A 63-year old male presented with abdominal pain and a CT scan showed a right kidney mass and multiple lung metastases. Liver appears normal on scan. Radiologic imaging favours a renal cell carcinoma. However, his liver tests show low albumin, bilirubin is at upper limit of normal. He has increased alkaline phosphatase (2X normal), and less than 1.5X normal ALT and AST. You order hepatitis serology which are all negative. Which of the following would be correct?
| 1. |
He is likely to have liver metastases hence prognosis is very bad and no treatment should be considered. |
| 2. |
Do a tri-phasic CT scan of liver to rule out primary hepatoma in addition to renal cell carcinoma. |
| 3. |
Consider nephrectomy as that may improve the liver condition as well. |
| 4. |
Consider nephrectomy, orthoptic liver transplant and pulmonary metastatectomy. |
Answer : (3)- What is this syndrome?
Discussion
Patient A is a 47-years old man who presented with chronic cough and weight loss. Clinical examination and investigation confirmed the diagnosis of renal cell cancer with metastasis to lungs; no bone or brain metastases were present. He was dehydrated and delirious at presentation.
This was associated with a corrected serum calcium level of 3.84 mmol/L. He was treated with hyperhydration and intravenous zoldenronic acid. Despite all effects, the serum calcium level remained persistently elevated. Patient’s general condition deteriorated with disease progression and died within 3 months of diagnosis.
Patient B is a 63-years old man diagnosed with renal cell cancer when he presented with abdominal pain and swelling. CT scan revealed a right kidney tumour with multiple lung metastases. There was no bone metastasis on bone scan.
Despite no CT evidence of liver secondaries and negative viral hepatitis serology, his liver function test was deranged with alkaline phosphatase (ALP) 190-260 U/L, alanine transferase (ALT) 37-50 U/L, AST aspartate transferase (AST) 37-52 U/L. Like Patient A, Patient B also deteriorated rapidly and died within 5 months of diagnosis.
The above two scenario epitomised the many faces of renal cell carcinoma. Both patients demonstrated paraneoplastic biochemical abnormalities after excluding bony or liver involvement. Among patients with RCC, hypercalcaemia is the most common paraneoplastic syndrome affecting up to 20% of patients.
Typically, they present with dehydration and in the more severe situation, with delirium. A negative bone scan most probably exclude the bone metastasis as a cause of hypercalcaemia, which is likely to be associated with bone pain as well.
Paraneoplastic hypercalcaemia is due to secretion of hormonal peptides by the renal tumour cells. These peptides are now known as parathyroid hormone-related peptide (PTHrP), which induced higher bone resorption, decreased renal clearance of calcium and increased clearance of phosphate.
Laboratory studies will reveal a low PTH level and low levels of 1.25 dihydroxylase –D3, the renal tubule enzyme responsible for activating the more potent form of vitamin D. Other factors that may be involved include transforming growth factor a and b , osteoclast activating factor, interleukin-1 and tumour necrosis factor.
The management of paraneoplastic hypercalcaemia is more difficult than hypercalcaemia associated with bony metastasis. As illustrated in Patient A, paraneoplastic hypercalcaemia tends not to respond to medical treatment which involves hydration and intravenous bisphosphonates. Nephrectomy to reduce the tumour volume remains the more effective way to treat paraneoplastic hypercalcaemia. Unfortunately, in this case, patient was too ill to undergo the procedure.
In the second patient, the hepatic abnormalities and its associated constellation of symptoms and signs are known as Stauffer’s syndrome. This syndrome was first described in the ‘60s and elevated hepatic enzymes are seen in 66% of cases.
The cause of this syndrome is poorly understood but is postulated to be due to hepatocellular injury as a result of hepatotoxins released by tumour cells. The hepatotoxins may directly cause liver injury by itself or increased insult with subsequent activation of immune system via local recruitment of T cells and production of antibodies against the liver antigens. There has also been suggestion that aberrant tumour production of interleukin-6 may play a primary role in Stauffer’s syndrome.
Regardless of the exact mechanism, a liver biopsy, if performed, will reveal a hepatitic picture with lymphocytic infiltration and hepatocellular degeneration without biliary obstruction. Again, the treatment of Stauffer’s syndrome involves effective treatment of the primary disease and in many instances, palliative nephrectomy will reverse the liver dysfunction in 70% of patients.
It is interesting to note that the presence of Stauffer’s Syndrome is not a prognostic indicatior but the response of the liver enzymes following nephrectomy has been shown to predict survival. Patients with stauffer’s syndrome are prone to hepato-renal syndrome, hence nephrotoxic agents should be avoided like CT contrast.
