were identified as potential risk factors in developing hypertension.

  Renal Disease with Multitargeted RTK Therapy [161]

Proteinuria was shown to occur with 18.7 percent. In contrast, high-grade proteinuria was shown to have an incidence of 2.4 percent, in an analysis of 33 trials of patients with solid tumors treated with TKI’s. An analysis of biopsy specimens revealed podocytopathies such as minimal change disease and focal segmental glomerulosclerosis. Tyrosine phosphorylation of nephrin has been postulated as the mechanism underlying the development of glomerular disease.

• Consultations

Multidisciplinary care is needed in the management of clear renal cell carcinoma.

• Nephrologist
• Radiologist
• Pathologist
• Surgical oncologist
• Deterrence and Patient Education

Patients must consult a urologist whenever they detect any hematuria, abdominal mass, or flank pain. The interprofessional team should ensure that the patients are well informed about renal cancer. Patients should be informed about educational websites to help them better understand this malignant neoplasm, its outcome, and its treatment. Patient education helps in the deterrence of the processes that can cause renal cancer. Specialty-trained nurses often do this. For instance, advise the patient to stop smoking since renal cancer is linked to tobacco.

• Enhancing Healthcare Team Outcomes

Discussion about the chosen modality of surgery should involve a core multidisciplinary team consisting of specialists from medical oncology, surgical oncology, radiation oncology, radiology, interventional radiology, and nursing. Specialists from nuclear medicine, geriatric oncology, oncology pharmacy, psycho-oncology, and palliative medicine usually form a part of the extended MDT. The presence of a nephrologist in the MDT may be necessary, given the risk of development of chronic kidney disease post-surgery, and given the common adverse effects of targeted therapy, like hypertension (and it’s potential to impact residual renal function). [162]

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Disclosure: Rahul Arora declares no relevant financial relationships with ineligible companies.

Disclosure: Faten Limaiem declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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RICHARD E. GRAY, DO, AND GABRIEL T. HARRIS, MD

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2019;99(3):179-184

Related editorial: Stumbling onto Cancer: Avoiding Overdiagnosis of Renal Cell Carcinoma

Author disclosure: No relevant financial affiliations.

Kidney cancer is one of the 10 most common cancers in the United States with 90% being attributed to renal cell carcinoma. Men, especially black men, are more likely to be affected than women. Renal masses, either cystic or solid, are best detected with contrast-enhanced, triple-phase computed tomography. Renal tumors are often detected incidentally during a computed tomography scan of the abdomen or chest that was ordered for unrelated symptoms. Hematuria serves as a warning sign that necessitates further evaluation and imaging leading to a diagnosis and treatment plan. Treatment options include active surveillance, ablation, nephron-sparing tumor excision, nephrectomy, and systemic treatment. Predictors of a poor prognosis include poor functional status and metastasis. In recent years new therapies have improved the prognosis for patients with metastatic disease. The family physician should be aware of risk factors (e.g., hypertension, tobacco use, exposure to trichloroethylene, familial syndromes) and lifestyle and dietary modifications that may reduce risk.

Kidney cancer is one of the 10 most common cancers in the United States. 1 Renal cell carcinoma accounts for 90% of all kidney cancers. 2 Death attributed to renal cell carcinoma accounted for 2% of all cancer deaths or approximately 14,000 persons in 2016. 1 , 2 Men are diagnosed with renal cell carcinoma at almost twice the rate of women, and there is a greater prevalence in black men. 3 Most cases are diagnosed between 60 and 70 years of age. 1 , 2

Renal cell carcinoma is classified in three major histological subtypes: clear cell (75%), papillary (15% to 20%), and chromophobe (5%). 4 Disease-specific survival is worst with clear cell renal cell carcinoma as it tends to be discovered at a more advanced stage. 5

Risk Factors

Risk factors for renal cell carcinoma include hypertension, tobacco use, obesity, and acquired cystic kidney disease in the setting of end-stage renal disease. 1 , 3 , 6 Occupational exposure to trichloroethylene can lead to the development of renal cell carcinoma and increased mortality from renal cell carcinoma. 5 , 7 – 9 The International Agency for Research on Cancer labels trichloroethylene as carcinogenic to humans and specifically associates it with renal cancer. 10 Occupational exposure to trichloroethylene is most commonly encountered by mechanics, dry cleaners, oil processors, polyvinyl chloride manufacturers, and low-nicotine tobacco producers. 8

There are 10 familial syndromes that confer greater risk of developing renal cell carcinoma. 11 The most common of these is von Hippel-Lindau disease which leads to the development of clear cell renal cell carcinoma through the activation of vascular endothelial growth factor (VEGF). 11 Approximately 60% of sporadic clear cell renal cell carcinomas follow the same pathogenesis. This discovery has led to the development of new therapies that inhibit VEGF receptors and are being used to treat heritable and sporadic cases of clear cell renal cell carcinoma. 11 , 12

Screening and Prevention

Screening for renal cell carcinoma is not recommended, except in the setting of a known heritable syndrome associated with the development of renal cell carcinoma. 1 The management of hypertension and obesity, and the avoidance of tobacco use are the only established methods of primary prevention. 8 Evidence from prospective and observational studies suggest that consuming fatty fish (relative risk [RR] = 0.56; 95% confidence interval [CI], 0.35 to 0.91), three or more servings of fruits and vegetables (RR = 0.68; 95% CI, 0.54 to 0.87), and one alcoholic beverage daily (RR = 0.76; 95% CI, 0.68 to 0.85) may reduce the risk of developing renal cell carcinoma. 5 , 13 – 15

Clinical Presentation

More than 50% of patients with renal cell carcinoma are asymptomatic and diagnosed incidentally during thoracoabdominal imaging ordered for unrelated issues. 5 , 16 The history and physical examination triad of gross hematuria, flank pain, and palpable abdominal mass is now an uncommon presentation, and is associated with advanced disease. 6 , 12 , 16 Nonreducing or isolated right-sided varicocele and bilateral lower extremity edema can also be symptoms of advanced disease through occlusion of the right testicular venous system that drains directly to the inferior vena cava [ corrected ]. Similarly, bilateral lower extremity edema can occur from tumor occlusion of the inferior vena cava. Approximately 20% of patients present with paraneoplastic disease, manifested by hypertension, hypercalcemia, and polycythemia. 5 Fever, weight loss, cough, adenopathy, and bone pain may indicate metastatic disease.

CLINICAL EVALUATION

An isolated right-sided varicocele and nonreducing bilateral varicocele should be evaluated with abdominal imaging. Gross hematuria requires computed tomography (CT), urography, and urology consultation for cystoscopy. 17 Signs of paraneoplastic or metastatic disease require evaluation for malignancy, including chest and abdominal imaging.

LABORATORY EVALUATION

Hematuria should be diagnosed by microscopic examination that shows three or more red blood cells per high-powered field, not by urine dipstick alone. The urine should be without pyuria or red blood cell casts, which indicates infection or glomerulonephritis, respectively. If asymptomatic microscopic hematuria is detected, management is recommended per American Urological Association guidelines ( Figure 1 ) . 17 , 18 Benign causes should be ruled out, including infection, recent vigorous exercise, menstruation, and instrumentation. Identified causes should be treated and a repeat urinalysis should be obtained. Further laboratory evaluation includes assessment of urinary sediment, creatinine, C-reactive protein, hemoglobin, erythrocyte sedimentation rate, alkaline phosphatase, and serum calcium. 7 Routine urine cytology is not recommended for the initial evaluation of asymptomatic microscopic hematuria. 17 Patients 35 years or older who have asymptomatic microhematuria should have cystoscopy and imaging with multi-phasic CT urography performed. 17

A contrast-enhanced, triple-phase helical CT scan that images the urinary tract before, during, and after contrast load is the preferred imaging study for evaluating renal masses or persistent microscopic hematuria. 19 , 20 CT detects 90% of renal masses, identifies benign and pathologic features, and evaluates surrounding anatomy to detect lymphadenopathy or an associated thrombus. A contrast-enhanced CT scan will also identify benign masses that do not require further testing.

The Hounsfield unit scale measures a tissue's density or attenuation. Fat has very low attenuation (i.e., −100 to −10 HU), and masses containing fat are almost always benign angiomyolipomas. Homogeneous masses with low attenuation (−10 to +20 HU) can be identified as benign, fluid-filled, simple cysts. Masses with attenuation greater than 20 HU, heterogeneous appearance, septations, or calcifications, may be malignant and require further evaluation 21 ( Figure 2 ) . The differential diagnosis of renal masses is included in Table 1 . 22

For incompletely characterized masses or contraindications to CT, magnetic resonance imaging with and without intravenous contrast is recommended. 21

The management of cystic lesions should be guided by the Bosniak classification system ( Table 2 ) . 21 Shared decision-making between the urologist, the family physician, and the patient is recommended when deciding on a course of treatment. The tumor's stage and characteristics as well as the patient's baseline health and patient preferences should be considered ( Table 3 23 , 24 ) .

