Renal cell carcinoma

Renal cell carcinoma (RCC) carries different names like “hypernephroma”, “renal adenocarcinoma” or simply renal or kidney cancer. It’s by far the most common kind of kidney cancer found in adults. The first time a reference was made to the tumor was in 1613 when Daniel Sennert published an article in the “Practicae Medicinae” and later in1810 it was described in a 35 years-old female patient in her late stage of pregnancy. Koenig divided the tumor into classification with different forms of scirrhous, fungoid and medullary.

It took us time to realize that many other factors were influencing the incidence. A geographic and demographic factor as well as hereditary factors were discovered, Worldwide the incidence of renal malignancies had increased in frequency according to age, sexes and race. Men have a higher incidence than women in a ratio 1.6 to 1 and the vast majority of the tumors are discovered after the age of 65. Asians appear to have a lower incidence than whites while Africans have reported the lower numbers. Inversely, African Americans carry the highest incidence in the American population. Il looks like the rates have increased as well in developed countries.

The kidneys are retroperitoneal organs that are responsible of the elimination of waste and the regulation of fluid in the body. As we know well, there are tiny tubes in the kidneys called tubules responsible for the filtration of the fluid and the blood excreting the waste through the urine. Such a tumor occurs when malignant cells start growing uncontrollably in the lining of the tubules (proximal convoluted tubules). Renal Cell carcinoma is a fast growing tumor which often spread to the lungs and the surrounding organs. It is the most common type of kidney cancer in adults (90%). There is a male predominance over women and it is generally seen during the 6th and 7th decades.

What cause such malignancy?  Nobody knows for sure the reason why an individual will develop a renal cell carcinoma but we do know that it is a tumor commonly encountered in the mid 60’s, especially in men. Once it is discovered, symptoms like a family history of malignancy, hypertension, obesity, a history of smoking are looked for. Genetic conditions like congenital polycystic kidney disease, Von Hippel-Lindau disease (cyst in kidney and in other organs, excessive use of non-steroidal anti-inflammatory medications and also acetaminophen may precipitate the disease.

The body is remarkably good at hiding symptoms and as a result, anybody with a renal cell carcinoma often will present with an advanced stage of the disease by the time of it is discovery. What are the symptoms associated with the renal cell carcinoma? In the early stages, one should be generally asymptomatic but as the disease progresses, a mass can be appreciated while palpating the abdomen (25%), with flank pain or side pain (40%), blood in the urine (40%), a loss of appetite. an unexplained weight loss (33%), fever (20%), night sweats, fatigue, excessive hair growth especially in women and even vision problems can be in the picture.

The examining physician is looking for a triad of signs with hematuria, flank pain between the hip and the ribs and an abnormal abdominal mass. This triad is seen in almost 15% of the cases meaning often that the tumor is generally in an advanced stage. As we already said it, many patients are asymptomatic and the tumor is detected incidentally at a routine examination. Malaise, feeling of unwillingness, weight loss can be seen. An anemia may be present because of an increase in the erythropoietin secretion or an overproduction of the red blood cells (erythropesis). In a man, varicose veins of the pampiniform plexus of the testes can be noted while examining the scrotum more often involving the left testes. Hypertension can develop because of an increase secretion of renin by the tumor. High level of calcium (hypercalcemia), sleep disturbance with possibly night sweats, high temperature and a chronic fatigue or even depression can be encountered.

What are the risk factors? Smoking and Obesity as well as high blood pressure has been found in almost 50% of the cases. Exposition to some chemical like cadmium, asbestos, lead, chlorinated solvents, petrochemical agents’ hydrocarbon have all been found associated but without any conclusive evidences. Non-steroidal anti-inflammatory drugs in excess also have increased the risks in developing the disease. It is important to note that women who have had a hysterectomy, have also doubled their chances in developing renal cell carcinoma. Moderate use of alcohol has shown a protective effect but it remains unclear.

Heredity has little impact on the susceptibility of an individual and its immediate relatives to develop this condition. It is estimated that there is a 3% increased risk for the disease. There are other genetically linked conditions like hereditary papillary renal carcinoma, hereditary leiomyomatosis, hyperparathyroidism-jaw tumor syndrome, sickle cell disease, familial papillary thyroid carcinoma, or von Hippel-Lindau disease and Birt-Hogg-Dube syndrome. Patients with acquired cystic disease requiring dialysis have shown a 30-fold chances in developing renal cell carcinoma.

