NORD gratefully acknowledges Pavlos Msaouel, MD, PhD, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, for the preparation of this report.
Renal medullary carcinoma, also known as RMC, is a rare cancer of the kidney that predominantly afflicts young people of African descent who carry the sickle cell trait, sickle cell disease, or other sickle hemoglobinopathies that can cause sickling of the red blood cells. Renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP) is a very rare subtype of RMC that occurs in people who do not carry any sickle hemoglobinopathies. All RMC and RCCU-MP tumors characteristically do not express a protein called INI1, also known as SMARCB1, hSNF5, or BAF47. Most patients with RMC are young and the cancer will most often have spread to the lymph nodes or other organs by the time it is diagnosed. RMC is twice more likely to occur in men than women, and in the right kidney compared with the left. The most common symptoms are blood in the urine and pain on the kidney side. RMC is treated with chemotherapy, surgery (when feasible), and sometimes radiation therapy. The exact cause of RMC is not fully understood.
RMC was originally described in 1995 and is one of the most aggressive kidney cancers. Half of the patients with RMC described in the original 1995 study did not survive longer than 4 months from diagnosis. With current therapies this has improved to 13 months and research is under way to find new and better treatments. RMC can be easier to treat if diagnosed early. Therefore, young black individuals (particularly those who are known to carry the sickle cell trait or sickle cell disease) should immediately contact their healthcare provider if they experience symptoms that can suggest RMC. By the time it is diagnosed, RMC will have spread to the lymph nodes or other organs in more than 90% of patients. If left untreated, RMC can quickly spread to the lymph nodes or other organs even in those patients who initially have RMC contained within the kidney. RMC most commonly spreads to the lymph nodes (85% of patients), lungs (46%), liver (15%) and bone (15%), but almost never spreads to the brain.
The most common first sign of RMC is blood in the urine (hematuria) and patients may also feel pain in their flank around the kidney area or (less commonly) feel a mass in their abdomen, usually on the right side. About half of the patients with RMC will begin losing weight unintentionally and may develop fevers and night sweats.
The exact reason why RMC develops is not fully understood but almost all patients will have a blood disorder that can make their red blood cells sickle. These disorders are called “sickle hemoglobinopathies” and include sickle cell trait and sickle cell disease. Of note, most individuals with sickle cell trait are otherwise healthy and many are not aware that they have this blood disorder. Other than the presence of sickle hemoglobinopathy, there are no other known family predispositions or risk factors in the environment that can explain why only certain individuals will develop RMC. There is currently no evidence to suggest that family members of a patient with RMC are at increased risk for developing RMC themselves. Although individuals with sickle hemoglobinopathies should take early signs and symptoms of possible RMC very seriously, there are currently no known effective strategies to prevent or screen for RMC in individuals without symptoms.
Notably, all RMC tumors lack a protein called INI1, also known as SMARCB1, hSNF5, or BAF47. This protein is also often lost in other rare cancers such as malignant rhabdoid tumors (MRT), atypical teratoid rhabdoid tumors (ATRT), and epithelioid sarcomas. INI1 is a “tumor suppressor” that normally protects cells from turning into cancer.
The red blood cells of individuals with sickle cell disease have changed into a sickle shape throughout the body and this can produce multiple health problems and symptoms unrelated to RMC. On the other hand, the red blood cells of individuals with sickle cell trait change into a sickle shape only in specific locations within the body, such as a part of the kidney called the “renal medulla”. This sickle shape makes red blood cells sticky, rigid, and prone to blocking the blood supply of the renal medulla. It is thought that this process can sometimes damage the INI1 gene in cells within the renal medulla thus resulting in RMC. In rare cases, INI1 may be lost in the cells of the renal medulla in individuals without any sickle hemoglobinopathies, thus resulting in a subtype of RMC provisionally called “renal cell carcinoma, unclassified with medullary phenotype” (RCCU-MP).
RMC predominantly afflicts young adults and adolescents of African descent with sickle cell trait, sickle cell disease or other hemoglobinopathies that can cause red blood cells to change into a sickle shape. Men are twice as likely to be affected by RMC than women, and about 70% of RMC cases start from the right kidney. RMC is the third most common kidney cancer among children and young adults. Half of the patients diagnosed with RMC will be 28 years old or younger with some being as young as 9 years old. Less commonly, patients can be 35 years old or older.
Although all sickle hemoglobinopathies are risk factors for RMC, the vast majority of patients with RMC have sickle cell trait and only a handful have sickle cell disease or other sickle hemoglobinopathies such as hemoglobin SC disease or sickle beta thalassemia. This may in part be because sickle cell trait is 55 times more common than other sickle hemoglobinopathies. Pure thalassemias, such as alpha or beta thalassemia, are not risk factors for RMC.
