Evaluating incidental renal cysts

Last week, I got an email from a residency friend asking me what I would do with a patient who had a Bosniak II renal cyst. Since “I don’t know” no longer seemed a satisfactory answer for someone who specializes in kidneys, I looked it up, returned her email, then decided to review the radiologic classification of renal cysts on the blog, for anyone else who would like a refresher. An excellent review by Glickman et al can be found in the journal Radiology.

Renal cysts are masses filled with fluid. They are extremely common: some studies have estimated their incidence in the general public at around 50%. Most are discovered incidentally, since they rarely cause symptoms. Flank pain and hematuria are occasionally seen. Radiologic features of renal cysts convey important information about their malignant potential—our main concern as physicians. Does the wall of the cyst appear thin and simple, or does it have a thickened lining? Is the fluid in the cyst attenuated? How heterogeneous does the cyst appear? Are there septae or enhancing soft tissue components? In 1986, a classification scheme was published by Bosniak that stratified malignant risk based on characteristics of the cyst on CT scan. The Bosniak classification remains a useful guide for management of incidentally-discovered renal cysts. It should be emphasized, however, that evaluation of cysts must take into account a patient’s demographics and medical history: a diagnosis cannot be made by imaging alone.

Bosniak Classification of Renal Cysts

Bosniak I- benign, simple cysts, with thin walls. Note that size is not a factor in classifying cysts in this category. Bosniak I cysts are always benign, and can be ignored. These cysts are not attenuated, and tend to have Hounsfield units of 0-20.

Bosniak II- benign, minimally complicated cysts; may have hairline-thin septa with some perceived enhancement. There may be fine calcification or areas of calcified thickening along the wall or septa. Fine calcification or a short segment of slightly thickened calcification may be present in the wall or septa. Homogeneous hyperattenuating cysts also belong in this category—high Hounsfield units usually signify proteinaceous fluid. Bosniak II cysts are also felt to have non-malignant potential, and can be ignored by the physician.

Bosniak IIF- these are slightly more complicated that class II cysts, and so warrant observation. IIF cyts may contain multiple, hairline-thin septa that demonstrate perceived (but not measurable) enhancement. There may be minimal smooth thickening of the wall or septa. Calcification that is more irregular and thicker than in Bosniak II cysts may be present. Soft tissue elements are absent. Hyperattenuating cysts otherwise classified as category II cysts, but are > 3cm and completely within the renal parenchyma are included in class IIF. The general recommendation for observation of these cysts is to reimage with CT or MR in six months, then yearly for a minimum of five years. If they remain stable, it can be assumed that they are benign, and no further follow-up is needed.

Bosniak III- the malignant potential of class III masses is indeterminate on imaging; therefore, surgical removal is recommended. These cysts have thickened walls or septa, and display enhancement. They include multilocular cysts (in which the walls have fibrous lining), hemorrhagic or infected cysts, multilocular cystic nephroma (which conatin blastemal elements), or cystic renal cell carcinoma. It is estimated that 50% are malignant (studies have shown malignancy rates ranging from 31% to 100%).

Bosniak IV- share features of Bosniak III, plus enhancing soft-tissue components adjacent to or separate from the wall or septa. They are almost always malignant. Management is surgical.


The Bottom Line: radiologic followup is needed only for class IIF lesions. The others are either ignored or referred for surgical management secondary to the high rates of malignancy.

Renal Malignancy Syndromes

I had a patient come to see me last week with the rare disorder, Birt Hogg Dube Syndrome (BHD). She was referred with a mildly elevated serum creatinine and microalbuminuria against a background of a single kidney following nephrectomy for renal cancer, which, along with skin abnormalities, is a feature of the syndrome (see left). She initially presented to dermatology with multiple small papule like lesions on the face, which on biopsy were fibrofolliculomas (skin follicle hamartomas). Her renal cancer presented as an incidental finding in 1993 with a 10cm lower pole tumor attached to small bowel. It was removed and pathology was a chromophobe tumor. It has not recurred despite it's large size and local invasion at presentation.
BHD may present with multiple or bilateral renal cancers; it is also associated with oncocytomas of the kidney, and with pulmonary cysts and spontaneous pneumothorax (which she does not have). It is due to a loss of function mutation of a gene on chromosome 17 which may be a tumor suppressor gene and the gene product is folliculin.

We see a lot of patients (relatively) in our clinic with Tuberous Sclerosis Complex, as we are a referral center. TSC is also rarely associated with renal cancer (in 1-2% of cases). There are numerous skin manifestations of TSC, including facial angiomas. Other major manifestations include lymphangiomyomatosis of the lung, cardiac rhabdomyomas, CNS cerebral tubors and renal angiomyolipomas (AML's), as well as renal cysts. It is an autosomal dominant condition. TSC has two genotypes. The gene defect for TSC1 is on Chromosome 9 (encodes for Hamartin); the gene defect for TSC 2 is on Chromosome 16 (encodes for Tuberin). Hamartin and Tuberin are involved in cell cycle regulation.