I can’t re-enforce more than a renal cell tumor is generally diagnosed after a good familial and personal medical history review and through a physical examination.  A detailed evaluation of the past health state and a consideration to the signs and symptoms during the exam will be helpful to appreciate the risk factors and asset a diagnosis.  Often, enlarged veins in the scrotal sac can bring the suspicion in men necessitating a work-up. Based on the symptoms presented, biomechanical tests will be ordered. A complete blood count to search for anemia and a urine test for the search of blood or tumoral cells as well as an evaluation of the electrolytes, a liver function and a kidney function tests to check on the clotting factors. Upon the findings of the physical examination further investigation will be needed especially if an abdominal or a flank mass is discovered.

At the early stages, the disease maybe be ill defined but the assessment will rely first on the clinical findings. The main diagnostic tools after the clinical manifestations are discovered on regular X-rays of the chest and abdomen, ultrasound, CT scans and MRI scans of the abdomen and the kidney’s function. A CT scan will visualize both kidneys and detect any abnormal growth. An abdominal and a kidney ultrasound can create a picture of the organs, allowing the discovery of any tumor or other problems as well a cyst formation or other organs masses or lymph nodes enlargement. Ultrasound and Fluoroscopy can help in performing a needle biopsy for taking a specimen to be sent to the lab to asset a diagnosis. Pet scan can be also necessary.

Laboratory studies can be conducted when a patient become symptomatic or presents with characteristic of kidney impairment. As we already discussed, patients often are asymptomatic or an abnormality can be found incidentally when a test is performed for other reasons like a gallbladder disease. They generally do not cause pain or discomfort but an assessment of the health can help in the discovery of an abdominal or flank mass or even masses in other parts of the body or even metastasis.

Urine can be examined for the search of blood or excessive proteins or looking for cancerous cells. The presence of blood is a presumptive sign of a renal cell carcinoma. Because of the blood, the urine become rusty, brown or red in color. Sugar and bacteria can be discovered as well in the urine analysis and can be an indicator of malignancy. A complete blood cell count will provide more information and possibly an anemia.

A CBC is a vital test which will give an overview of the blood cells like the erythrocytes, the leucocytes and the platelets. It is very common to discover an anemia. It is an important screening tool in the evaluation. A sedimentation rate (ESR) as well as Prothrombin time (PT), and an activated partial thromboplastin time (APTT) are essential in any patient with a hematuria.

If a renal cell carcinoma is suspected, the liver enzymes like alanine aminotransferase (AL and aspartate aminotransferase (AST) can be found in abnormal levels. A biopsy can also be performed to take a specimen or a sample tissue, drawn through a needle guided by ultrasound of fluoroscopy, to determine or rule out a tumor. We will review those techniques soon. Further studies like Chest and abdominal X-rays as well as CT scan or Pet scan can bring additional information. Abnormal levels of calcium can be detected if there is a suspicion of metastasis to the bones and blood chemistry to assess the kidney function.

Almost 90% of the renal cell carcinoma are generally presented in a solid renal lesion which disfigure the normal morphology of the kidney. It can be irregular as well or multi-lobulated or can represent a lump in the abdomen or the lower pelvis.  Occasionally the mass can be cystic in nature. Around 10% of the carcinoma will contain calcifications and macroscopic fat. There is a “Bosniak” classification which allow to differentiate features of benign cystic lesions with other which necessitate surgical excision. This is why abdominal CT Scans, Ultrasound, MRI scans, Intravenous pyelograms (IVP) and renal Angiography have bought so much sophistication in the search of the diagnosis.

Excretory urography, positron-emission tomography (PET) as well as ultrasonography, arteriography. venography and even bone scanning are extremely useful in the staging of the disease and to differentiate a benign from a malignant tumor with metastasis.

By example, CT Scan is routinely used to determine the stage of a renal cell carcinoma. This is the best study to differentiate a solid from a cystic mass with a precise localization in relation to other organs, or lymph nodes. This will allow the surgeon to appreciate the proximity of these masses to the renal veins or the vena cava. The CT scan can differentiate cells at a cytogenic level.