Solid tumors are managed according to size. Masses measuring less than 1 cm are observed, and masses greater than 1 cm are usually excised or biopsied. There is an increasing role for renal mass biopsy, instead of partial or radical nephrectomy, because active surveillance is a treatment option for renal cell carcinoma. However, a biopsy has an increased risk of false-negative results. The risk of metastatic spread of cancer cells related to a biopsy is rare and should not preclude the use of biopsy to help clarify a diagnosis and guide treatment. Twenty percent of large (greater than 3 cm) solid masses discovered incidentally will be benign. 5 Metastatic potential increases significantly when the mass is 4 cm or greater. If there is concern for metastatic disease, radiography or CT scan may be necessary based on other risk factors. 5 , 23

INDICATIONS FOR REFERRAL

A urology consultation for further evaluation is indicated for microscopic or gross hematuria without urinary tract infection or other benign causes. 17 , 18 , 25 Patients should also be referred for any Bosniak III or IV cystic lesions, and for selected, low-risk patients with a Bosniak IIF lesion, or any solid mass greater than 1 cm that does not contain fat. 21

INTERVENTION STRATEGIES

The preferred treatment for any nonmetastatic, solid, or Bosniak III or IV complex cystic kidney mass is surgical excision, preferably using a minimally invasive approach. 23 In select patients, nephron-sparing partial nephrectomy is recommended with a priority of achieving negative surgical margins while preserving nephron mass. Radical nephrectomy is indicated in patients with an increased oncologic risk based on clinical indicators (solid masses greater than 3 cm, complex cystic masses, no preexisting chronic kidney disease, normal contralateral kidney and if partial nephrectomy would be challenging) and in patients who plan to undergo targeted pharmaceutical treatment. 12 , 23 Lymph node dissection should be performed for staging purposes in patients with clinically concerning regional lymphadenopathy. Adrenalectomy should be performed in patients where imaging and/or intraoperative indications of adrenal invasion are evident. 23

Other options for treatment of renal masses less than 3 cm include thermal ablation, cryoablation, and radiofrequency ablation. All patients undergoing these treatment options should have a renal mass biopsy (preferably multiple core biopsies) performed to allow histologic diagnosis and guide subsequent surveillance. The patient must also understand the increased risk of local recurrence or persistence of the tumor with these treatment options. 12 , 23

Active surveillance is an acceptable option in some patients when the renal mass measures less than 2 cm (grade C). A plan of active surveillance with repeat imaging every three to six months is acceptable when it is preferred by the patient or when risk of an intervention outweighs the benefits because of complicated comorbidities that decrease life expectancy or increase the risk of death. Renal mass biopsy (preferably performed using a percutaneous approach) should be considered for further risk stratification for patients considering active surveillance. 12 , 23 If expected benefits of the intervention outweigh the benefits of active surveillance, then active treatment is preferred, and patients must clearly understand the risks of surveillance. 23

Approximately 30% of all patients with renal cell carcinoma have metastatic disease at diagnosis. 6 Treatment of metastatic renal cell carcinoma is more complicated and challenging because of the cancer cells' resistance to treatment. 12 Available interventions include various VEGF receptor inhibitors, tyrosine kinase inhibitors, and immunotherapies. First-line treatment for patients with good to intermediate prognosis, who have not been treated previously, includes antiangiogenic VEGF/tyrosine kinase inhibitors (sunitinib [Sutent], pazopanib [Votrient], or bevacizumab [Avastin] with interferon-alpha). Second-line treatment includes another VEGF receptor/tyrosine kinase inhibitor, immunotherapy with nivolumab [Opdivo], and the immunosuppressant everolimus for patients who experience disease progression despite first-line treatment. 26 – 28 Although these interventions may improve overall survival, complete remission is rare in that advanced renal cell carcinoma is a deadly disease. 28

The most significant indicator of prognosis for renal cell carcinoma is based on pathological staging. Patients with stage I or II cancer at the time of diagnosis have a five-year survival rate of 80% to 90%. 23 Poor prognostic indicators include: low functional status scores using the Karnofsky performance scale or Eastern Cooperative Oncology Group Performance Status scale, high levels of serum lactate dehydrogenase, low hemoglobin, high serum corrected calcium levels, and comorbid diabetes mellitus. 12 , 29

Data Sources: Searches were conducted in Essential Evidence Plus, PubMed, Cochrane Database of Systematic Reviews, and the U.S. Preventive Services Task Force using the key terms renal cancer diagnosis and treatment and renal cell carcinoma diagnosis and treatment. The searches included meta-analyses, randomized controlled trials, clinical trials, guidelines, and reviews. Search dates: July to August 2017, and October 2018.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Air Force at large.

American Cancer Society. Cancer Facts & Figures 2016. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2016/cancer-facts-and-figures-2016.pdf . Accessed August 10, 2017.

Motzer RJ, et al. Kidney cancer, version 2. 2017. NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(6):804-834.

Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. J Urol. 2006;176(6 pt 1):2353-2358.

Ricketts CJ, et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma [published correction appears in Cell Rep . 2018;23(12):3698]. Cell Rep. 2018;23(1):313-326.

Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. 2009;182(4):1271-1279.

Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol. 2007;51(6):1502-1510.

Alanee S, Clemons J, Zahnd W, Sadowski D, Dynda D. Trichloroethylene is associated with kidney cancer mortality: a population-based analysis. Anticancer Res. 2015;35(7):4009-4013.

Agency for Toxic Substances & Disease Registry. Toxicological profile for trichloroethylene. https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=173&tid=30 . Accessed August 10, 2017.

Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7(5):245-257.

International Agency for Research on Cancer. Trichloroethylene, tetrachloroethylene, and some other chlorinated agents. 2014;106:35-217.

Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21(1):81-90.

Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353(23):2477-2490.

Song DY, Song S, Song Y, Lee JE. Alcohol intake and renal cell cancer risk: a meta-analysis. Br J Cancer. 2012;106(11):1881-1890.

Wolk A, Larsson SC, Johansson JE, Ekman P. Long-term fatty fish consumption and renal cell carcinoma incidence in women. JAMA. 2006;296(11):1371-1376.

Lee JE, et al. Intakes of fruit, vegetables, and carotenoids and renal cell cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1730-1739.

Loo RK, Lieberman SF, Slezak JM, et al. Stratifying risk of urinary tract malignant tumors in patients with asymptomatic microscopic hematuria. Mayo Clin Proc. 2013;88(2):129-138.

Davis R, et al. Diagnosis, evaluation, and follow-up of asymptomatic microhematuria (AMH) in adults. J Urol. 2012;188(6 suppl):2473-2481.

Sharp VJ, Barnes KT, Erickson BA. Assessment of asymptomatic microscopic hematuria in adults. Am Fam Physician. 2013;88(11):747-754.

Gray Sears CL, et al. Prospective comparison of computerized tomography and excretory urography in the initial evaluation of asymptomatic microhematuria. J Urol. 2002;168(6):2457-2460.

Kang SK, Chandarana H. Contemporary imaging of the renal mass. Urol Clin North Am. 2012;39(2):161-170.

Herts BR, Silverman SG, Hindman NM, et al. Management of the incidental renal mass on CT. J Am Coll Radiol. 2018;15(2):264-273.

Higgins JC, Fitzgerald JM. Evaluation of incidental renal and adrenal masses. Am Fam Physician. 2001;63(2):288-294.

American Urological Association. Renal mass and localized renal cancer: AUA guideline. 2017. https://www.auanet.org/guidelines/renal-mass-and-localized-renal-cancer-new-(2017) . Accessed September 29, 2017.

American Cancer Society. Survival rates for kidney cancer by stage. 2017. https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html . Accessed October 20, 2017.

National Institute for Health and Care Excellence. Suspected cancer. 2017. https://www.nice.org.uk/guidance/ng12/chapter/1-Recommendations-organised-by-site-of-cancer . Accessed August 25, 2017.

Wagstaff J, et al. Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK. Ann Oncol. 2016;27(1):159-165.

Molina AM, Motzer RJ. Clinical practice guidelines for the treatment of metastatic renal cell carcinoma. Oncologist. 2011;16(Suppl 2):45-50.

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Clear Cell Renal Cell Carcinoma

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What is clear cell renal cell carcinoma? 

Clear cell renal cell carcinoma, or ccRCC, is a type of kidney cancer. The kidneys are located on either side of the spine towards the lower back. The kidneys work by cleaning out waste products in the blood. Clear cell renal cell carcinoma is also called conventional renal cell carcinoma. 

Clear cell renal cell carcinoma is named after how the tumor looks under the microscope. The cells in the tumor look clear, like bubbles.

How common is ccRCC?

In adults, ccRCC is the most common type of kidney cancer, and makes up about 80% of all renal cell carcinoma cases. ccRCC is more common in adults than children. Renal cell carcinoma makes up 2-6% of childhood and young adult kidney cancer cases. 

How is ccRCC diagnosed? 

Patients with ccRCC may have pain or feel tired. Sometimes, patients do not have any noticeable symptoms. Symptoms can include:

• Blood in the urine
• Weight loss
• Feeling tired
• A lump in the side

For people without symptoms, these tumors can be discovered if the person has an imaging test for another reason.

Imaging: If are suspected to have clear cell renal cell carcinoma, your doctor will use imaging scans such as X-rays, CT or MRI to look at the size of the tumor. They will also check for signs that the tumor has spread to other parts of the body. 

Biopsy: To check if the tumor is ccRCC your doctor will perform a biopsy, taking a small sample from the tumor with a needle. An expert, called a pathologist, will study cells from the sample under the microscope to see what kind of tumor it is.

How is ccRCC treated?

Treatments for people with ccRCC include surgery and immunotherapy. Treatment will depend on how much the cancer has grown.

Surgery: Once ccRCC is diagnosed, you may have surgery to remove the cancer and part of the kidney surrounding it. In early stage ccRCC, part of the kidney with the cancer is taken out. If ccRCC is in the middle of the kidney, or if the tumor is large, sometimes the entire kidney must be removed. In later stage ccRCC, removal of the kidney is controversial but may be appropriate in some patients. 

Immunotherapy: Immunotherapy helps the body’s immune system fight the cancer cells. 

Targeted therapy: Targeted therapy targets the changes in cancer cells that help them grow, divide, and spread. Some targeted therapies that are used to treat clear cell renal carcinoma include cabozantinib, axitinib, sunitinib, sorafenib, and pazopanib. 

