Most RCC are detected incidentally when patients undergo imaging studies in order to identify the causes of urological or non-urological complaints. The symptom triad of flank pain, hematuria and a palpable abdominal mass is sometimes described as characteristic of RCC - and it should surely prompt further studies - but most patients remain asymptomatic for prolonged periods of time. Thus, RCC don't usually cause specific symptoms, and even less so are there any symptoms that would allow for the distinction between subtypes of RCC.

In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight. If metastases have formed in other organs, e.g., in lungs, liver, or bones, these may interfere with organ function. Accordingly, RCC patients may suffer from dyspnea, nausea and vomiting, and bone pain, among others. ccRCC most commonly metastasize to the lungs [1].

• Anemia

  The most common grade 3 side effects were anemia (26%) and hypoxia (15%). “A phase III trial of MK-6482 is ongoing in patients with previously treated advanced clear cell renal cell carcinoma,” Choueiri said. [curetoday.com]

  Clinically it may present with hematuria, flank pain, anemia or, less commonly, a palpable abdominal mass. [orpha.net]

  […] associated with oncocytic adenomas ) hereditary papillary renal cell cancer type 1 : papillary type I hereditary non-polyposis colon cancer (Lynch type II): predominantly transitional cell carcinoma of the renal pelvis hereditary renal oncocytoma sickle cell anemia [radiopaedia.org]

  History Part I: Pattern Recognition: Solid renal mass Hematuria Flank pain Flank mass Weight loss Anemia or polycythemia B. [clinicaladvisor.com]

  […] and signs Although RCC frequently causes no symptoms in its early development, eventually signs and symptoms may develop and include fatigue, weight loss, constant back pain, a mass or lump on the lower back or side, blood in the urine (hematuria), anemia [medicinenet.com]

• Weight Loss

  Lifestyle measures such as exercise, weight loss and diet changes can help. Some people may need to add medications to lower their blood pressure. Discuss your options with your doctor. [mayoclinic.org]

  In other words, inheriting a single defective copy of the gene is enough to cause the disease The typical symptoms of Papillary Renal Cell Carcinoma are blood in the urine, a lump on the side, unexplained fever, flank pain, and unexplained weight loss [dovemed.com]

  Signs and symptoms of renal cell cancer may include the following: Hematuria (blood in the urine) Lower back pain or pain in the flank (side or back above the waist) that will not go away Noticeable lump in the flank Weight loss Fatigue (feeling tired [emedicinehealth.com]

  Renal cell carcinoma symptoms and signs Although RCC frequently causes no symptoms in its early development, eventually signs and symptoms may develop and include fatigue, weight loss, constant back pain, a mass or lump on the lower back or side, blood [medicinenet.com]

  loss (33%) fever (20%) hypertension (20%) hypercalcemia (5%) night sweats malaise variocele, usually left sided, due to obstruction of the testicular vein (2% of males) cytokine release by tumor frequently causes paraneoplastic conditions metastasis [en.wikibooks.org]

• Fever

  In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight. [symptoma.com]

  There was no history of fever, dysuria, urgency or hematuria. There was no history of renal calculus disease, tuberculosis, or diabetes. On examination, patient was thin built. [cancerjournal.net]

  In other words, inheriting a single defective copy of the gene is enough to cause the disease The typical symptoms of Papillary Renal Cell Carcinoma are blood in the urine, a lump on the side, unexplained fever, flank pain, and unexplained weight loss [dovemed.com]

  The procedure can be painful and cause fevers. The use of arterial embolization prior to radical nephrectomy has been shown to have survival benefit and is not recommended in operable kidney cancers. [emedicinehealth.com]

  […] in its early development, eventually signs and symptoms may develop and include fatigue, weight loss, constant back pain, a mass or lump on the lower back or side, blood in the urine (hematuria), anemia (low red blood cell counts), and intermittent fevers [medicinenet.com]