Finally, Von Hippel Lindau (VHL) is much more frequently associated with renal cell cancer. It is also autosomal dominant with the loss of function defect on chromosome 3 which is also tumor suppressor gene. VHL is associated with

• Hemangioblasomas of the brain, retinal angiomas
  
• Pheochromocytoma
• Pancreatic neuroendocrine tumors
• Renal cysts
• Renal cell cancer - usually a clear cell cancer

Posted by David Steele MD

Telomeres, Renal Cell Carcinoma, and the 2009 Nobel Prize in Medicine

The winners of the 2009 Nobel Prize in Medicine were revealed today, shared by three Americans: Carol Greider, Elisabeth Blackburn, and Jack Szostak, the latter of whom works at my home institution of Massachusetts General Hospital. The award was given for their work on telomeres, the regions of repetitive DNA which form protective "caps" on the ends of chromosomal DNA, necessary for preventing the degradation of DNA ends. The study of telomeres has implications not only for basic molecular biology, but also for cancer biology: many tumor lines express an enzyme called telomerase, which catalyzes the addition of telomeres onto DNA ends by virtue of a reverse transcriptase-based mechanism, allowing cancer cells to sustain their high rate of cell division.

For instance, in a 1999 KI study by Dahse et al, increased telomerase activity was detected in 55 out of 60 different primary renal cell carcinoma lines.

Tuberous Sclerosis Complex and the Kidney

Tuberous sclerosis complex (TSC) is a rare genetic disease, caused by mutations within one of two genes (TSC1 or TSC2) which is named for the formation of hard tumors ("tubers") within a variety of tissues, including the CNS, kidneys, eyes, heart, lungs and skin. Often, dermatologic clues can be essential to making a diagnosis; common examples include facial angiofibromas (a rash of reddish spots appearing on the nose and cheeks in a butterfly distribution), "ash leaf spots" (hypopigmented macules), ungual or subungual fibromas, Shagreen patches (areas of thick, leathery skin, often found at the nape of the neck), and cafe au lait spots.

Most patients with tuberous sclerosis have some renal lesion, though fortunately it is usually not severe. There are a wide range of renal manifestation of TSC, many of which are detailed in this 2006 Kidney International review by Rakowski et al. About 80% of patients have renal angiomyolipomas, an abnormal collection of blood vessels, smooth muscle, and fat cells; these are best identified on CT as fat-containing lesions. They are felt to pose little to no risk of evolving into anything malignant, though they are at risk for bleeding (and sometimes even catastrophic bleeding). In addition to angiomyolipomas, up to 45% of TSC patients get cysts. Rarely, TSC and ADPKD can occurs simultaneously, as the TSC1 gene and PKD1 gene are located near one another and may be deleted in some instances. Finally, about 1-2% of TSC patients will develop renal cell carcinoma. This can be tricky to diagnose (especially given the high likelihood of angiomyolipomas or simple cysts). Individuals with TSC who get kidney failure and enjoy a transplant generally do well, though the current recommendation here is to perform a bilateral native nephrectomy at the time of transplant in the hopes of minimizing the cancer risk in the setting of immunosuppression.

Genetics of Wilms Tumor

Wilms Tumor--named after the German surgeon/pathologist Max Wilms (pictured at left)--is an embryonal tumor that derives from developing kidney tissue. Wilms was the first to postulate that tumors may arise from precursor cells which arise during development, and indeed study of the molecular pathways active in these "nephroblastoma" shed light on normal kidney development.

There are several genes associated with patients with Wilms Tumor. Here are some of the main ones:

1. WT1 is a transcription factor and considered a tumor suppressor gene. Mutations in WT1 account for between 10-15% of sporadic Wilms tumor. It interacts with p53, a classic tumor suppressor involved in a wide variety of cancers. Denys-Drash Syndrome, a familial and severe form of Wilms tumor, is usually caused by congenital WT1 mutations.

2. beta-catenin is a key component of the canonical Wnt signaling pathway, long known to be a key player in kidney development. Interestingly, most patients with WT1 also have gain-of-function point mutations in the beta-catenin gene which result in increased stability of the beta-catenin protein and subsequent unregulated Wnt signaling.

3. WTX is mutated in a different subset of patients than those with WT1 mutations, and is found on the X-chromosome.

4. BDNF (brain-derived neurotrophic factor): mutations in this growth factor are postulated to result in the WAGR Syndrome--a constellation of symptoms that includes Wilms Tumor along with aniridia, GU abnormalities, and mental retardation.