Other treatments can be used that do not involve removing the kidney, such as:

• Radiation therapy , which uses radiation to kill the tumor cells
• Thermal ablation , which uses heat to kill the tumor cells
• Crysosurgery , which uses liquid nitrogen to freeze and kill the tumor cells

Does ccRCC run in families? 

ccRCC can run in families.  Almost all cases of ccRCC that run in families are found in people with a genetic condition called Von Hippel-Lindau syndrome, but other hereditary conditions may also be associated with ccRCC. People with Von Hippel-Lindau syndrome have mutations in the VHL gene.

How does ccRCC form?

Scientists are always working to understand how cancer forms, but it can be hard to prove. Because ccRCC can run in families, we know that changes in the VHL gene are important in causing ccRCC. The VHL gene is also changed in ccRCC from people without a family history of Von Hippel-Lindau syndrome. Scientists have learned a lot about what the VHL gene does in the body. This has given scientists clues about treatments to try for ccRCC.

What is the prognosis for people with ccRCC? 

The estimate of how a disease will affect you long-term is called prognosis. Every person is different and prognosis will depend on many factors, such as

• Where the tumor is in your body
• If the cancer has spread to other parts of your body
• How much of the tumor was taken out during surgery

If you want information on your prognosis, it is important to talk to your doctor. NCI also has resources to help you understand cancer prognosis .

Doctors estimate ccRCC survival rates by how groups of people with ccRCC have done in the past. Because there are so few pediatric ccRCC patients, these rates may not be very accurate. They also don’t take into account newer treatments being developed. 

With this in mind, ccRCC patients with smaller tumors have a better chance of survival than patients with larger tumors. The 5-year survival rate for patients with ccRCC is 50-69%. When ccRCC is already large or has spread to other parts of the body, treatment is more difficult and the 5-year survival rate is about 10%.  

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At the time the article was created Hamish Smith had no recorded disclosures.

At the time the article was last revised Mohammad Taghi Niknejad had no financial relationships to ineligible companies to disclose.

• Clear cell kidney carcinoma
• Clear cell renal carcinoma
• Clear cell kidney cancer

Clear cell renal cell carcinoma is the most common type of renal cell carcinoma . 

On this page:

Epidemiology, clinical presentation, radiographic appearance, treatment and prognosis.

• Related articles
• Cases and figures

The average age of onset of sporadic clear cell renal carcinoma is 61 years. In cases associated with von Hippel-Lindau disease , the average age of onset is 37 years 1 .

Patients with the clear cell subtype of renal cell carcinoma are more likely to present with symptomatic disease and metastatic disease than with other types of renal cell carcinoma 5 .

Clear cell renal cell carcinoma represents around 75-80% of cases of renal cell carcinoma and arises from the epithelium of the proximal tubule 1 . Clear cell carcinoma is sporadic in over 95% of cases; in the 5% of familial cases, most are seen in von Hippel-Lindau disease 1 .

Common to both sporadic and familial forms is the loss of sequences on the short arm of chromosome 3 in 98% of tumors, usually by deletion or unbalanced translocation resulting in loss of 3p12 to 3p26. The second allele often shows somatic mutation or epigenetic inactivation through hypermethylation. Interestingly, this region contains the sequence for the von Hippel-Lindau ( VHL ) gene, which is a tumor suppressor gene that normally results in increased expression of proteins of the ubiquitin ligase complex 1 . The ubiquitin ligase complex normally identifies and tags proteins for destruction. Of particular relevance to clear cell carcinoma is ubiquitin mediated degradation of hypoxia inducible factor 1 (HIF-1), which is a pro-angiogenic factor normally expressed in hypoxic environments. As such, the loss of the VHL allele results in increased levels of HIF-1 and the resulting increase in pro-angiogenic factors such as VEGF, PDGF, TGF-α and TGF-β, leading to cellular dysplasia and, ultimately, neoplasia.

Macroscopic appearance

Tumors have a yellowish, golden appearance on sectioning due to the high lipid content 5 .

Microscopic appearance

Microscopically, the tumor is characterized by 2 :

large cells with a uniform appearance

abundant clear cytoplasm rich in glycogen and lipid

high vascularity

Clear cell carcinoma, compared to other forms of renal cell carcinoma, is said to have 3,5 :

an exophytic appearance

a greater degree of enhancement on the corticomedullary and nephrographic phases on multiphasic CT (compared to papillary cell carcinoma)

a more heterogeneous appearance (due to multiple areas of internal necrosis, cystic change or hemorrhage)

MRI offers similar accuracy to CT in detecting clear cell renal cell carcinoma 3 .

T1:  heterogeneous appearance (due to multiple areas of internal necrosis, cystic change or hemorrhage)

T2: hyperintense 4

in and out of phase: frequently contains microscopic fat resulting in focal or diffuse non-curvilinear signal loss in the opposed phase (in 60%  7 ); this must not be mistaken for macroscopic fat frequently found in angiomyolipomas   6

Clear cell renal carcinoma has a worse prognosis than papillary and chromophobe types but not as bad as rare and aggressive forms such as medullary and collecting duct renal cell carcinoma. The 5-year survival rate for patients with clear cell renal cell carcinoma is 50-70%, but it decreases to 10% when metastatic 9 .

WHO classification of tumors of the kidney

RENAL nephrometry scoring system

• 1. Cairns P. Renal Cell Carcinoma. Cancer Biomark. 2010;9(1-6):461-73. doi:10.3233/CBM-2011-0176 - Pubmed
• 2. Ng C, Wood C, Silverman P, Tannir N, Tamboli P, Sandler C. Renal Cell Carcinoma: Diagnosis, Staging, and Surveillance. AJR Am J Roentgenol. 2008;191(4):1220-32. doi:10.2214/AJR.07.3568 - Pubmed
• 3. Young J, Margolis D, Sauk S, Pantuck A, Sayre J, Raman S. Clear Cell Renal Cell Carcinoma: Discrimination from Other Renal Cell Carcinoma Subtypes and Oncocytoma at Multiphasic Multidetector CT. Radiology. 2013;267(2):444-53. doi:10.1148/radiol.13112617 - Pubmed
• 4. Oliva M, Glickman J, Zou K et al. Renal Cell Carcinoma: T1 and T2 Signal Intensity Characteristics of Papillary and Clear Cell Types Correlated with Pathology. AJR Am J Roentgenol. 2009;192(6):1524-30. doi:10.2214/AJR.08.1727 - Pubmed
• 5. Low G, Huang G, Fu W, Moloo Z, Girgis S. Review of Renal Cell Carcinoma and Its Common Subtypes in Radiology. World J Radiol. 2016;8(5):484-500. doi:10.4329/wjr.v8.i5.484 - Pubmed
• 6. Schieda N, Davenport M, Pedrosa I et al. Renal and Adrenal Masses Containing Fat at MRI: Proposed Nomenclature by the Society of Abdominal Radiology Disease-Focused Panel on Renal Cell Carcinoma. J Magn Reson Imaging. 2019;49(4):917-26. doi:10.1002/jmri.26542 - Pubmed
• 7. Jhaveri K, Elmi A, Hosseini-Nik H et al. Predictive Value of Chemical-Shift MRI in Distinguishing Clear Cell Renal Cell Carcinoma From Non-Clear Cell Renal Cell Carcinoma and Minimal-Fat Angiomyolipoma. AJR Am J Roentgenol. 2015;205(1):W79-86. doi:10.2214/AJR.14.13245 - Pubmed
• 8. Sauk S, Hsu M, Margolis D et al. Clear Cell Renal Cell Carcinoma: Multiphasic Multidetector CT Imaging Features Help Predict Genetic Karyotypes. Radiology. 2011;261(3):854-62. doi:10.1148/radiol.11101508 - Pubmed
• 9. Padala S & Kallam A. Clear Cell Renal Carcinoma. 2022. - Pubmed

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INTRODUCTION

Tumor dedifferentiation can develop in any RCC, independent of histology [ 1 ]. Sarcomatoid dedifferentiation, the most common form of tumor dedifferentiation, consists of cell components that are spindled or otherwise resemble sarcoma cells [ 1,2 ]. However, sarcomatoid RCC is not classified as a distinct tumor subtype because it can be seen in any histologic subtype of RCC [ 1,2 ]. Rather, these tumors are characterized by distinct molecular and biologic characteristics, including clinical response to systemic therapies. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" .)

This topic will review the epidemiology, pathology, clinical presentation, and management of RCC with sarcomatoid features. The management of clear cell and non-clear cell RCC histologies are discussed in detail separately.

● (See "Overview of the treatment of renal cell carcinoma" .)

● (See "Systemic therapy for advanced and metastatic clear cell renal carcinoma" .)

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KCRS23 Presentations & Video

Each video is the full session length; to jump to a particular presentation, note the timestamp in red beneath the speaker’s name.

BIOMARKERS SYMPOSIUM Session 1: Biomarker Technologies in RCC

Moderated by toni choueiri, dfci & mahrukh huseni, genentech, genomic dna/rna biomarkers.

Ari Hakimi, Memorial Sloan Kettering

(Video presentation begins at 00:45)

Spatial Biomarkers: Tissue-Based in situ Analyses Including IF for Biomarker Development

High-dimensional/spatial tools for biomarker discovery in rcc, how can ai guide biomarker development and progress in rcc, developing metabolic imaging agents in kidney cancer, ct-based radiomics model for the prediction of genomic alterations in renal cell carcinoma (rcc), circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma.

Note presentation time stamps to locate specific speakers.

Biomarkers Session One Q&A begins at 1:10:55.

BIOMARKERS SYMPOSIUM Session 2: Clinical Biomarkers: Trial Data and Directions

Moderated by medhi mollapour, state university of new york, and tom powles, barts cancer centre, emerging biomarkers for the ipi/nivo: new data from prism.

