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Is Clear Cell Renal Carcinoma Aggressive

Discussion: Recommendations For The Next Who Classification

Biology of Clear Cell Renal Cell Carcinoma

Eosinophilic solid and cystic RCC

ESC RCC is an emerging renal tumor entity not yet part of the 2016 WHO classification of genitourinary tumors . It was recently described as a sporadic neoplasms occurring in young women, usually solitary, small and with indolent behavior. Subsequent studies have reported identical tumor also in males and multifocal, in a minority of cases. Metastases have been reported in four cases so far. Ten percent of the patients with tuberous sclerosis-complex can present this type of tumor, firstly described with granular eosinophilic-macrocystic morphology by Guo et al. . In a case series of unclassified eosinophils tumor in patients of 35 years of age or younger, 30% of the cases were classified as ESC-RCC . Solid and cystic architecture, voluminous eosinophilic cytoplasm, granular cytoplasmic stippling, CK20 positivity either diffuse or focal are the typical features of these tumors, although CK 20 negative cases have been reported . Next generation sequencing analysis and karyotype profiling evidenced that ESC-RCC are characterized by somatic tuberous sclerosis gene mutations in the great majority of cases and recurring chromosomal copy number gains and losses. Since many of the genes involved in these alterations are part of the regulation of MTOR signaling pathway, therapies targeting the mTOR pathway in these RCC can be considered .

Figure 5

Biphasic squamoid papillary RCC

Papillary renal neoplasm with reverse polarity

Table 1

Review Of Prognostic Expression Markers For Clear Cell Renal Cell Carcinoma

  • 1Programme Cartes d’Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
  • 2Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Equipe Inflammation, Complément et Cancer, Paris, France

Context: The number of prognostic markers for clear cell renal cell carcinoma has been increasing regularly over the last 15 years, without being integrated and compared.

Objective: Our goal was to perform a review of prognostic markers for ccRCC to lay the ground for their use in the clinics.

Evidence Acquisition: PubMed database was searched to identify RNA and protein markers whose expression level was reported as associated with survival of ccRCC patients. Relevant studies were selected through cross-reading by two readers.

Evidence Synthesis: We selected 249 studies reporting an association with prognostic of either single markers or multiple-marker models. Altogether, these studies were based on a total of 341 distinct markers and 13 multiple-marker models. Twenty percent of these markers were involved in four biological pathways altered in ccRCC: cell cycle, angiogenesis, hypoxia, and immune response. The main genes involved in ccRCC carcinogenesis are not the most relevant for assessing survival.

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.

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Immunohistochemistry In Atypical Ccrcc Variants

Distinguishing between unusual variants of the common RCC histologic types and other types of tumors can be difficult. For example, CCRCCs composed predominantly of granular eosinophilic cells may show a morphological resemblance to the eosinophilic variant of chromophobe RCC or to oncocytoma. Immunohistochemical markers suggested for this distinction include E-cadherin, CD117/KIT, or parvalbumin, which are rarely expressed in CCRCC.

Other markers that may prove useful include the RCC marker and vimentin. These are commonly expressed in CCRCC, including the granular eosinophilic variant. By contrast, the RCC marker is expressed in only 0-4% of chRCC and 0-14% of oncocytomas, while immunostaining for vimentin is positive in only 1-25% of oncocytomas and is negative in chRCC.

Rare tumors composed mainly of clear cells but with a predominant papillary architecture tend to be classified as papillary RCC with extensive clear cell change. However, genetic analysis has, in some cases, found specific translocations characteristic of Xp11 translocation RCC, a tumor with clear and/or eosinophilic cells that can show both papillary architecture and a nested pattern with vascular stroma similar to compact-alveolar CCRCC.

How Is Ccrcc Treated

Translocation renal cell carcinoma composed of clear cells arranged in ...

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 bodys 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

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Development Of Radiomics Signature And Radiomics Nomogram

The prevention of the overfitting of the signature can be realized through the conduction of dimension reduction of the features before signature construction. Only were the radiomics chosen to be kept when meeting a criterion of inter- and intra-observer ICCs greater than 0.75, then the minimum-Redundancy Maximum-Relevancy method was performed to eliminate the redundant and irrelated features and kept 30 features. The remaining features were enrolled into the least absolute shrinkage and selection operator regression model to select the most valuable features in the training cohort. Then the radiomics signature was calculated by summing the selected feature values weighted by their corresponding features.

To provide a more individualized predictive model, a nomogram combining the final radiomics signature and significant clinical variables were built in the training cohort. The calibration of the nomogram was evaluated with a calibration curve. The HosmerLemeshow test was conducted to assess the goodness-of-fit of the nomogram. A radiomics nomogram score for each patient was obtained in the training and validation cohorts.

How Is Clear Cell Renal Cell Carcinoma Treated

Treatments for ccRCC include:

  • Surgery to remove the cancerous part of your kidney or your entire kidney .
  • Immunotherapy to engage your bodys immune system to destroy cancer cells. Medications include aldesleukin .
  • Targeted therapy to stop cancer cells from growing and multiplying. Drugs include sorafenib and temsirolimus .
  • Radiation therapy to kill cancer cells with radiation. Similar treatments include cryosurgery or thermal ablation to destroy cancer cells.