• Malaise

  […] men lack of early warning signs 25-30% are asymptomatic Symptoms and presentation [ edit ] hematuria (40%) flank pain (40%) palpable mass in the flank or abdomen (25%) weight loss (33%) fever (20%) hypertension (20%) hypercalcemia (5%) night sweats malaise [en.wikibooks.org]

  Common signs and symptoms include anaemia, liver dysfunction, haematuria, weight loss, low protein (hypoalbuminaemia), flank pain, malaise, high calcium (hypercalcaemia) or anorexia. [healthengine.com.au]

  […] may include the following: Hematuria (blood in the urine) Lower back pain or pain in the flank (side or back above the waist) that will not go away Noticeable lump in the flank Weight loss Fatigue (feeling tired) Loss of appetite Fever Night sweats Malaise [emedicinehealth.com]

  Clinically, it can present as a typical radiographic appearance of interstitial pneumonitis with or without signs and symptoms (pleural effusion, hypoxia, cough, dyspnea, malaise). [cancertherapyadvisor.com]

  […] stage.[8] Today, RCC is often asymptomatic (meaning few to no symptoms) and is generally detected incidentally when a person is being examined for other ailments.[9] Other signs and symptom may include haematuria;[8] loin pain;[8] abdominal mass;[9] malaise [en.wikipedia.org]

• Anorexia

  Common signs and symptoms include anaemia, liver dysfunction, haematuria, weight loss, low protein (hypoalbuminaemia), flank pain, malaise, high calcium (hypercalcaemia) or anorexia. [healthengine.com.au]

  The most common adverse events of immune checkpoint inhibitors are fatigue, low-grade nausea, and anorexia. No standard premedication is given. Autoimmune toxicities affecting specific organs occur in a minority of patients. [cancertherapyadvisor.com]

  […] of new blood vessels in the tumors, hence slowing growth and in some cases reducing the size of the tumors.[97] Side effects unfortunately are quite common with these treatments and include:[98] Gastrointestinal effects – nausea, vomiting, diarrhea, anorexia [en.wikipedia.org]

• Abdominal Mass

  Clinically it may present with hematuria, flank pain, anemia or, less commonly, a palpable abdominal mass. [orpha.net]

  Mostly asymptomatic; classic triad of abdominal mass, flan pain and hematuria detected in only 1/3 of patients. [auanet.org]

  If affected individuals experience RCC-related symptoms, these may comprise flank pain, hematuria and a palpable abdominal mass, but also fatigue, fever, night sweats, loss of appetite and weight. [symptoma.com]

  See separate articles Abdominal Masses, Loin Pain and Haematuria which discuss the various causes. Investigations Urinalysis, cytology, culture and sensitivity should be performed to exclude urinary tract infection. [patient.info]

  Initial presentation may include the classic triad of hematuria, abdominal pain and abdominal mass (10-20% of cases) but is increasingly common as an incidental finding on abdominal imaging. [clinicaladvisor.com]

• Abdominal Pain

  We report the case of a 48-year-old female who presented with diffuse abdominal pain. MATERIALS AND METHODS: We reviewed the case of woman who underwent a robotic assisted partial nephrectomy for an enhancing renal mass. [ncbi.nlm.nih.gov]

  Case Presentation A 12-year-old female child presented with complaints of abdominal pain. Abdomen examination revealed a soft tender mass measuring 4 cm in left lumbar region. [austinpublishinggroup.com]

  A 42-year-old lady presented with abdominal pain of 3 months duration. Contrast-enhanced computerized tomographyic scan of abdomen revealed a 6 cm 4.3 cm mass lesion in the right kidney with multiple retroperitoneal nodal and liver metastases. [ijpmonline.org]

  Initial presentation may include the classic triad of hematuria, abdominal pain and abdominal mass (10-20% of cases) but is increasingly common as an incidental finding on abdominal imaging. [clinicaladvisor.com]

• Hypertension

  A 74-year-old male with remote history of vocal cord malignancy and hypertension presented with abdominal pain. [ncbi.nlm.nih.gov]