Tom Powles , Barts Cancer Centre

(Video presentation begins at 01:06)

Learning from the Atezolizumab Biomarker Program in RCC: Lessons for Future Trial Designs

David McDermott , Beth Israel Deaconess Medical Center

(Video presentation begins at 11:20)

Biomarkers for PD-1 Based Therapies in RCC

Saurabh Gupta , Bristol Myers Squibb

(Video presentation begins at 23:15)

Designing Clinical Trials in the Perioperative Setting in RCC

Axel Bex , Royal Free Hospital London

(Video presentation begins at 35:40)

Development and Clinical Application of ctDNA in RCC

Sylvan Baca , Dana-Farber Cancer Institute

(Video presentation begins at 46:20)

Biomarkers of Toxicity to Immune Checkpoint Blockers

Alexander Gusev , Dana-Farber Cancer Institute

(Video presentation begins at 56:05)

KIM 1 and Kidney Cancer: Multiple Setting or an Ideal Setting?

Wenxin (Vincent) Xu , Dana-Farber Cancer Institute

(Video presentation begins at 1:07:05)

Utilization of ctDNA for RCC Disease Monitoring and Treatment Response

Adam ElNaggar , Natera

(Video presentation begins at 1:18:35)

Biomarkers Session Two Q&A begins at 1:28:30.

MENTORSHIP & SPONSORSHIP Challenges and Opportunities

Moderated by hans hammers, utsw, and tom powles, barts cancer centre.

Session 1: Modulating Tumor Microenvironment in Kidney Cancer

The bone metastasis immunological niche: unraveling its complexity and role in therapy response and resistance.

Eleonora Dondossola , MD Anderson Cancer Center

(Video presentation begins at 01:35)

Metabolic Demands and Determinants in the RCC Tumor Microenvironment

Kimryn Rathmell , Vanderbilt University Medical Center

(Video presentation begins at 14:55)

Identifying Novel Immune Evasion Tumor Immune Networks as Targets for ccRCC Immunotherapy

Hartland Jackson , Samuel Lunenfeld Research Institute

(Video presentation begins at 32:30)

Targeting a Combined VHL and 3p Chromatin Remodeler Deficit in Renal Cell Carcinoma

Ruhee Dere , Baylor College of Medicine

(Video presentation begins at 46:10)

Session 2: Biology of Non-Clear Cell Subtypes

Defining cellular and genetic factors for renal cell carcinoma subtypes.

Jung Wook Park , Duke Cancer Institute

(Video presentation begins at 00:35)

Targeting GPNMB in Renal Tumors in Tuberous Sclerosis Complex and Translocation Renal Cell Carcinoma

Kaushal Asrani , Johns Hopkins University

(Video presentation begins at 16:15)

Deep Functional Characterization of MiT/TFE Fusions in Translocation Renal Cell Carcinoma

Srinivas Viswanathan , Dana-Farber Cancer Institute

(Video presentation begins at 29:40)

Targeting TFEB and TFE3 in Renal Tumorigenesis

Elizabeth Henske , Brigham and Women’s Hospital

(Video presentation begins at 45:15)

Session 3: Trials in Progress: Moving the Needle

Zanzalintinib in combination with immune checkpoint inhibitors: design of the renal cell carcinoma expansion stage cohorts in stellar-002.

Neil Shah , Memorial Sloan Kettering

(Video presentation begins at 00:50)

LITESPARK-024: A Randomized Phase 1/2 Study of Belzutifan with or without Palbociclib for Previously Treated Advanced Renal Cell Carcinoma

David McDermott , Beth Israel

(Video presentation begins at 05:40)

SAMETA: A Phase III Study of Savolitinib + Durvalumab vs Sunitinib and Durvalumab Monotherapy in Patients with MET-Driven, Unresectable, Locally Advanced/Metastatic Papillary Renal Cell Carcinoma

Toni Choueiri , Dana-Farber Cancer Institute

(Video presentation begins at 09:00)

A Phase 1/2, Open Label Dose-Escalation and Expansion Trial of NKT2152, an Orally Administered HIF2α Inhibitor, to Investigate Safety, PK, PD and Clinical Activity in Patients with Advanced ccRCC

(Video presentation begins at 14:15)

NRG-GU012: Randomized Phase II Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Unresected Renal Cell Carcinoma (RCC) Receiving Immunotherapy (SAMURAI)

Rana McKay , UC San Diego

(Video presentation begins at 17:05)

STARLITE 1: Phase 1b/2 Study of Combination 177Lu Girentuximab Plus Cabozantinib and Nivolumab in Treatment Naïve Patients with Advanced Clear Cell RCC

Eric Jonasch , MD Anderson

(Video presentation begins at 22:45)

Phase 1/2 Study of PRO1160, a CD70-Directed Antibody-drug Conjugate, in Patients with Advanced Solid Tumors and Hematologic Malignancies

(Video presentation begins at 26:35)

Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (INC) (Adenosine A2a Receptor Antagonist) in First-Line Advanced Renal Cell Carcinoma

Katy Beckermann , Vanderbilt University Medical Center

(Video presentation begins at 29:30)

Optimal Treatment by Invoking Biologic Clusters in Renal Cell Carcinoma (OPTIC RCC)

(Video presentation begins at 33:15)

Session Three Q&A begins at 37:20.

BREAKING BARRIERS TO TRIAL ENROLLMENT Special Session Four

Moderated by michael atkins, georgetown lombardi comprehensive cancer center.

The panelists discussed the challenges and opportunities in clinical trial enrollment, focusing on how to decrease barriers of entry for kidney cancer patients. They explored strategies to make clinical trials more inclusive for all kidney cancer patients, regardless of race, age, location, or gender, which are all currently limiting access. The panelists also shared their insights on the role of regulatory bodies, pharmaceutical companies, and healthcare providers in facilitating trial enrollment.

FEATURED SPEAKER: New Directions in Basic Kidney Cancer Research

New directions in basic kidney cancer research.

SESSION 5: Clinical and Scientific Updates in Kidney Cancer

Front line systemic therapy sessions, subsequent line treatments for advanced disease.

Robert Motzer , Memorial Sloan Kettering Cancer Center

(Video presentation begins at 13:00)

Adjuvant Treatment Options

Bradley McGregor , Dana-Farber Cancer Institute

(Video presentation begins at 28:15)

Radiation Therapy Strategies in RCC

Raquibul Hannan , UTSW

(Video presentation begins at 38:30)

Strategies for Patients with Non-Clear Cell RCC

Chung-Han Lee , Memorial Sloan Kettering Cancer Center

(Video presentation begins at 49:40)

Novel Therapies Outside Immunotherapy

Rana McKay , University of California (San Diego)

(Video presentation begins at 1:00:45)

Novel Immunotherapy Strategies

David Braun , Yale 

(Video presentation begins at 1:15:10)

Session Five Q&A begins at 1:24:30.

SESSION 6: Immunotherapy Advances and Research

Car t therapies for rcc: what we've learned.

Avery Posey , Penn Medicine

Targeting Interleukin-1beta to Overcome Adaptive Immune Resistance in Renal Cell Carcinoma

Matthew Dallos , MSKCC

(Video presentation begins at 25:00)

Targeting RNA Sensing to Enhance Immunotherapy Responses in Kidney Cancer

John Wilson , Vanderbilt

(Video presentation begins at 40:55)

A Novel STAT3 Antisense Oligonucleotide-Based Immunotherapy for Renal Cell Carcinoma

Marice Alcantara , City of Hope

(Video presentation begins at 52:55)

Derepression of Human Endogenous Retrovirus and Implications for Immunotherapy for Clear Cell Renal Cell Carcinoma

Qinqin Jiang , DFCI

(Video presentation begins at 1:04:30)

SESSION 7: Oral Abstract Presentations

Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a pd-1/pd-l1-containing therapy in metastatic clear cell renal cell carcinoma.

Chung-Han Lee , MSKCC

(Video presentation begins at 01:20)

ORCHID: A Phase II Study of Olaparib in Metastatic Renal Cell Carcinoma Patients HarborIng a BAP1 or Other DNA Repair Gene Mutations

Yasser Ged , Johns Hopkins

(Video presentation begins at 09:15)

Circulating KIM-1 is a Minimally Invasive Biomarker Correlated with Treatment Response to Nivolumab in Patients with Metastatic Renal Cell Carcinoma

Wenxin (Vincent) Xu , DFCI 

(Video presentation begins at 28:55)

Functional and Translational Consequences of Immunometabolic Coevolution in ccRCC

Ed Reznik , MSKCC

(Video presentation begins at 36:15)

Host Immune Signatures as Predictors of Response to Immunotherapy-Based Regimens in Patients with Metastatic Renal Cell Carcinoma (mRCC)

Eddy Saad , DFCI

(Video presentation begins at 57:45)

Spatial Proteomics Enables Identification of Prognostic Biomarkers in Papillary Renal Cell Carcinoma

Anupama Reddy , Vindhya Data Science Inc.

(Video presentation begins at 1:06:00)

Session Seven is structured with two presentations, followed by Q&A, then two more presentations, etc. The Q&A sessions are at 18:00, 44:20, and 1:15:30.

