Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levels of particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT] are found to be at abnormally high levels. The staging of the cancer can also be determined by abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones. In this case, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of the kidneys and can allow the doctor to decide upon further radiological tests.

The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells. CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) should be considered.

The diagnosis of renal medullary carcinoma is typically made after individuals with sickle cell trait present with the typical signs and symptoms outlined above, in combination with radiographic imaging (usually abdominal/pelvic CT scan) studies and ultimately surgical biopsy and pathological examination of the tumor. Findings on radiographic examination are non-specific and can reveal a mass deep within the kidney. Histopathology studies show a distinctive pattern that can be distinguished from other renal tumors.

Renal medullary carcinoma is extremely rare and it is not currently possible to predict those individuals with sickle cell trait who will eventually develop this cancer. It is hoped that early detection could result in better outcomes but screening is not feasible.

The United States' NIH estimates for 2013 around 64,770 new cases of kidney cancer and 13,570 deaths from the disease.

The incidence of kidney cancer is also increasing in the United States. This is thought to be a real increase, not only due to changes in the way the disease is diagnosed.

The most recent estimates of incidence of kidney cancer suggest that there are 63,300 new cases annually in the EU25. In Europe, kidney cancer accounts for nearly 3% of all cancer cases.

Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan, or MRI. However, molecular diagnostics can be necessary in the following situations: 1- when a definite diagnosis is required in young individuals, such as a potential living related donor in an affected family with equivocal imaging data; 2- in patients with a negative family history of ADPKD, because of potential phenotypic overlap with several other kidney cystic diseases; 3- in families affected by early-onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can be involved; and 4- in patients requesting genetic counseling, especially in couples wishing a pre-implantation genetic diagnosis.

The findings of large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis. In some cases, intracranial aneurysms can be an associated sign of ADPKD, and screening can be recommended for patients with a family history of intracranial aneurysm.

Molecular genetic testing by linkage analysis or direct mutation screening is clinically available; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations who are younger than age 30 years.

Renal oncocytoma is considered benign, cured by nephrectomy. There are some familial cases in which these tumors are multicentric rather than solitary. However, they may be resected to exclude a malignant tumor, e.g. renal cell carcinoma.

The 1973 WHO grading system for TCCs (papilloma, G1, G2 or G3) is most commonly used despite being superseded by the 2004 WHO grading (papillary neoplasm of low malignant potential [PNLMP], low grade, and high grade papillary carcinoma).

There are three methods of scanning that detect angiomyolipoma: ultrasound, CT and MRI. Ultrasound is standard and is particularly sensitive to the fat in angiomyolipoma but less so to the solid components. However it is hard to make accurate measurements with ultrasound, particularly if the angiomyolipoma is near the surface of the kidney (Maclean Grade III). Computed tomography (CT) is very detailed and fast and allows accurate measurement. However, it exposes the patient to radiation and the dangers that a contrast dye used to aid the scanning may itself harm the kidneys. Magnetic resonance imaging (MRI) is safer than CT but many patients (particularly those with the learning difficulties or behavioural problems found in tuberous sclerosis) require sedation or general anaesthesia and the scan cannot be performed quickly. Some other kidney tumours contain fat, so the presence of fat isn't diagnostic. It can be difficult to distinguish a fat-poor angiomyolipoma from a renal cell carcinoma (RCC). Both minimal fat AMLs and 80% of the clear cell type of RCC display signal drop on an out-of-phase (OOP) MRI sequence compared to in-phase (IP). Thus, a lesion growing at greater than 5 mm per year may warrant a biopsy for diagnosis.

Incidental discovery of angiomyolipomas should trigger consideration of tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis, especially if they are large, bilateral and/or multiple. Screening for TSC includes a detailed physical exam, including dermatologic and ophthalmologic evaluations, by TSC expert clinicians and a CT or MRI of the brain. Screening for LAM includes a high resolution CT of the lung and pulmonary function testing.

In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the course of the disease, glomerular filtration rate (GFR) remains normal for decades before kidney function starts to progressively deteriorate, making early prediction of renal outcome difficult. The CRISP study, mentioned in the treatment section above, contributed to build a strong rationale supporting the prognostic value of total kidney volume (TKV) in ADPKD; TKV (evaluated by MRI) increases steadily and a higher rate of kidney enlargement correlated with accelerated decline of GFR, while patient height-adjusted TKV (HtTKV) ≥600 ml/m predicts the development of stage 3 chronic kidney disease within 8 years.

