Renal cysts are present in 59-63% of individuals with VHL and if one excludes families with pheochromocytomas and performs careful screening with CT the number may be as high as 85% (60). Renal cell carcinoma (RCC) is reported to develop in 24-45% of VHL patients (1,4,9,18). Renal disease is an unusual first presentation of VHL; eye and CNS findings usually precede discovery of renal involvement (61) (Figure 1).
Mean age of discovery of renal disease is 37 years which is 20 years earlier than the mean age of discovery for sporadic RCC (18,23,61). Renal cancers have been reported in patients as early as 15 years (62). Unlike sporadic RCC, the male to female ratio is approximately equal in RCC associated with VHL. As patients survive their CHbs, RCC is expected to increase in relative importance as a cause of morbidity and surveillance should continue throughout a patient's lifetime (4,17). Metastatic RCC historically has caused about one third of deaths among VHL patients and in some studies it is the leading cause of death (4,12,50,63).
Renal involvement in VHL is multicentric and bilateral in at least 75% of patients (60,61). It is unclear whether the basic lesion in the kidneys of patients with VHL is the renal cyst or whether solid renal tumors can form independently without arising from a cyst. Solomon et al observed that most cysts contained foci of tumor and many large tumors contained remnants of cysts, leading to the conclusion that the renal cyst was a precursor to the renal tumor (64). Quantitative DNA analysis of clear cells lining cyst walls and clear cells from tumors show these two cell types are very similar with respect to this parameter (65,66). This is supported by the observation that cysts generally precede tumors by 3-7 years (23,60). Kragel et al, however, using tissue markers showed that the solid and complex renal masses containing RCC arose from proximal tubular epithelium whereas benign cysts arose from distal tubular epithelium (67). Thus, two groups of cysts occur in VHL; one with malignant potential and one with little or no malignant potential (67). In vivo observations of serial CTs support the concept that tumors can arise either de novo or from complex cystic precursor lesions (23,60). Gardner and Evan suggest that the basic lesion may be epithelial hyperplasia which leads to either a simple cyst (on an obstructive basis) or tumors (with or without a cyst) (68). Other renal lesions associated with VHL are renal adenomas and renal angiomas but there is doubt to the existence of the former and the frequency of the latter (18).
VHL renal cysts demonstrate a continuum from simple cysts with a single or double layer of clear cell epithelium to carcinoma presenting as complex papillary projections into the cystic lumina or as dysplastic lining epithelium (64). Small nodules of low grade clear cells can be found within the walls of the cyst (23). Studies with serial CTs have shown that the solid components of such lesions may enlarge while the cystic components regress (60) (Figure 11,12). The majority of cysts, however, remain "cystic" over time although they may change in size. Cysts commonly grow, typically at rates of 0.5 cm/yr, but some cysts involute over time leaving small scars on the renal surface which may be the cause of the hyalinized fibrotic nodules that are reported in VHL (60,64). Neither cyst size nor number correlates with malignant potential (64). Extensive renal cystic disease in VHL can mimic autosomal dominant polycystic kidney disease (ADPCKD) replete with renal failure (9,23,69) (Figure 13). However, unlike ADPCKD, it is important to completely remove end-stage kidneys due to VHL because of the potential for malignancy (69,70). It is likely that some of the early reports showing an increased risk of malignancy in ADPCK were really advanced cases of VHL (66).
Figure 11. Serial CT images of renal cell carcinoma with growth in VHL. a.) Initial
CT demonstrates a subtle lesion deep in the renal parenchyma (arrow). b.)
CT scan four years after the initial study demonstrates further growth of
the original lesion and new growth of a second deep lesion. This sequence
illustrates that growth of VHL renal cancers can be quite rapid.
Figure 12. MRI in renal VHL. This patient had renal dysfunction. a.) The CT scan
demonstrated an inhomogeneous nephrogram and an enlarged renal pelvis (P)
due a post operative ureteropelvic junction narrowing. b.) Contrast enhanced
MRI demonstrates numerous solid (bottom arrow) and cystic (top arrow) lesions
within the kidney.
Figure 13. Polycystic VHL simulating autosomal dominant polycystic kidney disease.