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Molecular And Genetic Aspects Of Ccrcc

Studies in patients with VHL disease established the importance of genetic alterations involving chromosome 3p in the development of CCRCC, while subsequent research has shown that chromosome 3 or 3p is lost in 80-98% of sporadic CCRCCs.

Inactivation or loss of the VHL gene results in the absence of a functional VHL protein, which under normoxic conditions usually targets the alpha subunit of the transcription factor hypoxia-inducible factor for degradation. Loss of functional VHL protein therefore leads to accumulation of HIF and activation of its hypoxia-inducible target genes under normoxic rather than hypoxic conditions. HIF target genes include the vascular endothelial growth factor gene VEGF, which may explain the prolific angiogenesis associated with CCRCC.

A less common pathway followed in 18% of CCRCCs mainly involves gains of entire chromosomes resulting in a hyperdiploid karyotype. Common gains involve chromosomes 7 , 16 , 20 , 12 , and 2 . This second pathway is similar to the genetic events seen in papillary RCC, except that most papillary RCCs also show gain of chromosome 17.

Progression of CCRCC can eventually involve reduplication of the entire genome to give a polyploid karyotype, followed by further losses or gains of genetic material. Complex polyploid karyotypes are particularly common in tumors with sarcomatoid differentiation.

Rare Non Clear Cell Rcc Subtypes

Pathology 690 Renal Cell Carcinoma Gross Microscopy Kidney Tumor Causes Classification Types Clear
  • Collecting duct carcinoma: A very rare and aggressive type of RCC. At initial diagnosis, it is usually metastatic and has spread to other parts of the body. It is more common in younger people.
  • Translocation RCC: A rare type of kidney cancer. This cancer can be identified by seeing mutations, or changes, in a gene called TFE3. This type affects children and young adults but can also affect older adults.
  • Renal medullary carcinoma : This is a very rare type of kidney cancer. It affects young people who carry the sickle cell trait or have sickle cell disease. These cancers are usually metastaticspread to other parts of the bodyat diagnosis.
  • Unclassified RCC: Less than 1% of RCCs are unclassified. They are very rare and do not easily fit into one of the more common subtypes. They tend to be more aggressive.

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Living With Clear Cell Renal Cell Carcinoma

Your medical team will develop a treatment plan to help you fight ccRCC, but there are some very important parts of your care that cant happen in an operating room.

Managing your everyday life with ccRCC can feel like a huge challenge. But there are some simple steps you can take at home, with friends, and with other healthcare professionals. Great ways to take care of yourself during treatment include:

  • Eating healthier. There isnt a set diet plan for ccRCC, but eating healthy can help you feel better during treatments and recovery. Talk with your doctor before making any major changes to your diet.
  • Taking time for mental health. It can be hard to talk about a cancer diagnosis, even with family and friends. Mental health professionals such as counselors and psychologists can help you sort through the stress and emotions of managing ccRCC.
  • Asking for help. Its a good idea to turn to friends, family, loved ones, or other supportive people when youre managing ccRCC. Local charities and cancer support groups can help you find support if youre in need.

How Will I Feel

The symptoms of kidney cancer are different for each person. In most cases, youâll see blood in your pee. You may feel generally sick, tired, and like you donât want to eat much. And you may have:

  • A fever that comes and goes
  • A lump in your belly
  • Night sweats, so much that you need to change your clothes or sheets
  • Pain in your back or side that wonât go away
  • Weight loss for no reason

You might also get symptoms where the cancer spreads. If itâs in one of your bones, you might feel pain there. In your lungs, it can give you a cough or trouble breathing.

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T1 Stage Clear Cell Renal Cell Carcinoma: A Ct

  • 1School of Medicine, Shandong University, Jinan, China
  • 2Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
  • 3Department of Radiology, Shandong Medical Imaging Research Institute, Jinan, China
  • 4GE Healthcare, Shanghai, China

Objectives: To develop and validate a radiomics nomogram to improve prediction of recurrence and metastasis risk in T1 stage clear cell renal cell carcinoma .

Methods: This retrospective study recruited 168 consecutive patients with T1 ccRCC between January 2012 and June 2019, including 50 aggressive ccRCC based on synchronous metastasis or recurrence after surgery. The patients were divided into two cohorts at a 7:3 ratio. Radiomics features were extracted from contrast enhanced CT images. A radiomics signature was developed based on reproducible features by means of the least absolute shrinkage and selection operator method. Demographics, laboratory variables and CT findings were combined to develop clinical factors model. Integrating radiomics signature and independent clinical factors, a radiomics nomogram was developed. Nomogram performance was determined by calibration, discrimination, and clinical usefulness.

The CT-based radiomics nomogram could help in predicting recurrence and metastasis risk in T1 ccRCC, which might provide assistance for clinicians in tailoring precise therapy.

How Does Kidney Cancer Spread

Clear Cell Renal Cell Carcinoma

As the tumor grows, it spreads into fat or major blood vessels around the kidney. It may also creep into the adrenal gland, which sits right on top of the organ.