More the ultrasonography can be use in an asymptomatic patient to detect a mass or a cystic lesion of the kidney especially if a CT scan is inconclusive. This is a noninvasive radiologic test, very safe using high frequency waves, then an image is generated as the sound reflects on the surface of the organs or the masses to determine if we are dealing with a solid or a cystic mass. Ultrasonography and CT Scans have both been used to enhance techniques of percutaneous biopsies to help guiding in the placement of the needle and to obtain a pathologic specimen. There are certainly risks for false negativity or complications but if such techniques can safely be used, it brings a tremendous advantage in assessing a diagnosis prior to the surgical procedure.

Magnetic Resonance Imaging (MRI) is the best study to evaluate the soft tissues using radio waves and magnets. This study can replace a CT Scan especially if one can develop an allergy to the IV contrast material like Gadolinium, Technetium etc. These contrast material may enhance the images but are not recommended in patients on dialysis or in renal insufficiency risking a rare and severe condition called” nephrogenic systemic fibrosis”. A bone scan or a brain imaging is not routinely warranted unless other symptoms suggest any metastatic involvement. MRI is certainly used to evaluate the expansion of the tumor in relation to the arteriovenous tree in the abdomen or in the brain or anywhere else like the spinal cord.

A procedure useful in the detection of abnormal renal mass in the urinary system, is the Intravenous pyelogram (IVP). It involves the intravenous injection of a dye into the bloodstream and to the kidneys but nowadays if a CT scan or an MRI was already performed, it may not be necessary to use this test. Renal angiography uses the same principle as the IVP through the injection of a dye to visualize the blood vessels in the kidneys. The dye is absorbed by the cancerous cells outlining the relation between the blood vessels and the tumor. It is a tremendous help to the surgeon in the mapping and the preparation of the surgical treatment.

Typically, when the tumor arises from the cells of the proximal renal tubular epithelium, it is considered as an Adenocarcinoma. There are two subtypes a sporadic form (non-hereditary) and a hereditary type which both are related to a mutation of the short arm of the chromosome 3 with the implicated gene suppressor VHL and TSC or the oncogenes (c-Met). It is believed that one-third of individual diagnosed with renal cell carcinoma may have already spread the tumor at the time of the diagnosis.

The staging of a renal cell carcinoma is the most important factor in predicting its prognosis. The TNM staging system has used the size (T) and the extension of the tumor to the tissue around or to the lymph nodes (N) with metastasis (M) since its original form with a revision in 1997 by the AJCC:

A stage one is described by a tumor less than 7 cm in size without any metastasis to the lymph nodes or the kidney.

A stage 2 is a tumor larger than 7 cm without any metastasis to organs.

A stage 3 involve the lymph nodes but not the distant organs. In this stage, it can spread to the fat around the kidney and their blood vessels.

A stage 4 spreads further to the kidney, and other organs like lungs, brain and lungs.

At diagnosis, 30% of renal cell carcinomas have already spread to the ipsilateral renal vein, and 5–10% have continued into the inferior vena cava. [What are the options in our armamentarium for treatment of such a tumor…?

Surgery if it is a first recommended option includes a variety of treatment from a partial nephrectomy (excision of part of a kidney) to a total nephrectomy where the entire kidney is removed.  If the cancer is confined to the kidney, like it is generally found in more than 60% of the cases, the disease can be cured at the time of the surgical treatment.

The surgeon will determine how far the disease has spread into the abdomen or in the chest or anywhere else but removal of the kidney will come also with removal of the adrenal glands, the tissue surrounding the kidney and an exploration of the lymph nodes where the kidney drains. The more the disease spreads, the more the surgical procedure becomes extensive.

A nephrectomy with lymph nodes dissection with excision of the adrenal gland with the fascia (Gerota’s) is called a “Radical Nephrectomy” can be offered but if both kidneys are involved in the process, a bilateral nephrectomy will necessitate dialysis or even a kidney transplant. Renal Cell Carcinoma commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones. Different procedures may be most appropriate, depending on the circumstances. Many surgeons may treat a tumor less than 4 cm in size with a partial nephrectomy (Nephron-sparring) especially when they manifest an indolent biological behavior or when there are comorbidities associated like High Blood pressure or Diabetes. Once the remaining kidney is preserved, one needs to be sure that it is functional. If the tumor has spread around the renal vein or the inferior vena cava, a “Cytoreductive Nephrectomy” with excision of the metastases will improve the survival rate.