Besides TKV and HtTKV, the estimated glomerular filtration rate (eGFR) has also been tentatively used to predict the progression of ADPKD. After the analysis of CT or MRI scans of 590 patients with ADPKD treated at the Mayo Translational Polycystic Kidney Disease Center, Irazabal and colleagues developed an imaging-based classification system to predict the rate of eGFR decline in patients with ADPKD. In this prognostic method, patients are divided into five subclasses of estimated kidney growth rates according to age-specific HtTKV ranges (1A, 6.0%) as delineated in the CRISP study. The decline in eGFR over the years following initial TKV measurement is significantly different between all five patient subclasses, with those in subclass 1E having the most rapid decline.

Prognosis is highly variable and dependent upon a multitude of factors. Reoccurrence does occur. Treatment is determined on a case-by-case basis.

In gross appearance, the tumors are tan or mahogany brown, well circumscribed and contain a central scar. They may achieve a large size (up to 12 cm in diameter).

The main differential diagnosis of renal oncocytoma is "chromophobe renal cell carcinoma oncocytic variant", which like the renal oncocytoma has eosinophilic cytoplasm, but has perinuclear clearing and, typically, some degree of nuclear atypia.

"FLCN" mutations are detected by sequencing in 88% of probands with Birt–Hogg–Dubé syndrome. This means that some people with the clinical diagnosis have mutations that are not detectable by current technology, or that mutations in another currently unknown gene could be responsible for a minority of cases. In addition, amplifications and deletions in exonic regions are also tested. Genetic testing can be useful to confirm the clinical diagnosis of and to provide a means of determining other at-risk individuals in a family even if they have not yet developed BHD symptoms.

The cutaneous manifestations of Birt–Hogg–Dubé were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by histology. Most individuals (89%) with BHD are found to have multiple cysts in both lungs, and 24% have had one or more episodes of pneumothorax. The cysts can be detected by chest CT scan. Renal tumors can manifest as multiple types of renal cell carcinoma, but certain pathological subtypes (including chromophobe, oncocytoma, and oncocytic hybrid tumors) are more commonly seen. Although the original syndrome was discovered on the basis of cutaneous findings, it is now recognized that individuals with Birt–Hogg–Dubé may only manifest the pulmonary and/or renal findings, without any skin lesions. Though these signs indicate BHD, it is only confirmed with a genetic test for FLCN mutations.

Transitional refers to the histological subtype of the cancerous cells as seen under a microscope.

Biochemical blood tests determine the amount of typical markers of renal function in the blood serum, for instance serum urea and serum creatinine. Biochemistry can also be used to determine serum electrolytes. Special biochemical tests (arterial blood gas) can determine the amount of dissolved gases in the blood, indicating if pH imbalances are acute or chronic.

Urinalysis is a test that studies urine for abnormal substances such as protein or signs of infection.

- A Full Ward Test, also known as dipstick urinalysis, involves the dipping of a biochemically active test strip into the urine specimen to determine levels of tell-tale chemicals in the urine.

- Urinalysis can also involve MC&S microscopy, culture and sensitivity

Urodynamic tests evaluate the storage of urine in the bladder and the flow of urine from the bladder through the urethra. It may be performed in cases of incontinence or neurological problems affecting the urinary tract.

Ultrasound is commonly performed to investigate problems of the kidney and/or urinary tract.

Radiology:

- KUB is plain radiography of the urinary system, e.g. to identify kidney stones.

- An intravenous pyelogram studies the shape of the urinary system.

- CAT scans and MRI can also be useful in localising urinary tract pathology.

- A voiding cystogram is a functional study where contrast "dye" is injected through a catheter into the bladder. Under x-ray the radiologist asks the patient to void (usually young children) and will watch the contrast exiting the body on the x-ray monitor. This examines the child's bladder and lower urinary tract. Typically looking for vesicoureteral reflux, involving urine backflow up into the kidneys.

As metanephric adenomas are considered benign, they can be left in place, i.e. no treatment is needed.

Angiomyolipomas are the most common benign tumour of the kidney and are found either in patients with tuberous sclerosis or sporadically. About 80–90% of cases are sporadic and these are most commonly found in middle-aged women.