  The most common grade 3 adverse events were skin toxicity (rash and palmar-plantar erythrodysesthesia; 4%) and hypertension (4%). No treatment-related deaths were observed. [ascopost.com]

  The most common grade 3 AEs were skin toxicity and hypertension. [cancernetwork.com]

  Hypertension, urinary tract infection, dietary intake of fat and other food ingredients, and occupational exposure to solvents like trichloroethylene are controversially discussed as potential risk factors for ccRCC. [symptoma.com]

  GS, glomerulosclerosis; HTN, hypertension; IF, interstitial fibrosis; VS, vascular sclerosis. [jasn.asnjournals.org]

• Night Sweats

  In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight. [symptoma.com]

  sweats malaise variocele, usually left sided, due to obstruction of the testicular vein (2% of males) cytokine release by tumor frequently causes paraneoplastic conditions metastasis [ edit ] lung 75% soft tissues 36% bone 20% liver 18% cutaneous sites [en.wikibooks.org]

  sweats High levels of calcium in your blood High blood pressure Getting a Diagnosis Your doctor will want to find out more about your symptoms to figure out what’s going on. [webmd.com]

  Contact a health care provider if any of the following symptoms occur: Blood in the urine Pain in the side that will not go away A lump in the side or belly Unexplained fevers Weight loss Night sweats If any unexplained symptoms last more than a few days [emedicinehealth.com]

  sweats Generalized weakness and pain in the body The signs and symptoms may depend on the size of the kidney tumor. [dovemed.com]

• Flank Pain

  A 50-year-old female presented with dull right flank pain and hematuria. Computed tomography indicated a 2.5 cm right renal mass as well as a 5 cm right adrenal mass. Both masses were surgically resected concurrently. [ncbi.nlm.nih.gov]

  Clinically it may present with hematuria, flank pain, anemia or, less commonly, a palpable abdominal mass. [orpha.net]

  If affected individuals experience RCC-related symptoms, these may comprise flank pain, hematuria and a palpable abdominal mass, but also fatigue, fever, night sweats, loss of appetite and weight. [symptoma.com]

  In other words, inheriting a single defective copy of the gene is enough to cause the disease The typical symptoms of Papillary Renal Cell Carcinoma are blood in the urine, a lump on the side, unexplained fever, flank pain, and unexplained weight loss [dovemed.com]

• Macroscopic Hematuria

  They usually occur in 50-70-year old patients and macroscopic hematuria occurs in 60% of the cases. [radiopaedia.org]

  Urinalysis – micro- or macroscopic hematuria occurs in 60% of patients Complete blood count (CBC) – patients may have anemia of chronic inflammation (normo- or microcytic), some have erythrocytosis from paraneoplastic erythropoietin (Epo) production, [clinicaladvisor.com]

Most commonly, pathological findings in diagnostic imaging studies provide first hints as to the presence of RCC. The following observations can be made with regard to ccRCC [1]:

• Most ccRCC originate from the renal cortex and show exophytic growth.
• They are well-circumscribed tumors that often have a heterogeneous structure: cystic changes, hemorrhages and necrotic foci are common.
• High contents of intratumoral fat may indicate ccRCC, but this is not a specific finding.
• Few ccRCC contain calcifications.

These and other properties can be displayed using distinct imaging techniques: In sonographic images, ccRCC appear as isoechogenic or mildly hyperechoic with respect to the renal parenchyma [2]. They show strong enhancement after contrast agent administration in computed tomography or magnetic resonance imaging studies. Furthermore, most ccRCC are hyperintense on T2-weighted images, and this feature may help to distinguish ccRCC from papillary and chromophobe RCC, which tend to appear as hypointense lesions on T2-weighted images. Vascularity is sometimes mentioned as another, type-specific feature of RCC. In this context, ccRCC are described as hypervascular neoplasms, while papillary RCC are characterized as hypovascular tumors and chromophobe RCC are usually of intermediate vascularity [1]. In sum, imaging studies may raise a strong suspicion of ccRCC, but in order to obtain a reliable diagnosis, tissues samples have to be examined. Tissue samples may be obtained by means of fine-needle aspiration or biopsy, or during surgery.