Nowadays, surgery can be performed through Laparoscopic or Robotic techniques avoiding large incisions, allowing a shorter hospital stay and a quicker recovery. A partial or a total nephrectomy can be achieved though the scope. Mannitol is often used to limit damages to the kidney. Cryotherapy can also be used through these techniques especially when biopsy is needed. The use of an intra-operative ultrasound can facilitate the placement of the freezing probes allowing the undertaken of pathological tissue.

If metastatic disease is already present at the time of the discovery, there are other surgical options to choose although a radical or a partial nephrectomy can still be performed especially if the metastases are small. The stage of grow as well as the extension of the metastasis will need to be evaluated. Radiologists are capable of treating localized lesions with percutaneous ablation therapies especially if an elderly patient experiences already severe renal dysfunction or other comorbidities. Tumors smaller than 3.5 cm are ideal for such ablation procedures.

In Radio Frequency Ablation, the probe reaches the affected tissue and the heat is distributed to the tumoral cells imposing a cell death to the tissue exposed at temperature reaching more than 50 degrees Centigrade. In the Cryoablation, the probe uses cold temperature instead of the heat to freeze the tumoral cells causing as well their death by osmotic dehydration. It is believed that in pulling the water out of the cells, it freezes the cytoplasm with all the organelles and enzymes.

Gross examination of the biopsied tissue often showed a yellowish tissue with zones of necrosis or hemorrhage mixed with blood vessels and cysts. Four major histologic types can be found but the most common is the clear cell carcinoma type (75%) followed by the papillary type (15%) and finally the chromophobic (5%) and the rarest the collecting ducts (2%). Finally, a sarcomatoid type, very aggressive with the worst prognosis can be discovered involving the papillae or the tubules. These last cancerous cells accumulate glycogen and lipids in a clear cytoplasm mimicking the tubular cells and producing a clear pseudocapsule. These clear cells are least likely to spread and may respond better to treatment but in the most aggressive renal cancer, the cells are mixed with clear and granular cells.

Through the 1982 Fuhrman system, the neoplastic cells were studied with eosin and hematoxylin and a grading based on the nuclear characteristics was given from 1 to 4. Depending on the histologic size of the nuclei, the Fuhrman system can bring a prognostic factor to the renal cell carcinoma. This system may have its limitation when one is studying a “chromophobe renal cell carcinoma” but Delahunt has recommended to use the staging with CT scan as well as to relate with the Heidelberg classification dealing with genetic defects.

Radiation therapy kills cancer cell and this can become an adjunct treatment to the previous surgery. Many institutions like Howard university Hospital can offer such treatment intra-operatively through seeds or wires but more often, it is offered after a definitive pathologic diagnostic is determined with the extend of involvement of the lymph nodes. Radiation therapy is commonly used in the metastatic forms especially when involving bones, liver, brain. While not curative, it provides relief.

Renal cell carcinoma maybe resistant to radiation therapy but may answer to other kind of treatment like Interleukin-2 or interferon-alpha, biologic or targeted. Even Cryotherapy as we have discussed above, can be used in the early stages. Chemotherapy using chemical drugs to kill cancer cells can be needed orally or intravenously. The drugs will reach the bloodstream and then will extend to the cancerous cells through the entire body to provide relief.

Immunotherapy is a biologic therapy which works by attacking the cancerous cells. Enzymes and other substances in a body are used by the immune system to defend against the cancer. Some drugs are selective in the process attacking cancerous cells without damaging healthy cells. Some other drugs work on the blood vessels to destroy the blood supply to the tumoral cells, in a way to starve the cells to death, allowing them to shrink. Many new treatments have become available but patients will need to be closely monitored. Immunotherapy activate the person’s immune system at an advantage to fight the cancer cells. There are many drugs on the market used to destroy the tumoral cells or inhibit growth factors like Lenvatinib, Nivolumab, Interleukin-2, and many other one not even on the market.