SESSION 8: Rapid Abstract Presentations

Moderated by:  Sumanta Pal, City of Hope & Deepak Kilari, Medical College of Wisconsin

Dissection of Tumor-Intrinsic and Tumor-Extrinsic Features of MiT/TFE Translocation Renal Cell Carcinoma Via Single-Cell RNA Sequencing

Prathyusha Konda , DFCI

Characterization of the Cellular Origin and Oncogenic Mechanisms of Chromophobe Renal Cell Carcinoma (ChRCC) and Renal Oncocytic Neoplasms

Chris Labaki , DFCI

(Video presentation begins at 06:00)

Epigenomic Profiling Nominates Master Transcription Factors (TFs) Driving Sarcomatoid Differentiation (SD) of Renal Cell Carcinoma (RCC)

Karl Semaan , DFCI

(Video presentation begins at 10:45)

A Modified IL-18 Drug in Combination with CTLA-4 Blockade Enhances Anti-Tumor Efficacy in Preclinical Models of Renal Cell Carcinoma

David Schoenfeld , Yale 

(Video presentation begins at 22:35)

The Identification of a Novel Orally Available Ferroptosis Inducer for the Treatment of Clear Cell Renal Carcinoma

Mei Koh , Kuda Therapeutics, Inc.

(Video presentation begins at 28:25)

The Impact of Insurance Status on Progression-Free Survival (PFS) and Overall Survival (OS) in Patients with Metastatic Renal Cell Carcinoma (mRCC)

Daniela Castro , City of Hope

(Video presentation begins at 38:20)

Examining Trends in Kidney Cancer Mortality by Gender and Race in the United States: A 20-Year AnalysisccRCC

Chinmay Jani , Univ. of Miami

(Video presentation begins at 44:35)

Impact of Time to Metastasis (Synchronous vs. Metachronous) on Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with First Line Immune-Checkpoint Inhibitors (ICI)-based Combinations

George Gebrael , Huntsman

(Video presentation begins at 50:00)

Session Eight is structured with three presentations, followed by Q&A, then more presentations, etc. The Q&A sessions are at 15:55, 34:40, and 54:40.

Special Session for Investigators: Expert Insights on the Research Funding Landscape

Writing a grant: the nci perspective, cdmrp grant proposals: tips for the first time applicant, arpa-h opportunities for research funding.

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• Published: 02 April 2024

Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma

• Weijing Hu 1 ,
• Yongquan Chen 2 ,
• Lin Zhang 3 ,
• Xiaoling Guo 4 ,
• Xin Wei 3 ,
• Yuan Shao 5 ,
• Dongwen Wang 6 &

Scientific Reports volume  14 , Article number:  7704 ( 2024 ) Cite this article

Metrics details

• Computational biology and bioinformatics
• Urological cancer

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor, and the role of carbohydrate sulfotransferase 11 (CHST11) in this cancer remains unclear. Here, by using bioinformatics methods, we comprehensively analyzed the relationship between CHST11 and clinical significance, immune infiltration, functional enrichment, m 6 A methylation, and protein–protein interaction networks. We found that CHST11 expression was significantly higher in ccRCC samples than in normal tissues. Additionally, CHST11 levels correlated with the clinicopathological features of ccRCC patients and functioned as a prognostic factor for patient survival. Functional analysis revealed the involvement of CHST11 in metabolic pathways. Immune infiltration and m 6 A methylation analysis suggested the association of CHST11 with immune cell abundance in the tumor microenvironment and specific methylation patterns in ccRCC. The in vitro analysis of the clinical samples and ccRCC cell lines demonstrated that the overexpression of CHST11 promotes ccRCC cell proliferation, migration, and invasion, while its suppression has the opposite effect. Thus, CHST11 may play a remarkable role in the occurrence and progression of ccRCC. Functionally, CHST11 promotes the aggressiveness of ccRCC cells. These findings provide insights into the role of CHST11 in ccRCC progression.

Registry and the Registration No. of the study/trial: No. 2021K034.

Introduction

In recent years, the global incidence of renal cell carcinoma (RCC) has steadily increased. Clear cell renal cell carcinoma (ccRCC) is the predominant type of RCC and accounts for approximately 80% of RCC cases 1 . Radical nephrectomy remains the primary treatment approach for ccRCC in clinical practice. In the past decade, the widespread application of novel biological agents and other technologies has improved the treatment efficacy for advanced renal cancer. However, given the mild early clinical symptoms of ccRCC, metastasis often occurs by the time the tumor is diagnosed. Consequently, the overall survival (OS) rate of patients with metastatic RCC is < 10% at 5 years after diagnosis 2 . Hence, it is crucial to explore novel treatment strategies for patients with advanced stage RCC and improve the OS rate.

The tumor metastasis process is intricate and involves several factors and alterations at the molecular level. Chondroitin sulfate (CS) is a member of glycosaminoglycans (GAGs) and performs critical physiological functions. GAGs show various biological effects and play a pivotal role in the interconnection of tumor cells. CS is significantly involved in processes such as cell proliferation, differentiation, and migration and even influences the biological behavior of cancer cells by participating in the activation of cancer-related signaling pathways 3 .

CHST11, also known as chondroitin-4- O -sulfotransferase-1 (C4ST-1), is located on chromosome 12q23.3. It plays a critical role in mediating the sulfation reaction of N -acetyl galactosamine (GalNAc) and serves as a crucial regulatory enzyme in CS synthesis 4 . Recent studies have indicated that CHST11 is associated with the development of several types of cancer. The elevated expression of CHST11 in patients with lung cancer and pancreatic cancer is correlated with poor prognosis 5 , 6 . The aberrant expression of CHST11 facilitates the proliferation, migration, and invasion of tumor cells and promotes the emergence of biological behavior characteristics of cancer stem cells 7 , 8 . However, the role of the CHST11 gene in ccRCC remains uncertain.

In the present study, we investigated the differential expression of the CHST11 gene between ccRCC tissues and normal tissues, its association with clinicopathological characteristics, and its prognostic relevance. We performed immune infiltration analysis, functional enrichment analysis, m 6 A methylation analysis, and protein–protein interaction (PPI) network analysis by using relevant databases. Finally, we validated the mRNA and protein expression levels of CHST11 in ccRCC and adjacent normal tissues by qRT-PCR and immunohistochemistry (IHC) experiments. We also assessed the effect of overexpression or under-expression of the CHST11 gene in ccRCC cell lines. This comprehensive approach could help establish the role of CHST11 as a prognostic biomarker and potential therapeutic target in ccRCC.

Materials and methods

Collection of clinical specimens.

Tissue samples were collected from patients who underwent radical nephrectomy in the Department of Urology at the First Hospital of Shanxi Medical University from January 2021 to October 2021. The patients were pathologically diagnosed to have ccRCC after surgery, and both cancerous tissues and adjacent normal tissues were included as research samples. The exclusion criteria were as follows: (1) preoperative exposure to antineoplastic therapies such as chemotherapy, radiotherapy, or molecular targeted therapy; (2) absence of a signed informed consent form; and (3) lack of comprehensive clinical and pathological data. Fifty specimens were included in this study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the First Hospital of Shanxi Medical University (No. 2021K034), and informed consent was obtained from all the patients.

Determination of the CHST11 gene expression levels from the database

Datasets were obtained from The Cancer Genome Atlas (TCGA) database 9 . Gene Expression Omnibus (GEO) dataset was downloaded from the NCBI GEO database. The following datasets were included in this study: GSE53757, GSE40435, GSE15641, and GSE36895 (Table S1 ).

The HPA database 10 was used to perform an IHC analysis of CHST11 protein expression. We used the program AlphaFoldDB 11 to predict the three-dimensional structure of the CHST11 gene. Receiver operating characteristic (ROC) curve analysis was conducted on the TCGA-KIRC, GSE53757, GSE40435, GSE15641, and GSE36895 datasets. The area under the curve (AUC) is a commonly used metric to assess diagnostic tests.

Clinicopathological analysis of CHST11 and its prognostic value

We used the TCGA-KIRC dataset to estimate the prognostic value of CHST11 in ccRCC patients. Kaplan–Meier (KM) survival curves were generated using the survival package, and log-rank tests were performed. The prognostic outcomes were OS, disease-specific survival (DSS), and progression-free interval (PFI).

Immune infiltration analysis

The Tumor Immune Estimation Resource (TIMER) 12 was used to investigate the correlation between the CHST11 gene expression and immune infiltration levels in ccRCC patients. KM Plotter 13 was utilized for further analysis to determine whether CHST11 expression affects the prognosis of ccRCC patients following immune cell infiltration. Additionally, single-sample Gene Set Enrichment Analysis (ssGSEA) was used to quantitatively assess the correlation between the infiltration levels of 24 types of immune cells and CHST11 expression 14 . The Tumor and Immune System Interaction Database (TISIDB) was used to examine the relationship between CHST11 expression and tumor lymphocyte infiltration, immune suppressors, immune stimulators, and major histocompatibility complex. Tumor Immune Single-cell Hub 2 (TISCH2) 15 was used to demonstrate the relationship between the colocalized expression of CHST11 and immune cells at the single-cell RNA sequencing level.

m 6 A methylation analysis of CHST11

Enzymes involved in m 6 A methylation include methyltransferases (writers), demethylases (erasers), and methylation readers (readers). We conducted a study to investigate the relationship between CHST11 expression and the aforementioned 23 types of m 6 A methylation regulators. We used LASSO regression to calculate a risk score and established a model. The patients were stratified into high-risk and low-risk groups, and the KM survival analysis was conducted to assess the prognostic value. ROC curves were used to analyze the sensitivity and specificity of the model. We then obtained the relevant methylation data for ccRCC from the Xena database 16 . We finally identified the core methylation regions associated with patient prognosis.

PPI and enrichment analysis

We used the STRING database 17 to generate a PPI network of proteins associated with CHST11. We then conducted a comprehensive analysis of CHST11 and its associated genes by Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, including GO biological process (BP), cellular constituent (CC), molecular function (MF), and KEGG pathway functional enrichment analysis.