Macroscopically, ccRCC appear as solid, well-circumscribed nodules of yellow color. This type of tumor is often covered by a pseudocapsule and its yellow color is due to its high lipid content; this color also dominates the cut surface. Furthermore, the cut surface reveals a lobulated structure. The tumor may contain cystic or necrotic lesions, and such lesions are frequently found in larger ccRCC. As has been mentioned above, ccRCC are hypervascular neoplasms. In general, there is a dense network of branched, thin-walled vessels traversing the tumor. Tumor cells are arranged in nests or trabeculae and usually contain abundant clear cytoplasm, a feature that gave this type of RCC its name. It is less evident, though, in ccRCC of higher grades: The cytoplasm of cells of more aggressive tumors may be eosinophilic and granular [3]. The appearance of nuclei and nucleoli should also be considered for tumor grading: conspicuous, eosinophilic nucleoli indicate higher tumor grades, particularly if they are visible at low magnifications, and this also applies to nuclear pleomorphism and the presence of multinucleated giant cells. (Pseudo-)papillary architecture, typically ascribed to papillary RCC, as well as rhabdoid or sarcomatoid differentiation are suggestive of high-grade neoplasms, too [4]. In case of doubt, immunohistochemical studies may be carried out to confirm the diagnosis of ccRCC. This type of RCC is known to express CA9, CD10, CK AE1/AE3, and EMA. AMACR expression is variable. CK7 expression is negative or focal in most cases, a fact that distinguishes ccRCC from the majority of papillary and chromophobe RCC [3].

The presence of multiple ccRCC, either in one or both kidneys, indicates a predisposition for the disease and is more likely to be encountered in patients with hereditary renal cancer. Such findings, a positive family history of ccRCC and/or phakomatosis, and comorbidities characteristic of von Hippel-Lindau disease should prompt genetic analyses. Of note, genetic studies may also yield valuable results in patients diagnosed with sporadic ccRCC. They may reveal possible targets for molecular therapies, e.g., constitutively active tyrosine kinases.

• Erythrocytosis

  Clear cell renal cell carcinoma is occasionally associated with erythrocytosis, hypothesized to result from tumoral production of erythropoietin. [ncbi.nlm.nih.gov]

  Urinalysis – micro- or macroscopic hematuria occurs in 60% of patients Complete blood count (CBC) – patients may have anemia of chronic inflammation (normo- or microcytic), some have erythrocytosis from paraneoplastic erythropoietin (Epo) production, [clinicaladvisor.com]

  […] other ailments.[9] Other signs and symptom may include haematuria;[8] loin pain;[8] abdominal mass;[9] malaise, which is a general feeling of unwellness;[9] weight loss and/or loss of appetite;[10] anaemia resulting from depression of erythropoietin;[8] erythrocytosis [en.wikipedia.org]

• Thrombocytosis

  […] macroscopic hematuria occurs in 60% of patients Complete blood count (CBC) – patients may have anemia of chronic inflammation (normo- or microcytic), some have erythrocytosis from paraneoplastic erythropoietin (Epo) production, and rarely some have thrombocytosis [clinicaladvisor.com]

  […] determined according to MSKCC criteria (Memorial Sloan Kettering Cancer Center): Time from initial diagnosis to systemic treatment Karnofsky index 80% LDH 1.5xN Hemoglobin Serum calcium 10 mg/dl The presence of neutropenia (Heng’s criteria) The presence of thrombocytosis [medichub.ro]

Most RCC are highly resistant to both chemotherapy and radiotherapy. Thus, surgery is opted for whenever the patient's general condition doesn't rule out the corresponding intervention. Partial and radical nephrectomy are most commonly carried out [5]. In this context, nephron-sparing surgery should be preferred over more radical interventions in order to maintain kidney function. This applies particularly to patients suffering from hereditary ccRCC, who are prone to relapse [6] [7]. Concomitant lymphadenectomy is recommended in case of visible or palpable adenopathy and needn't be done preventively. Selected patients suffering from stage 1 renal cancer may alternatively be considered for ablative therapies like cryotherapy, radiofrequency ablation, and embolization [5].