In patients with TSC, a longitudinal study found 80% will have some form of renal lesion by around 10 years of age. Of these, 75% are angiomyolipomas and 17% cysts. The angiomyolipomas increased in size in around 60% of these children. An autopsy study and TSC clinic survey found a prevalence of 67% and 85% respectively for patients with TSC. Both genders are affected equally.

Acquired cystic kidney disease-associated renal cell carcinoma is rare subtype of renal cell carcinoma.

As of 2010 there is insufficient evidence to determine if screening for bladder cancer in people without symptoms is effective or not.

In 2013 a preliminary, small study of 98 samples of urine, all from men—24 who had cancer, and 74 with bladder-related problems but no cancer yet used a gas chromatograph to successfully examine the vapor from heated urine samples to identify cancer.

Metanephric adenoma is diagnosed histologically. The tumours can be located at upper pole, lower pole and mid-hilar region of the kidney; they are well circumscribed but unencapsulated, tan pink, with possible cystic and hemorrhagic foci. They show a uniform architecture of closely packed acinar or tubular structures of mature and bland appearance with scanty interposed stroma. Cells are small with dark staining nuclei and inconspicuous nucleoli. Blastema is absent whereas calcospherites may be present. Glomeruloid figures are a striking finding, reminiscent of early fetal metenephric tissue. The lumen of the acini may contain otherwise epithelial infoldings or fibrillary material but it is quite often empty. Mitoses are conspicuously absent.

In the series reported by Jones "et al." tumour cells were reactive for Leu7 in 3 cases of 5, to vimentine in 4 of 6, to cytocheratin in 2 of 6, to epithelial membrane antigen in 1 of 6 cases and muscle specific antigen in 1 of 6.

Olgac "et al." found that intense and diffuse immunoreactivity for alpha-methylacyl-CoA racemase (AMACR) is useful in differentiating renal cell carcinoma from MA but a panel including AMACR, CK7 and CD57 is better in this differential diagnosis.

Differential diagnosis may be quite difficult indeed as exemplified by the three malignancies initially diagnosed as MA that later metastasized, in the report by Pins et al.

Cystic nephromas are diagnosed by biopsy or excision. It is important to correctly diagnose them as, radiologically, they may mimic the appearance of a renal cell carcinoma that is cystic.

Cystoscopy, a procedure in which a flexible tube bearing a camera and various instruments is introduced into the bladder through the urethra allows diagnosis and by biopsying suspicious lesions.

The gold standard for diagnosing bladder cancer is biopsy obtained during cystoscopy. Urine cytology can be obtained in voided urine or at the time of the cystoscopy ("bladder washing"). Cytology is not very sensitive (a negative result cannot reliably exclude bladder cancer). There are newer non-invasive urine bound markers available as aids in the diagnosis of bladder cancer, including human complement factor H-related protein, high-molecular-weight carcinoembryonic antigen, and nuclear matrix protein 22 (NMP22). NMP22 is also available as a prescription home test. Other non-invasive urine based tests include the CertNDx Bladder Cancer Assay, which combines FGFR3 mutation detection with protein and DNA methylation markers to detect cancers across stage and grade, UroVysion, and Cxbladder.

The diagnosis of bladder cancer can also be done with a Hexvix/Cysview guided fluorescence cystoscopy (blue light cystoscopy, Photodynamic diagnosis), as an adjunct to conventional white-light cystoscopy. This procedure improves the detection of bladder cancer and reduces the rate of early tumor recurrence, compared with white light cystoscopy alone. Cysview cystoscopy detects more cancer and reduces recurrence. Cysview is marketed in Europe under the brand name Hexvix

However, visual detection in any form listed above, is not sufficient for establishing pathological classification, cell type or the stage of the present tumor. A so-called cold cup biopsy during an ordinary cystoscopy (rigid or flexible) will not be sufficient for pathological staging either. Hence, a visual detection needs to be followed by transurethral surgery. The procedure is called transurethral resection of bladder tumor (TURBT). Further, bimanual examination should be carried out before and after the TURBT to assess whether there is a palpable mass or if the tumour is fixed ("tethered") to the pelvic wall. The pathological classification obtained by the TURBT-procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow-up routines.

A 2009 revision of the traditional Chompret criteria for screening has been proposed:

A proband who has:

- tumor belonging to the LFS tumor spectrum - soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia or lung bronchoalveolar cancer - before age 46 years;

and at least one of the following:

- at least one first or second degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumours

- a proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before age 46 years

- a proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history