Quantitative real-time polymerase chain reaction

The CHST11 mRNA expression was assessed in 50 pairs of ccRCC tissues and adjacent noncancerous tissues. Total RNA was extracted using TRIzol (Transgene, Beijing, China) reagent, followed by the synthesis of the first-strand cDNA using the Uni All-in-One SuperMix mRNA reverse transcription kit (Transgene, Beijing, China). The obtained cDNA was then subjected to qPCR using the PerfectStart Green qPCR SuperMix reagent kit (Transgene, Beijing, China). GAPDH was used as the internal reference. The primer sequences were as follows: GAPDH-F: 5′-GCTCTCTGCTCCTCCTGTTC-3′; GAPDH-R: 5′-ACGACCCHST11TCCGTTGACTC-3′. For CHST11, the primer sequences were as follows: CHST11-F: 5′-CACAAGCCGTAAGCGGAGG-3′; CHST11-R: 5′-CATGGGGTCGCTGTACTTCC-3′. The relative gene expression levels were calculated using the 2 −ΔΔCt method.

IHC analysis

IHC was used to evaluate the CHST11 protein expression levels in 50 paired sets of ccRCC tissues and the corresponding adjacent normal tissues. Tissue sections of pathological origin were obtained from patients with confirmed ccRCC through pathological assessment. These sections were subjected to deparaffinization, hydration, and removal of endogenous peroxidase with hydrogen peroxide to retrieve tissue antigens. The sections were then washed thrice with PBS for 3 min each. The sections were then incubated with anti-CHST11 antibodies (1:300, ZSGB-BIO, Chengdu, China) at 37 °C for 1.5 h, followed by cooling at room temperature for 35 min. Following a rinse in PBS, secondary antibodies (Boster, Wuhan, China) were added, and the sections were incubated for 30 min. Another round of rinsing in PBS was performed before using the DAB kit (Boster, Wuhan, China) for color development; the reaction was terminated after microscopic observation. Hematoxylin was used for counterstaining acidophilic structures, which produced a blue hue. The sections were subsequently dehydrated, treated for transparency, and mounted with neutral resin. The stained sections were then examined by pathologists.

Cell culture and transfection

Human renal epithelial normal cells (293T) and human ccRCC cells (786O, 769P, and ACHN) were procured from the Cell Bank of the Shanghai Institute of Life Sciences. The cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) (Procell, Wuhan, China) supplemented with 10% fetal bovine serum (FBS) (Gibco, CA, USA) and 1% penicillin/streptomycin (Solarbio, Beijing, China). For transfection, the overexpression plasmid and knockdown small interfering RNA (siRNA) were obtained from Han-Bio (Shanghai, China). In accordance with the manufacturer’s instructions, transfection was performed using Lipofectamine 3000 (Thermo Fisher Scientific, CA, USA) for plasmids or siRNAs. Subsequent experiments were conducted 48 h post-transfection.

Cell counting kit-8 assay

After cell digestion with trypsin (Solarbio, Beijing, China), the cell suspension was adjusted to a concentration of 5 × 10 3 cells/100 µL/well and added to a 96-well plate (Solarbio). Next, 100 µL of the prepared CCK-8 reagent (MCE, NJ, USA) was added to each well. The absorbance values were measured using the microplate reader at 0, 24, 48, 72, and 96 h after cell culture. The absorbance was measured at 450 nm by using a microplate reader.

Wound healing assay

After the cells covered the entire 6-well plate, vertical scratches were made at the bottom of the plate by using a sterile 200 µL pipette tip. The cell debris was washed with PBS (Solarbio) three times. A basic culture medium without FBS was added to continue cell cultivation. At 0, 12, 24, and 48 h after cell growth, photographs were captured under a microscope. The area of wound healing was determined using the ImageJ software.

Transwell assay

The cells were digested with trypsin (Solarbio), neutralized with an FBS-free medium, and resuspended after centrifugation to prepare a cell suspension. After mixing the Matrigel matrix (Corning, NY, USA) with a basic culture medium, the mixture was added (or not added) to the Transwell chamber and incubated for 3 h. Next, the cell density was adjusted to 3 × 10 5 cells/mL, and the cells were then added to the Transwell chamber. The cells were cultured in a cell culture incubator at 37 °C for 24 h. The cells were fixed with paraformaldehyde, stained with crystal violet, and observed and counted under a microscope.

Statistical analysis

All data were analyzed using GraphPad Prism 9.0 software and R software (version 4.2.0). Student’s t-test was used to compare two groups, and one-way ANOVA was used to compare multiple groups. Survival analysis was conducted using KM curves, along with the determination of hazard ratio (HR) and p -value through the log-rank test with 95% confidence intervals. Pearson’s or Spearman’s correlation analyses were used to assess the correlation between genes. Differences at the P -value of < 0.05 were considered statistically significant.

Ethical approval

Approval of the research protocol by an Institutional Reviewer Board:the Ethics Committee of the First Hospital of Shanxi Medical University.

Informed consent

Informed consent was taken from all the patients.

CHST11 gene expression level in ccRCC tissues

Following the analysis of the downloaded TCGA-KIRC datasets, the results indicated that the CHST11 gene expression level was higher in tumor tissues (n = 541) than in normal tissues (n = 72) (Fig.  1 A). Regarding paired tissues, the CHST11 gene expression level was higher in tumor tissues (n = 72) than in normal tissues (n = 72); these findings were consistent with those of nonpaired tissues ( P  < 0.001) (Fig.  1 B). The analysis of mRNA expression on the gene chips GSE40435 and GSE53757 showed that the CHST11 gene was overexpressed in ccRCC (Fig.  1 C,D).

Expression of CHST11 at the mRNA and protein levels in online databases. ( A ) Expression of CHST11 in nonpaired tissues. ( B ) Expression of CHST11 in paired tissues. ( C ) Expression of CHST11 in the GSE40435 dataset. ( D ) Expression of CHST11 in the GSE53757 dataset. ( E ) Three-dimensional structure of CHST11. ( F ) IHC results of CHST11 in tumor and normal tissues (*** P  < 0.001, **** P  < 0.0001).

We then examined CHST11 protein expression levels in ccRCC and normal tissues by using the HPA database (Fig.  1 F). The three-dimensional structure was predicted using the AlphaFold database, as shown in Fig.  1 E.

Relationship between CHST11 expression levels and clinicopathological features in ccRCC patients

A total of 541 patients were included in the present study. The CHST11 mRNA expression level showed significant correlations with T-stage, N-stage, M-stage, AJCC staging, and WHO/ISUP-histologic grade. However, no correlation was observed between the CHST11 mRNA expression level and gender, age, or race (Table S2 ) (Fig.  2 ). The logistic regression analysis indicated a positive correlation between the CHST11 mRNA expression level and T-stage, N-stage, AJCC staging, and WHO/ISUP-histologic grade (Table S3 ).

The relationship between CHST11 mRNA expression level and clinical characteristics in the TCGA database. ( A ) Heatmap. Association between the CHST11 mRNA expression level and gender ( B ), age ( C ), ethnicity ( D ), T staging ( E ), N staging ( F ), M staging ( G ), AJCC staging ( H ), and WHO/ISUP histological grading ( I ) (* P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001) (This heatmap was generated by R software version 4.2.0, https://cloud.r-project.org/ ).

Diagnostic efficacy and prognostic value of CHST11 in ccRCC

We used ROC curves and AUC values to assess the diagnostic efficacy of CHST11 in ccRCC. The KM plotter was used to analyze the survival outcomes associated with CHST11 in ccRCC. The results indicated that the AUC values were 0.917, 0.877, and 0.914 in the TCGA-KIRC, GSE53757, and GSE15641 datasets, respectively (Fig.  3 A–C). Moreover, the AUC values exceeded 0.6 in both GSE36895 and GSE40435 datasets (Fig.  S1 ). KM survival analysis revealed a significant correlation between the high CHST11 expression and poor OS, DSS, and PFI (Fig.  3 D–F).

Diagnostic efficacy and survival prognosis of CHST11 in ccRCC. ROC curves of CHST11 for diagnosing ccRCC in the TCGA ( A ), GSE53757 ( B ), and GSE15641 ( C ) datasets. Correlation between CHST11 expression and OS ( D ), DSS ( E ), and PFI ( F ). (OS, overall survival; DSS, disease-specific survival; PFI, progression-free interval).

Correlation between CHST11 and immune cell infiltration in ccRCC

We used the TIMER database, ssGSEA, and TISIDB database to analyze the correlation between CHST11 expression levels and immune responses. The KM plotter database was used to conduct an in-depth analysis of the relationship between immune cell infiltration and prognosis of ccRCC patients. Finally, we used the TISCH2 database for single-cell RNA sequencing to provide information on the co-localization of immune cell infiltration.

The TIMER database revealed a close positive correlation between CHST11 expression and six immune cell types: B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells (Fig.  S2 A). Additionally, CHST11 expression showed a positive correlation with the expression of six immune checkpoint genes: HAVCR2 , CD274 , CTLA4 , PDCD1 , LAG3 , and PDCD1LG2 (Fig.  S2 B). The survival analysis module in the database, however, indicated that the infiltration of these six immune cell types was not significantly associated with the OS of ccRCC patients (Fig.  S2 C).

The results of ssGSEA indicated that CHST11 exhibited significant differences in immune cell infiltration levels between the high and low expression groups in the majority of somatic cells (Fig.  S3 A). The CHST11 expression levels showed a significant positive correlation with the enrichment of macrophages, T helper cell 1, and T helper cell 2 and exhibited a significant negative correlation with T helper cell 17 enrichment (Fig.  S3 B).

By using the TISIDB database, Spearman’s correlation analysis was performed between the CHST11 expression level and tumor lymphocytes, tumor immunostimulators, tumor immunoinhibitors, and major histocompatibility complex (MHC) proteins. The results showed a significant correlation between CHST11 and certain tumor immunostimulators (CD28, IL2RA, and TNFSF13B), tumor immunoinhibitors (CD96 and LGALS9), and MHC proteins (HLA-DRA and HLA-DMB) (Tables S4 – S7 ).