From there, it can spread farther through your:

  • Blood. Cancer cells that get into a blood vessel can travel to many body parts through your veins and arteries.
  • Lymph system. This is a network that runs throughout your body, much like your blood vessels. It helps you fight disease. But cancer cells that get into lymph nodes can hitch a ride to other organs.

Kidney cancer most often spreads to the lungs and bones, but it can also go to the brain, liver, ovaries, and testicles.

Because it has no symptoms early on, it can spread before you even know you have it. If you do find it early, but treatment doesnât get rid of all the cancer cells, it can come back in your kidney or somewhere else.

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What Is The Survival Rate For Clear Cell Renal Cell Carcinoma

As many as 7 in 10 people with small ccRCC tumors are alive five years after the initial diagnosis. Treatment is less effective on large tumors or metastatic cancer. In those cases, five-year survival rates may drop to about 1 in 10. A cancer prognosis depends on many factors, including:

  • Cancer spread.
  • Location, size and number of tumors .

The Role Of Lipid Droplets In Ccrcc

As the most significant pathological feature of ccRCC, the existence of lipid droplet accumulation not only reveals the abnormal lipid metabolism of ccRCC, but also indicates some death pathways of ccRCC cells. It has been pointed out that lipid droplets in ccRCC cells can be used as bioenergy fuel and raw materials for cell membrane generation, and can also be involved in endoplasmic reticulum stress . Therefore, we are very interested in the formation and role of lipid droplet itself.

Fatty acids are substrates for the synthesis of various lipid types. Diacylglycerol acyltransferase catalyzes diacylglycerol to synthesize triacylglycerol with FAs and plays an important role in lipid synthesis . DGAT1 and DGAT2, two genes encoding DGAT, have been identified, and their main functions have been recognized in the past ten years. Researchers have used molecular tools to study the metabolic changes in mice lacking these two enzymes, revealing the function of DGAT1/2 . Currently, DGAT1/2 is known to play a positive regulatory role in many cancers related to lipid accumulation . Inhibitors targeting DGAT activity have also made significant progress . Related studies have tentatively confirmed the important role of DGAT in cancer, and we hope that more relevant studies can describe the detailed mechanism of DGAT in ccRCC, including other types of RCC.

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Clinical Factors Of The Patients And Construction Of The Clinical Factor Model

The patients demographic baseline characteristics are summarized in Table 1. No differences were detected in clinical characteristics between the training and validation cohorts . The rates of aggressive ccRCC were 29.7% and 30% in the training cohort and validation cohort, respectively, whereas no statistically significant difference was found between the two cohorts. The results of multiple logistic regression analysis are listed in Table 2, which suggested that only maximum diameter and albumin remained as independent predictors of aggressive ccRCC . Tumors with larger maximum diameter or lower albumin were likely to be aggressive ccRCC. The clinical factors model was constructed using the backward step-wise multivariate logistic regression with Akaike information criterion as criterion. This method only considered the AIC rather than the p value of each clinical factor so that the method determined the optimized feature subset. Finally, the sex, maximum diameter, neutrophils, and albumin were incorporated into the institution of the clinical factors model.

Table 1 Characteristics of patients in the training and validation cohorts.

Table 2 Risk factors for aggressive ccRCC.

Fumarate Hydratasedeficient Renal Cell Carcinoma

NIVOREN: Nivolumab in a ‘real world setting’ for metastatic clear-cell renal cell carcinoma

Fumarate hydratasedeficient renal cell carcinoma is characterized by loss of the FH gene and was first identified as part of the inherited disease hereditary leiomyomatosis and renal cell cancer in which patients have a germline loss of FH function. These patients develop benign uterine and cutaneous leiomyomas as well as very aggressive RCC cancers. More recently, this disease has been observed to develop in consequence to germline as well as somatic events. Patients with metastatic disease have a very poor prognosis with many patients presenting with metastatic disease at the time of initial diagnosis.

Historically, FHRCC has been included histologically as PRCC type 2, but given the specific molecular characterization and poor prognosis, it is more recently categorized separately. Unique surveillance strategies as well as systemic treatment recommendations exist for this disease.

A retrospective analysis of HFRCC patients was recently reported . This included twenty-four patients. The response rate to PD-1/PD-L1based therapy was only 18% with a median time to treatment failure of only 2.5 months. TKIbased therapy had superior results with an ORR of 50% for cabozantinib and 63% for sunitinib. The median time to treatment failure was 11.6 months. The ORR to mTORbased therapy was 0%.

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What Is Renal Cell Carcinoma

Renal cell carcinoma, or RCC, is the most common kidney cancer. RCC accounts for approximately 9 out of 10 kidney cancer diagnoses. Renal is the Latin word for kidney. Carcinoma is the medical term for cancer that begins in the cells that cover or line an organ.

RCC develops in the cells lining the small tubes that help your kidneys filter waste from the blood. The urinary system removes this waste from the body. You may also hear the terms renal cell cancer or renal cell adenocarcinoma.


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