In case of surgically unresectable ccRCC, systemic therapy may be carried out with interleukin 2 or interferon-α, with axitinib, erlotinib, pazopanib, sorafenib, sunitinib, temsirolimus, or bevacuzimab in combination with interferon. Precise recommendations regarding possible treatment regimens according to tumor histology and risk stratification of patients are given elsewhere and shall only be briefly outlined here [5] [7]:

• Cytokine-based immunotherapy may induce complete or partial remission in a small subset of patients, but is associated with severe side effects. Durable complete responses are rarely achieved with interferon-α.
• Tyrosine kinase inhibitors and anti-VEGF antibodies are widely used in ccRCC treatment. All compounds named above may serve as first-line therapies in ccRCC patients. Their efficacy and safety has been tested in clinical trials, and they have occasionally been proven to be superior to those of cytokines interleukin 2 or interferon-α.
• To date, bevacuzimab in combination with interferon, pazopanib, and sunitinib, are most commonly administered as first-line therapy in patients with a favorable or intermediate prognosis, while temsirolimus is generally considered the systemic treatment of choice in high-risk patients.

ccRCC is associated with a worse prognosis than the less common papillary and chromophobe RCC. ccRCC are more likely to metastasize and survival rates are lower. About 94% of metastatic RCC originate from ccRCC, and while >80% of patients diagnosed with papillary or chromophobe RCC remain alive five years after diagnosis, five-year survival rates of ccRCC patients range only between 44 and 69% [1].

Little is known about the precise causes of sporadic ccRCC. Nevertheless, certain risk factors have been identified that augment the individual risk of developing this type of cancer: For instance, there are weak but significant correlations between cigarette smoking and ccRCC, and between obesity and ccRCC. Furthermore, the incidence of such tumors is three to six times higher among individuals with acquired cystic kidney disease than in the general population. Hypertension, urinary tract infection, dietary intake of fat and other food ingredients, and occupational exposure to solvents like trichloroethylene are controversially discussed as potential risk factors for ccRCC [6].

Hereditary ccRCC is diagnosed in patients with determined chromosomal or gene aberrations:

• The most common hereditary disorder predisposing for the development of ccRCC is von Hippel-Lindau disease. This disease is caused by mutations in the VHL gene and is inherited in an autosomal dominant manner. Affected individuals are prone to develop ccRCC, but also angioma and hemangioblastoma of the retina or the central nervous system, and pheochromocytoma. For all those traits, penetrance is incomplete. In fact, less than 50% of those suffering from this hereditary disorder are diagnosed with ccRCC during their life [6].
• Occasionally, ccRCC may be detected in patients suffering from familial ccRCC with chromosome 3 translocation, PTEN hamartoma syndrome, or succinate dehydrogenase-associated renal cancer [8].

RCC accounts for about 3% of malignancies diagnosed in adult patients and is the most common type of malignant tumor originating from the kidneys. The individual risk of developing RCC increases with age: This type of tumor is most commonly diagnosed in patients aged >60 years. Histopathological analyses allow for the identification of ccRCC in approximately 70% of all cases [1]. The majority of these cases corresponds to sporadic ccRCC, but individuals with certain DNA sequence anomalies are predisposed to develop this type of tumors. As has been indicated in the previous paragraph, the most common hereditary condition predisposing for ccRCC is von Hippel-Lindau disease. Still, this is a rare disorder with an incidence of 1 in 36,000 births [6]. Males are slightly more affected by ccRCC than males are.