We also conducted a detailed investigation using the KM plotter database and confirmed that ccRCC patients with high CHST11 expression exhibited an increase in macrophage infiltration, along with a decrease in the infiltration of mesenchymal stem cells, natural killer (NK) T cells, type 1 T-helper cells, and type 2 T-helper cells, which correlated with poor patient prognosis (Fig.  4 A–Q).

Correlation between CHST11 expression and different immune cell subsets in ccRCC in the Kaplan–Meier (KM) plotter database. ( A ) Forest plot. ( B – Q ) Correlation between high CHST11 expression and prognosis of ccRCC patients in different immune cell subsets.

Finally, we conducted an analysis at the single-cell sequencing level with a focus on cell types and the TME in ccRCC. The result was visually represented in the form of a heatmap to demonstrate co-localization. We also analyzed the correlation between CHST11 expression and immune infiltration abundance (Fig.  5 A–E). In the GSE111360, GSE139555, GSE121636, GSE159115, and GSE171306 datasets, CHST11 was predominantly distributed in macrophages, CD4 + T cells, CD8 + T cells, B cells, and NK cells.

Co-localization of CHST11 expression with immune cell expression in the TISCH2 database. Co-localization heatmap from the GSE139555 ( A ), GSE111360 ( B ), GSE121636 ( C ), GSE159115 ( D ), and GSE171306 ( E ) datasets.

m 6 A methylation analysis of the CHST11 gene

We initially investigated the 23 associated m 6 A methylation genes of CHST11 in ccRCC. The results showed a significant positive correlation between CHST11 and RBM15B , VIRMA , ZC3H13 , YTHDF3 , YTHDC2 , and IGF2BP3 (Fig.  6 A). We also conducted LASSO regression analysis with tenfold cross-validation and determined the inclusion genes and the corresponding λ coefficient values for the scoring formula (Fig.  6 B,C). We then established a prognostic model and computed the risk scores for each ccRCC patient on the basis of the 10 genes (Fig.  6 D,E). Survival analysis indicated that patients in the high-risk group have a poor prognosis in terms of OS (Fig.  6 F). The ROC curves calculated for 1, 3, and 5 years of survival displayed high AUC values, thus indicating a favorable predictive accuracy of this model (Fig.  6 G).

( A ) Correlation heatmap between CHST11 and 23 m 6 A regulators in ccRCC. ( B ) The LASSO coefficient curve for m 6 A regulators with the minimal λ value determined by tenfold cross-validation in LASSO regression. ( C ) Diagnostic LASSO variable trajectory. ( D ) Correlated genes incorporated into the model and the risk scoring formula. ( E ) Risk factor chart along with the distribution of survival status in independent individuals. ( F ) KM curves for ccRCC patients in the high-risk and low-risk groups. ( G ) ROC curve for the prognostic model (This heatmap was generated by R software version 4.2.0, https://cloud.r-project.org/ ).

Subsequently, we downloaded and analyzed the relevant methylation data of TCGA-KIRC from the Xena database. The results indicated that almost all CpG islands were significantly hypermethylated in ccRCC tissues (Fig.  S4 A). Correlation analysis with CHST11 expression showed a positive association between the methylation status of 31 regions and the CHST11 mRNA expression level (Fig.  S4 B). We found that only higher methylation levels of cg24946597 were associated with a poor patient prognosis; this finding suggests that cg24946597 is a core methylation region within the CHST11 gene (Fig.  S4 C).

PPI and enrichment analyses of CHST11

First, we generated a PPI network related to CHST11 by using the STRING database. This network contained 20 proteins, including CHST11 (Fig.  7 A). Subsequently, we curated the top 10 genes most closely associated with CHST11. We then constructed an interaction chord diagram that illustrated their interplay and plotted a co-expression heatmap (Fig.  7 B,C). Finally, we created an interaction diagram that showed the direct interactions among the six genes centered around CHST11 (Fig.  7 D).

PPI network of CHST11 in ccRCC. ( A ) Interaction network constructed using the STRING database. ( B ) The top 10 genes most closely associated with CHST11. ( C ) Heatmap of the top 10 genes most relevant to CHST11. ( D ) PPI core network of CHST11 (This heatmap was generated by R software version 4.2.0, https://cloud.r-project.org/ ).

We selected the top 50 genes from the TCGA database that exhibited either positive or negative correlation with the CHST11 expression levels. An expression heatmap for these genes was then generated (Fig.  S5 ). The GO and KEGG enrichment analyses for CHST11 indicated that CHST11 is primarily localized in the Golgi apparatus in ccRCC cells. It is most significantly associated with processes such as proteoglycan metabolism, GAG biosynthesis, and aminoglycan biosynthesis (Fig.  S6 ).

CHST11 expression in ccRCC tissues and cells

First, we assessed the mRNA expression levels of CHST11 in samples (n = 50) (Table S8 ) and cells by using qRT-PCR. The results showed that the expression levels of CHST11 were significantly elevated in ccRCC tissues as compared to that in normal tissues ( P  < 0.001) (Fig.  8 A). Moreover, the mRNA expression levels of CHST11 in 786O, 769P, and ACHN cells were notably higher than that in 293 T cells (Fig.  8 B).

qRT-PCR assessment of the CHST11 mRNA expression levels in ccRCC tissues ( A ) and cell lines ( B ) (* P  < 0.05; **** P  < 0.0001).

We also conducted immunohistochemical staining of both ccRCC and normal tissues. The findings showed that the CHST11 protein primarily localizes in the cell membrane and cytoplasm of ccRCC cells (Fig.  9 A). The expression level of the CHST11 protein was significantly higher in ccRCC tissues than in normal tissues ( P  < 0.01) (Fig.  9 B). Additionally, the elevated expression of CHST11 was strongly correlated with higher clinical stages of the tumor ( P  < 0.01) (Fig.  9 C).

IHC assessment of CHST11 expression in ccRCC. The expression and localization of CHST11in normal tissues and in low-grade and high-grade ccRCC tissues ( A ). Quantitative analysis of CHST11 expression ( B ) and histological malignancy grade ( C ) according to IHC results (** P  < 0.01).

CHST11 knockdown inhibited the proliferation, migration, and invasive capabilities of ccRCC cells

To investigate the biological functions of CHST11 in ccRCC cells, we designed siRNA interference agents to knockdown the CHST11 gene. The transfection efficiency was confirmed by qRT-PCR analyses (Fig.  10 A,H).

CHST11 knockdown reduces the malignancy of ccRCC. Assessment of transfection efficiency ( A , H ). Wound healing assay ( B , I ). Quantitative analysis of the wound healing rate ( C , J ). Transwell assay results ( D , K ). Quantitative analysis of Transwell assay ( E , F , L , M ). Results of CCK-8 assay ( G , N ) (** P  < 0.01,*** P  < 0.001,**** P  < 0.0001).

Wound healing assay confirmed a reduction in the cell migration ability of the si-CHST11 group (Fig.  10 B,C,I,J). Transwell assays showed decreased cell migration and invasion capabilities in the si-CHST11 group as compared to that in the si-control group ( P  < 0.01) (Fig.  10 D–F,K–M). The results of the CCK-8 assay confirmed reduced cell proliferation in the si-CHST11 group as compared to that in the si-control group ( P  < 0.001) (Fig.  10 G,N). These findings indicate that the CHST11 gene knockdown inhibits the proliferation, migration, and invasive capabilities of ccRCC cells.

CHST11 overexpression promoted the proliferation, migration, and invasive capabilities of ccRCC cells

We constructed an overexpression plasmid for the CHST11 gene. The plasmid was transfected into 786O and 769P cells by using a transfection reagent. qRT-PCR analyses were then conducted to verify transfection efficiency (Fig.  11 A,H).

CHST11 overexpression promotes the malignancy of ccRCC cells. Assessment of transfection efficiency ( A , H ). Wound healing assay ( B , I ). Quantitative analysis of the wound healing rate ( C , J ). Transwell assay results ( D , K ). Quantitative analysis of Transwell assay ( E , F , L , M ). CCK-8 assay results ( G , N ) (** P  < 0.01, *** P  < 0.001, **** P  < 0.0001).

In 786O and 769P cells, wound healing assay confirmed the enhanced cell migration ability of the CHST11 overexpression group (Fig.  11 B,C,I,J). Transwell assays confirmed increased cell migration and invasive capabilities of the CHST11 overexpression group as compared to that of the control group ( P  < 0.01) (Fig.  11 D–F,K–M). The results of the CCK-8 assay confirmed enhanced cell proliferation in the CHST11 overexpression group as compared to that in the control group ( P  < 0.001) (Fig.  11 G,N). These findings indicate that CHST11 overexpression enhances the proliferation, migration, and invasive capabilities of ccRCC cells.

ccRCC not only represents an aberrant proliferation of renal cells, but it also indicates a metabolic disorder that manifests as alterations in lipid metabolism. As a metabolic disease, the metabolic pathways in ccRCC cells influence the phenotypic behavior of tumor cells and affect the TME, thereby facilitating the growth of cancer cells 18 . The alterations in these metabolic pathways primarily occur through diverse routes, including glycolysis, amino acid metabolism, oxidative phosphorylation impairment, and lipid metabolism 19 . Moreover, metabolic reprogramming is crucial in the incipient stages of cancer, which augments the malignancy of ccRCC cells 20 . A substantial shift in lipid metabolism occurs in ccRCC cells, accompanied by marked reshaping or anomalous upregulation of lipid proteins in the cellular membrane, thereby facilitating the growth and proliferation of ccRCC cells 21 .

