- von Hippel-Lindau syndrome: greater tendency for bilateral renal cell carcinomas as well as a presentation at a younger age; clear cell subtype
- tuberous sclerosis: renal cell carcinomas occur at a younger age
- Birt-Hogg-Dubé syndrome: often bilateral; chromophobe subtype
- sickle cell disease and particularly sickle cell trait: renal medullary carcinoma
Clinical presentation
Presentation is classically described as the triad of:
- macroscopic hematuria: 60%
- flank pain: 40%
- palpable flank mass: 30-40%
This triad is however only found in 10-15% of patients 1,2 , and increasingly the diagnosis is being made on CT for assessment of hematuria alone or as an incidental finding. The majority of cases are sporadic. In contemporary medicine, almost half of all identified renal cell carcinomas are found incidentally on imaging performed for other purposes.
Paraneoplastic syndromes
Around 25% of renal cell carcinoma patients will develop a paraneoplastic syndrome 19-21 :
- hypercalcemia (20%)
- hypertension (20%)
- polycythemia: from erythropoietin secretion (~5%)
- Stauffer syndrome: hepatic dysfunction not related to metastases
- feminization
- limbic encephalitis
Pathology
Renal cell carcinomas arise from tubular epithelium, and encompass a number of distinct histological varieties, including 4-6 :
- clear cell renal carcinoma (conventional): 70-80%
- arises from proximal convoluted tubules
- large uniform cells with clear cytoplasm (thus the name and T2 appearance (see below)
- highly vascular
- subtype: clear cell multilocular renal cell carcinoma
- arises from distal convoluted tubules
- can be multifocal and bilateral
- type I: sporadic, generally good prognosis 4
- type II: inherited, bilateral and multifocal
- arises from intercalated cells of collecting ducts
- similar histologically to renal oncocytomas 4
- best prognosis 5
- often younger patients
- worst prognosis 5
- seen primarily in patients with sickle cell disease or sickle cell trait 4
- advanced renal cell carcinomas may dedifferentiate into this highly aggressive subtype 15
Macroscopic appearance
Macroscopically, renal cell carcinomas are variable in appearance, ranging from solid and relatively homogeneous to markedly heterogeneous with areas of necrosis, cystic change, and hemorrhage 4 .
Low grade, smaller tumors typically have a pseudocapsule composed of compressed and ischemic normal renal tissue. The presence of a pseudocapsule is only seen in renal cell carcinomas, renal adenomas, and oncocytomas 8 .
Renal cell carcinoma is one of the more common causes of cannonball metastases to the lung.
Grading
The most widely used and most predictive histological nuclear grading system for renal cell carcinoma is the "Fuhrman nuclear grade". An alternative nuclear grading system is the "International Society of Urological Pathology (ISUP) grading classification". Both these systems grade tumors on a scale of 1-4, where grade 1 carries the best prognosis and grade 4 the worst.
Radiographic features
Imaging is essential in accurately staging renal cell carcinomas (see renal cell carcinoma staging (TNM) and Robson staging system) and in operative planning.
Ultrasound
Although ultrasound is very frequently requested to assess the renal tract, it is not as sensitive or specific as CT or MRI. Furthermore, it struggles to accurately locally stage the disease in many instances 4 .
Renal cell carcinoma has a widely varying sonographic appearance. It may appear solid or partially cystic and may be hyper-, iso-, or hypoechoic to the surrounding renal parenchyma 22 . The tumor pseudocapsule can sometimes be visualized with ultrasound as a hypoechoic halo. Although this is a relatively specific sign, it is not particularly sensitive (~20%). The use of harmonic scanning has been reported to increase sensitivity to up to 85% 8 .
Contrast-enhanced ultrasound 16 typically shows a lesion heterogeneously hypervascular in the arterial phase with early washout in the delayed phase.
CT
CT is frequently used to both diagnose and stage renal cell carcinomas.
On non-contrast CT, lesions are of soft tissue attenuation between 20-70 HU 23,24 . Larger lesions frequently have areas of necrosis. Approximately 30% demonstrate some calcification 7 .
During the corticomedullary phase of enhancement, 25-70 seconds after administration of contrast, renal cell carcinomas demonstrate variable enhancement, usually less than the normal cortex. Small lesions may enhance a similar amount and can be difficult to detect 7 . In general small lesions enhance homogeneously, whereas larger lesions have irregular enhancement due to areas of necrosis. The clear cell subtype may show much stronger enhancement 5 .