Note extensive bilateral renal and pancreatic cysts. This pattern can mimic
autosomal dominant polycystic kidney disease,including renal failure, however,
although these cysts appear benign they commonly contain foci of malignancy
within their wall.Solid renal cell cancers develop de novo and progress in VHL. Microscopic solid tumorlets have been identified within the renal parenchyma of patients with VHL. Some of these undoubtedly develop into macroscopic tumors. Solid tumors have been observed to grow at rates of between 0.2cm/yr and 2.2 cm/yr with a mean of 1.6cm/yr which is somewhat faster than those observed in sporadic renal cell carcinoma (60). There is also evidence that some tumors involute to hyalinized nodules presumably due to ischemic necrosis (18,64). Anecdotal evidence suggests that renal tumors grow faster in women while they are pregnant; until more is known about this, careful follow-up with renal ultrasound is recommended during pregnancy.
Metastatic disease is the unfortunate consequence of a neglected renal tumor. Metastatic renal cancer in VHL disease has not been reported with VHL with tumors smaller than 7 cm (62). This observation has justified a conservative approach to solid masses in the kidney.
Computed tomography is essential for the diagnosis of renal involvement in VHL. CT is more sensitive than ultrasound in detecting the small lesions (2cm) typically disclosed with a screening study. Thin section (3-5mm), contrast enhanced CT is mandatory (71,72,73) and spiral geometry is desirable to decrease the chances of missing lesions. Nonetheless, ultrasound is critical to help determine whether a lesion is principally cystic or solid. Some screening protocols recommend alternate yearly CT and ultrasound in order to lower cumulative radiation exposure; however, we are uncomfortable with using ultrasound exclusively to screen for renal cell carcinoma. Ultrasound is less sensitive for the detection of small renal masses than is CT. Because of the extraordinary frequency of microscopic RCC in VHL we never diagnose a renal lesion as a pure cyst and consider all renal lesions suspicious for harboring cancer regardless of their imaging appearance. Contrast enhanced MRI is sometimes useful in determining whether a lesion is principally solid or cystic. Breath-held, T1 weighted fat saturated images after contrast media demonstrate tumors with remarkable clarity. MRI is especially useful in patients with renal failure in whom screening for RCC is still necessary (Figure 12). Angiography is not as sensitive as other techniques for detecting RCC and is only used for preoperative "road mapping" to identify the renal vascular supply prior to partial nephrectomy (74). The optimal treatment for VHL related renal lesions must be tailored for each patient. There is considerable variability in the growth rates of renal masses. Some patients are discovered late in the course of the disease and bilateral nephrectomy is the only option (61). The well known disadvantages of bilateral nephrectomy and subsequent renal replacement therapy are further complicated by the multisystem nature of VHL. Renal transplantation, for instance, requires immunosuppression which carries the risk of promoting tumor growth. Moreover, patients with cancer have higher complication rates and greater mortality on dialysis (75). A delay of one year is usually advocated between nephrectomy and transplantation to ensure that no metastases will occur (50,75,76,77).
Most patients, however, present with normal renal function and small renal cysts and masses. Potential options for these patients include continued follow-up, enucleation and/or partial nephrectomy and bench surgery. The risk of indefinite follow-up is that a tumor may metastasize. One approach is to wait until the solid lesions attain a specific size (2-3cm for instance) and then perform nephron sparing surgery (62). This approach does not presume to cure but rather to minimize the risk of metastases while delaying the onset of renal failure. With extensive bilateral disease it may be preferable to operate first on the kidney that has the greater potential for partial salvage since it may sustain sufficient ischemic injury to result in a period of renal insufficiency. Simple enucleation must include a rim of normal tissue since microscopic invasion through the tumor's pseudocapsule may be seen even if it is uncommon (77). Good short term results are seen with enucleation and partial nephrectomy but recurrences, often at new sites, are frequent (78). Distant metastases which occur shortly after nephron sparing surgery probably represent microscopic metastatic deposits that predated the nephron sparing surgery (79). Color flow and gray scale intraoperative ultrasound have been used to help identify lesions deep to the surface of the kidney and to aid the surgeon in avoiding critical structures (78,80,81).
After surgery the patient needs to be closely followed. We perform CT scans every six months for two years followed by lifetime annual screening (79).
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