Deletions of the short arm of chromosome 3 are found in the vast majority of ccRCC [1]. Several genes that are assumed to be involved in the etiology of renal cancer are located on chromosome 3p, e.g. VHL, PBRM1, SETD2, and BAP1 [9]:

• VHL mutations are found in more than half of ccRCC cases and are thus not limited to the hereditary von Hippel-Lindau disease. VHL is a tumor suppressor gene; it is a protein-coding gene whose gene product is required for the ubiquitination and degradation of hypoxia-inducible factor. Hypoxia-inducible factor is a transcription factor regulating the expression of genes encoding for glucose transporter GLUT1 and vascular endothelial growth factor, among others.
• PBRM1 is another tumor suppressor gene. It encodes for a component of a nucleosome-remodeling complex and is thus involved in the regulation of the accessibility of DNA segments for transcription factors and RNA polymerases.
• Similar to VHL and PBRM1, SETD2 is a tumor suppressor gene. It encodes for a histone methyltransferase. Mutations in the SETD2 gene may thus interfere with the transcription of certain genes, and it has also been implicated in splicing.
• BAP1 encodes for a deubiquitinating enzyme that acts as a tumor suppressor. Although its precise role in ccRCC pathogenesis remains to be clarified, BAP1 mutations may entail disorders of transcription regulation, DNA repair, cell cycle and growth.

At this time, no measures can be recommended to prevent sporadic ccRCC with certainty. The individual risk of ccRCC, however, may be diminished by means of lifestyle adaptations. For instance, people should be encouraged not to start or to stop smoking, and to maintain a healthy body weight.

Families affected by hereditary ccRCC may benefit from genetic counseling.

Approximately 90% of all kidney cancers are RCC, so this type of tumor is the most common malignancy affecting the kidneys [6]. According to their histological features, several types of RCC are distinguished, namely clear cell, papillary, and chromophobe RCC. Other entities listed in the Classification of Tumors of the Urinary System, as published by the World Health Organization, comprise clear cell papillary RCC, RCC due to hereditary or non-hereditary disorders, and unclassified RCC [3]. About 70% of RCC are ccRCC [1]. In this context, "clear" refers to the characteristic appearance of the cytoplasm of tumor cells. However, as Williamson and colleagues stated, "not all that is clear is cancer" [10]. Clinical, histological and genetic features have to be considered to reach a reliable diagnosis and to avoid mistaking RCC with a lower malignant potential for ccRCC.

Renal cell carcinoma (RCC) is the most common malignancy of the kidneys. There are distinct types of RCC, e.g., clear cell, papillary, and chromophobe RCC. Clear cell RCC account for about 70% of all cases. In this context, the term "clear" refers to the light aspect of cells comprising this type of renal cancer, though this and other features of tumor cells can only be observed microscopically. There are no specific symptoms indicating the presence of clear cell RCC. Indeed, most patients with renal cancer are diagnosed incidentally. If affected individuals experience RCC-related symptoms, these may comprise flank pain, hematuria and a palpable abdominal mass, but also fatigue, fever, night sweats, loss of appetite and weight. But, as mentioned above, clear cell RCC are usually detected during imaging studies realized for other reasons. The majority of patients diagnosed with clear cell RCC undergoes surgery because this type of tumor doesn't typically respond to chemotherapy or radiotherapy. The patient's prognosis largely depends on tumor grade and stage at the time of diagnosis: Highly aggressive tumors are likely to relapse and often metastasize to lungs, liver, or bones. They are associated with a poor prognosis. By contrast, if a less aggressive tumor is detected in early stages, it can probably be removed completely. This improves the prognosis considerably.

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7. Vermassen T, De Meulenaere A, Van de Walle M, Rottey S. Therapeutic approaches in clear cell and non-clear cell renal cell carcinoma. Acta Clin Belg. 2017; 72(1):12-18.
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10. Williamson SR, Cheng L. Clear cell renal cell tumors: Not all that is "clear" is cancer. Urol Oncol. 2016; 34(7):292.e217-222.