The corticomedullary phase is also best for assessing vascular anatomy, both for renal vein involvement, and for arterial variation if partial nephrectomy is being contemplated 7 . Intraluminal growth into the venous circulation, in particular, the renal vein, occurs in ~10% (range 4-15%) 12 . The prognosis is significantly worse for those with IVC involvement compared to renal vein involvement alone, making identification on CT important 13 .
The nephrographic phase (80-180 seconds) is the most sensitive phase for detection of abnormal contrast enhancement.
Excretory phase is of less worth, but important in assessing the collecting system anatomy especially if the patient is a potential candidate for partial nephrectomy.
Follow-up imaging after treatment is typically done with CT, with dual-phase imaging of the abdomen advocated to maximize the detection of solid organ metastases 9 . Renal cell carcinoma typically causes hypervascular metastases, best appreciated on arterial phase imaging of the upper abdomen.
MRI
MRI is not only excellent at imaging the kidneys and locally staging tumors, but is also able to suggest the likely histology, on the grounds of T2 differences.
- T1: often heterogeneous due to necrosis, hemorrhage, and solid components
- T2: appearances depend on histology 6
- clear cell renal cell carcinoma: hyperintense
- papillary renal cell carcinoma: hypointense
The tumor pseudocapsule, essentially only seen in low-grade renal cell carcinomas, renal adenomas, and oncocytomas, appears as a hypointense rim between the tumor and the adjacent normal renal parenchyma 8 .
MRI is also useful for imaging renal vein and IVC tumor thrombus and the rostral extension (important in preoperative planning). The presence of enhancement in the thrombus is able to distinguish between bland and tumor thrombus 4 .
The use of diffusion-weighted sequences has been explored in assisting with characterizing indeterminate small renal lesions, which may be inflammatory or malignant in nature, both exhibit restricted diffusion, albeit the restriction is greater with an abscess than a tumor 10 .
Nuclear medicine
FDG-PET
Unlike many other malignancies, FDG-PET may have limited value in primary renal carcinoma mostly as a result of physiological excretion of FDG from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys 32 . However certain publications suggest it can effectively be used for postoperative surveillance and restaging as an adjunct when conventional imaging is not conclusive and in some situations such as differentiating benign or bland emboli from tumor emboli 32 .
Treatment and prognosis
Treatment of renal cell carcinomas is usually with radical nephrectomy if feasible. However, in elderly patients or those with co-morbidities, and especially those with smaller tumors suggestive of papillary histology (see MRI findings above) then organ-sparing treatment can be entertained. This ranges from adrenal sparing nephrectomy to partial nephrectomy, performed both open or laparoscopically. Additionally, percutaneous radiofrequency, chemical or cryoablation (typically under CT guidance), which can be carried out with only local anesthetic and sedation, has been introduced in selected cases 11 .
Prognosis varies depending on both the histological subtype and stage.
The chromophobe subtype carries the best prognosis 35 with an overall 5-year survival rate of 78-100%, followed by the papillary subtype (>80%). Clear cell (conventional) renal cell carcinoma carries a 5-year survival of 50-70%. The collecting duct subtype is extremely aggressive and carries a 2-year survival rate of 70% 6,35 . Medullary subtype is also extremely aggressive.
As far as the effects of tumor stage (see renal cell carcinoma staging) are concerned, there is a dramatic difference between stage I and IV tumors:
- stage I: 90% 5-year survival
- stage II: 50% 5-year survival
- stage III: 30% 5-year survival
- stage IV: 5% 5-year survival
Approximately one-third of newly diagnosed cases of renal cell carcinomas have metastatic disease at the time of initial presentation (synchronous metastases) 30 . The most common sites of metastasis are, in order, the lungs, bones, lymph nodes, liver, adrenals, and brain 25 .
Differential diagnosis
The broad differential is essentially that of all renal masses, particularly other renal tumors, and most commonly includes:
- renal tumors
- renal adenoma: should be considered small, early renal cell carcinomas
- renal oncocytoma: particularly for chromophobe type
- angiomyolipoma (AML):
- usually has a large component of fat
- 4-5% have little or no fat however 6
- hemorrhagic or complex renal cyst: see Bosniak classification
- renal abscess/pyelonephritis/lobar nephronia
- renal infarct
- hypertrophied column of Bertin
- transitional cell carcinoma of the renal pelvis
- adrenal tumors
- retroperitoneal tumors