The outlook after being diagnosed with a renal cell carcinoma largely depend on whether the cancer has spread or not and how soon the treatment is started, the sooner it is started the more chances in recovering fully. If the cancer has spread to other organs, the survival rate is much lower than if it was caught before spreading. The five-year survival rate, according to the National Institute of Health (NIH) for a renal cell carcinoma is over 70% which means that over two third of those diagnosed with the kidney tumor will live at least five years after the diagnosis. If the cancer is eradicated, one may have to live with long-term effects of the disease which certainly will include poor kidney function.

If a kidney transplant is performed, chronic dialysis may be needed as well as long term drug therapy.  Renal cell carcinoma is also associated to a number of syndromes called paraneoplastic caused by either the overproduction of hormones secreted by the tumor or by the way the body fight back at the tumor. Such syndrome can be encountered in 20% of the cases with a high blood calcium, a high red cell blood count, a high platelet counts and often a secondary amyloidosis.

Renal cell carcinoma (RCC) is not a single entity but rather a compilation of different types of tumors coming from the nephron itself meaning the tubules or the epithelium.  Karyotyping has been used to identify any chromosomal aberrations on tumors embedded in paraffin. Laboratories have also used virtual karyotype. The World Health Organization (WHO) has advanced a classification in 2004, recognizing around 40 types of renal neoplasms and several new subtypes have been recognized like the clear cell papillary, the mucinous tubular and spindle cell carcinoma, the tubule-, the thyroid-like follicular renal cell carcinoma, the cystic renal cell carcinoma, the acquired cystic kidney disease-associated renal cell carcinoma, the renal cell carcinoma with t8;11 translocation (TFEB), the Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) etc.

Many believe that if one maintains a normal body weight, the risk in being a victim of a renal cell carcinoma is less. This tumor is generally discovered late after the sixties and once discovered, there is a 30% chance that one has already a metastatic spread. The more common site for metastasis are the lymph nodes, lungs, liver and brain. The prognosis is poor once there are metastases and a 5-year-survival is generally less than 10% in spite of new drugs treatment keeping in mind that the lesions are vascular in nature. Staging remains the most important factor in the outcome of such tumor. The more confined is a tumor the more the 5-year-survival can reach 80%. If the disease is confined to the kidney, only 30% will develop metastatic disease after nephrectomy.

In dealing with a small size renal tumor, an active surveillance has been recommended in the old population, especially when they have co-morbidities while surgery is not an option. Various diagnostic procedures, studies and imaging to monitor the progression of a renal cell carcinoma are offered. For tumors less than 4cms and confined to the kidney, a 5-year-survival rate is at 90%. Tumors with extension through the renal capsule without venous invasion fall down to 80%. Once, out of the renal fascia, it will reach 65%. The histologic grade will deal with the aggressiveness of the tumor with a grade 1 have the best prognosis with a almost 90% survival rate while the grade 4 has the worst prognosis at 45%.

The earlier the tumor is detected when one is asymptomatic, the better is the survival rate. With metastasis is seen to the lymph nodes, the 5-year-survival rate is less than 15%. A low “Karnofsky performance score” is a way to measure the functional impairment in patient with renal cancer by the search of a low hemoglobin level, a high serum lactate dehydrogenase and a high level of serum calcium. For a non-metastatic case another scoring system, the Leibovich scoring is used to predict the post-operative progression. Renal cell carcinoma may be also strongly associated with paraneoplastic syndromes due to ectopic hormone production by the tumor but treatment will center on the underlying cancer

We have more to learn about such tumors. Paul Grawitz believes that the origin of the small yellow renal tumors (alveolar) were from the adrenals whereas the papillary type derives from the renal tissue. Pathologist like Paul Sudeck (1893) has challenged Grawitz while Otto Lubarsh (1894) has supports him and coining the term of “Hypernephroid tumor” later changed to Hypernephroma which persist in the literature nowadays. Other scientists are still debating on the ultrastructure of the clear cells or the presence of glycogen deposits and numerous mitochondria have concluded differently on the origin of the tumors perhaps from the renal tubules. The last word is not known about renal tumors.

I wish to dedicate this page to my friend J.P., an AMHE member who left us years ago, victim of such a malignant disease with metastasis. I also wrote this paper for a close relative J.C who just discovered that she had a nephrectomy for a renal cell carcinoma.

Maxime J-M Coles MD

Ste Croix, Virgin Island (2-6-2021



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