Recent studies have indicated a close correlation between alterations in the surface glycoproteins of ccRCC cells and the metastatic potential of tumors. Glycoproteins participate in the connections between cells and also between cells and the extracellular matrix and thus influence the invasive capabilities of cells 22 , 23 . Several studies have indicated that GAGs show elevated expression in various cancers and play a role in tumor progression and metastasis. GAGs serve as integral components of proteoglycans and provide structural support to the extracellular matrix (ECM); thus, they mediate cellular behavior by interacting with numerous proteins on the cell surface or within the ECM and regulate cellular processes such as adhesion, migration, proliferation, and differentiation 24 , 25 . Recent studies suggest that certain GAGs can regulate stem cell differentiation through their interactions with proteins 26 , 27 .

CHST11 is a critical enzyme in the synthesis of GAGs, particularly CS. According to previous studies, CHST11 is abnormally expressed in various malignant tumors, and it is closely associated with the clinicopathological features of cancer and the prognosis of cancer patients. Li et al. 28 found that the CHST11 expression level was significantly elevated in lung cancer tissues and correlated with a poor patient prognosis. Relevant studies have indicated that CHST11 may promote the progression of endometrial cancer by activating pathways such as the Wnt signaling pathway and promoting epithelial-mesenchymal transition 29 . CHST11 may promote the metastasis of non-small cell lung cancer cells through dysregulation of ceruloplasmin and intracellular iron balance 8 . However, the role of the CHST11 gene in ccRCC remains unclear.

Recent studies posit that cancer metabolic reprogramming may interfere with the antitumor immune response. Through Warburg’s effect, cancer cells can intricately influence the generation of the corresponding intermediates in oxidative-reductive reactions, thereby attenuating the proliferation, differentiation, activation, and functionality of immune cells 30 . The aberrant production of metabolites and intermediates in the TME also probably exerts a profound effect on these immune processes.

The tumor immune microenvironment plays a crucial role in tumor progression and prognosis, immune evasion, and immunotherapy. Immune cells can either promote or inhibit the growth and metastasis of tumors 31 . The analysis of tumor immunotherapy involves the activation of immune cells within the body and the enhancement of the organism’s anti-tumor immune response, with the specific aim of eliminating minuscule residual tumor foci, suppressing tumor growth, and using therapeutic strategies to disrupt immune tolerance 32 . Xiong et al. 33 showed that the CHST11 gene is upregulated in liver cancer cells, which promoted the infiltration of Treg cells in tumor tissues; thus, correlating with immunosuppressive function. Silencing the CHST11 gene inhibited cell proliferation and migration. Our results exhibited a high expression of CHST11 , which is concomitant with a reduction in the infiltration of mesenchymal stem cells, NK T cells, and T-helper cells. In this context, NK cells are regarded as the primary bastion against hematogenous metastatic tumor cells, and reduced NK cell levels may favor an impending metastasis 30 . The decreased NK cell levels frequently coincide with the increased CD47 expression, which is related to a more invasive phenotype and a poor prognosis of ccRCC patients 34 . During ccRCC occurrence, immunoglobulins play a critical role in the evolution of neoplastic cells. Because of the enrichment of proinflammatory cytokines and growth factors in the TME, their sustained presence may paradoxically facilitate cancer progression, leading to uncontrolled malignant proliferative responses 30 , 35 . It is plausible that CHST11 may mediate the malignant phenotype of ccRCC cells through the modulation of the TME. The immune microenvironment and tumor cells have an intricate relationship. In this context, we posit that CHST11 expression can enhance their interplay. Hence, these findings will help identify novel indicators or adjunct therapeutic targets to monitor immunotherapy efficacy.

m 6 A, which functions as a genetic regulatory mechanism, enables regulated proteins to drive aberrant transcription, processing, and translation of the target transcripts. This subsequently affects the development of various diseases, including the onset, progression, and prognosis of cancer 36 . m 6 A-associated genes comprise a total of 23 writers, erasers, and readers. The equilibrium among these genes is conducive to maintain the homeostasis of gene expression. Herman et al. 37 confirmed that the CHST11 gene is upregulated in breast cancer, with a lower CpG island methylation level in its gene sequence. Higher levels of methylation can silence genes, thereby significantly inhibiting tumor proliferation and differentiation. In the present investigation, we elucidated the intricate relationship between m 6 A regulatory factors and CHST11, along with their prognostic significance in ccRCC cells. The findings revealed a prominent positive correlation between CHST11 and RBM15B , VIRMA , ZC3H13 , YTHDF3 , YTHDC2 , and IGF2BP3 . The aberrant expression of these factors in ccRCC, coupled with their association with CHST11 , may enable the elucidation of anomalous expression of CHST11 in patients with ccRCC. We identified m6A-associated genes that exhibit the highest correlation with CHST11 . We utilized these correlated genes to construct a prognostic model to predict patient outcomes. The methylation of promoter regions also exerts a significant influence on CHST11 expression. Notably, cg24946597 represents the core methylation region in the CHST11 gene. Nevertheless, these outcomes necessitate substantiation through the execution of methylation-specific PCR. Overall, the findings of the present study underscore a novel epigenetic pattern of CHST11 . Moreover, we used the STRING database to construct a PPI network for CHST11 . The results of functional enrichment analysis further corroborate the involvement of CHST11 in processes such as proteoglycan metabolic processes and GAG biosynthetic processes.

Finally, our study conducted relevant experiments on clinically collected tumor tissues and matched normal tissues. IHC assay was used to provide additional evidence. To determine the intricate biological functions of CHST11 in ccRCC cells, we conducted scratch assays, Transwell experiments, and CCK-8 assays. The deletion of CHST11 confirmed a decrease in the proliferation, migration, and invasive capabilities of ccRCC cells. The malignancy of ccRCC cells reduced following CHST11 gene knockdown. Conversely, CHST11 gene overexpression amplified the proliferation, migration, and invasive capacities of ccRCC cells, indicating an augmentation of cell malignancy. In summary, the results of this study suggest that the CHST11 gene family may play a crucial role in the occurrence and development of ccRCC. It is also a promising prognostic marker and therapeutic target for ccRCC.

The present study has some limitations. First, a limited number of tissue samples were included, and future studies should include more clinical samples. Further support based on prospective studies and a larger sample size is required. Second, the biological functional studies in this experiment were primarily based on cell experiments, and further studies based on animal experiments are warranted.

In summary, bioinformatics analysis coupled with experimental evidence indicates a marked upregulation of CHST11 expression in ccRCC, which correlates with clinicopathological factors, poor prognosis, and the immune microenvironment. For the first time, we suggest that CHST11 overexpression promotes the proliferation, migration, and invasive capabilities of ccRCC cells. Thus, CHST11 may emerge as a novel biomarker for the therapeutic intervention of ccRCC.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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This work was supported by the Beijing Bethune Charitable Foundation, Special Research Fund for Urological Oncology [Grant Number mnzl202029]; the Research Project Supported by Shanxi Scholarship Council of China [Grant Number 2021-160].

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Weijing Hu & Bo Wu

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Yongquan Chen

Shanxi Medical University, Taiyuan, 030001, Shanxi, China

Lin Zhang & Xin Wei

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Xiaoling Guo

Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300070, China

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W.H.: Conceptualization, Methodology, Validation; Y.C.: Software, Data Curation; L.Z.: Investigation; X.G.: Validation; X.W.: Investigation; Y.S.: Formal analysis; D.W.: Resources; B.W.: Writing—Review & Editing, Supervision, Project administration.

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Hu, W., Chen, Y., Zhang, L. et al. Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma. Sci Rep 14 , 7704 (2024). https://doi.org/10.1038/s41598-024-58280-8

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Identifying and validating MMP family members (MMP2, MMP9, MMP12, and MMP16) as therapeutic targets and biomarkers in kidney renal clear cell carcinoma (KIRC)

Affiliations.

• 1 The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
• 2 Department of Pharmaceutical Engineering, Jiangsu Ocean University, Lianyungang, China.
• 3 Department of Biological Engineering, University of Salford, Salford, UK.
• 4 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
• 5 Department of Animal and Poultry Production, Faculty of Veterinary and Animal Sciences, Gomal University, Dera Ismail Khan, Pakistan.
• 6 Department of Arid Zone Research, PARC institute, Dera Ismail Khan, Pakistan.
• PMID: 38560573
• PMCID: PMC10972725
• DOI: 10.32604/or.2023.042925

Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that carries a substantial risk of morbidity and mortality. The MMP family assumes a crucial role in tumor invasion and metastasis. This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) through a comprehensive approach encompassing both computational and molecular analyses. STRING, Cytoscape, UALCAN, GEPIA, OncoDB, HPA, cBioPortal, GSEA, TIMER, ENCORI, DrugBank, targeted bisulfite sequencing (bisulfite-seq), conventional PCR, Sanger sequencing, and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC. By performing STRING and Cytohubba analyses of the 24 MMP gene family members, MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9), MMP12 (matrix metallopeptidase 12), and MMP16 (matrix metallopeptidase 16) genes were denoted as hub genes having highest degree scores. After analyzing MMP2, MMP9, MMP12, and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines, interestingly, all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls. The notable effect of the up-regulated MMP2, MMP9, MMP12, and MMP16 was also documented on the overall survival (OS) of the KIRC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (MMP2, MMP9, MMP12, and MMP16). In addition to this, hub genes were involved in various diverse oncogenic pathways. The MMP gene family members (MMP2, MMP9, MMP12, and MMP16) may serve as therapeutic targets and prognostic biomarkers in KIRC.

Keywords: Chemotherapy; KIRC; MMP gene family; Overall survival.

© 2024 Kunlun et al.