5. BRCA2: interestingly, mutations in the well-known breast cancer-susceptibility gene can also lead to Wilms tumor.

The Hatfields, the McCoys, and von Hippel Lindau Syndrome

I saw a patient in my clinic today with the diagnosis of von Hippel-Lindau Disease. She has a Cr in the mid 2's as a result of prior vascular disease as well as being status-post nephrectomy for a renal cell carcinoma discovered several years ago. To review, von Hippel-Lindau (VHL) disease is a rare, autosomal dominant genetic condition characterized by hemangioblastomas of the cerebellum, spinal cord and retina; individuals also have a high rate of nephrology-relevant tumors such as renal cell carcinoma and pheochromocytoma. The VHL gene is a tumor suppressor gene.

What do the Hatfields & McCoys have to do with VHL? In my rapid google search of VHL in the minutes preceding this patient's office visit, I found this interesting hit in which a Vanderbilt geneticist posits that this infamous Appalachian feud between two warring families could in part be due to the fact that the McCoy family is known to carry the VHL disease gene, with multiple affected family members who went public a few years ago. The theory states that pheochromocytomas within affected individuals would lead to an easily-angered and overly-aggressive phenotype as a result of unregulated adrenaline secretion by existing pheochromocytomas. Truth or fiction? It seems a matter of speculation, but a historically fun theory to consider.

Waiting Times for Potential Kidney Transplant Recipients With History of Cancer

I saw a patient in the renal transplant clinic today for evaluation to get onto the kidney transplant list, as he is just around the corner to starting dialysis (actually, he may actually start tonight since his routine labs came back with a K of 6.9...). 

His chronic kidney disease was thought secondary to (a) long-standing hypertension, and (b) a history of bilateral partial nephrectomies for a history of bilateral renal cell carcinomas which were diagnosed about 4 years ago.  

Given this patient's history of cancer and the possibility of recurrence, should this patient be recommended to go onto the kidney transplant list?  How long does he need to wait?  Could the administration of immunosuppresant medications really result in decreased immune surveillance of cancer cells which could potentially result in earlier recurrence of metastatic disease?

  

These are all good questions, and there seems to be a relative lack of data.  According to one seasoned renal transplant doctor I spoke with today, if there is any increased likelihood of cancer in these patients (other than skin cancers or PTLD), it is likely small and not a reason to postpone transplant; the main reason in his mind for waiting to ensure a lack of cancer recurrence is to minimize the likelihood that the patient would need to undergo toxic chemotherapy or a major surgery which could interfere with the graft function.  In addition, there is also the issue of wanting to preserve a scarce resource (donated kidneys) for patients who will benefit from them the longest.  

Nonetheless, the American Transplant Society (ATS) has come up with a list of guidelines for "waiting times" after being treated for various cancers before one should be considered for kidney transplant.  To generalize:  breast, colorectal and melanoma cancers have a recommended waiting time of 5 years unless they are early stage; most other cancers (e.g., renal cell cancer, leukemia, lung cancer, prostate cancer, etc) have a waiting time of only 2 years.  Non-melanoma skin cancers (basal cell, squamous cell) are generally not a reason for delaying kidney transplant as they are generally treatable.  

Bilateral Renal Cell Carcinomas

The case: a 50-ish yo woman, normal baseline renal function, and a history of nephrolithiasis x 2 episodes presented with gross, painless hematuria. She was initially thought to have another stone event, but she had no significant flank pain. Ultimately she underwent CT imaging which revealed bilateral renal masses suspicious for renal cell carcinoma.

Fortunately, there was no evidence of metastatic disease, and she underwent a R total nephrectomy followed by a partial L nephrectomy, leaving her with about 1/4 of her original nephron mass. Pathology reveals a clear cell-type RCC in both biopsy specimens. Her Cr remains in the 1.0-1.2 range. A question is raised as to why she developed two separate RCC's.

There is an interesting differential diagnosis of bilateral RCCs which includes some interesting genetic syndromes, the most common of which is von Hippel Lindau Syndrome, an autosomal dominant inherited gene caused by mutations in the VHL gene. Because the VHL gene is a tumor suppressor gene, there are other tumors which may occur in these patients, including pheochromocytomas and hemangioblastomas, among others. Specifically it is the clear cell RCC which occurs in VHL Syndrome. Other genetic disorders causing RCC's include Hereditary Papillary RCC (caused by mutations in the c-met gene), Tuberous Sclerosis (more likely to cause benign angiomyolipomas, but can result in RCCs), Hereditary Leiomyoma and Renal Cell Cancer Syndrome, and the Birt-Hogg-Dube (BHD) syndrome (resulting in chromophobe RCCs).

Despite these numerous possibilities of mutations causing RCC, a 1998 study revealed that amongst patients with bilateral RCC who underwent extensive mutation screening, only 12% had a hereditary form of RCC whereas the remaining 88% had "sporadic", bilateral RCCs.