About 1 in 14 African Americans carry the sickle cell trait and between 1/20,000 to 1/39,000 of individuals with sickle cell trait will develop RMC. Sickle cell trait is found in approximately 300 million individuals worldwide. The frequency of sickle cell trait varies among different populations and can range from approximately 7% among African Americans, 23.5% in the Chalkidhiki peninsula of Greece, 10% in the Çukurova region of southern Turkey, up to 13% among certain populations in central India, 20% in the eastern province of Saudi Arabia, and between 10%-40% across equatorial Africa, reaching up to 45% among the Baamba tribe in Uganda. However, most reports of RMC come from the United States or Europe. This is most likely because RMC is misdiagnosed in other countries, although it is possible that there may be environmental or other local regional risk factors for RMC in the United States and Europe.
Because RMC does not cause symptoms early in the disease, getting an early diagnosis is difficult. Since treatment of RMC can be more effective the earlier the disease is identified, early diagnosis is important.
The diagnosis of RMC should be suspected when a cancer arising from the kidney (most commonly from the right kidney) is found to look under the microscope like a “high-grade, poorly differentiated adenocarcinoma”, particularly if the patient is young and carries the sickle cell trait or other sickle hemoglobinopathies. The cancer tissue should be tested for expression of the INI1 protein using a method called “immunohistochemistry”. If the tissue is negative for INI1 then RMC is confirmed. If the tissue is positive for INI1 then the cancer is not RMC. If the tissue is negative for INI1 but the patient does not carry the sickle cell trait or other sickle hemoglobinopathies then this is the subtype of RMC provisionally called RCCU-MP.
Clinical Testing and Workup
Individuals with sickle cell trait or other sickle hemoglobinopathies who develop signs or symptoms (such as blood in the urine) suggestive of RMC can be evaluated using an ultrasound examination of their kidneys. During an ultrasound, reflected sound waves are used to create an image of the kidneys and other nearby structures. If a mass is found that is suspicious for cancer, then the doctors may recommend advanced imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to further investigate whether this is indeed a cancer. CT and MRI scans use x-rays or magnetic waves, respectively, that are processed by a computer to create images of certain tissue structures, such as the kidneys, within the abdomen and other areas of the body.
If the CT or MRI images show a mass in the kidney that is suspicious for cancer, then doctors may need to take a tiny sample of tissue from the kidney or from other areas that the cancer may have spread to. This is called “biopsy”. During a biopsy, a needle is passed through the skin to take a tiny sample of tumor tissue. The tissue is then studied under the microscope to confirm the diagnosis of RMC. The tissue needs to be tested for the presence or absence of INI1 (also known as SMARCB1, hSNF5 or BAF47) using a method called “immunohistochemistry”.
Treatment of RMC may require the coordinated efforts of a team of specialists who will need to systematically and comprehensively plan an affected patient’s treatment. This may include specialists who diagnose and treat cancer (medical oncologists), specialists who perform surgery on the kidney (urologists), specialists who use ionizing radiation to treat cancer (radiation oncologists), specialists who use minimally-invasive, image-guide technologies to diagnose and treat cancer (interventional radiologists), as well as other healthcare professionals. Psychosocial support for the entire family is also essential.
Specific therapeutic procedures and interventions may vary, depending upon many factors, such as disease stage (how extensive the disease is), the size of the tumor, the presence or absence of certain symptoms, whether the disease has spread (metastasized) to other areas of the body, an individual’s age and general health, and/or other elements. Decisions concerning the use of surgery, radiation, specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case as well as a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences, and other appropriate factors.
RMC is often treated with chemotherapy. Many of the therapies that are used for other kidney cancers do not work against RMC. If CT or MRI imaging suggests that RMC is confined only to the kidney and has not spread to other areas, then surgery can be considered to remove the whole kidney and the cancer inside it. If the RMC tumor is large, for example larger than 4 cm, then doctors may decide to use chemotherapy first in order to shrink the tumor and perform the surgery afterwards, even if there is no evidence on CT or MRI that RMC has spread to other areas. This is because all imaging tests, including CT and MRI, are imperfect and may not detect very small RMC tumors in the lymph nodes or other organs. In these situations, it is hoped that the chemotherapy will treat these areas first, before they are allowed to become too big. Other specific therapeutic procedures may include radiation therapy or other therapies.
Researchers are studying various medications as potential treatments for individuals with RMC. Such treatments include bortezomib and ixazomib, which are drugs that block the removal of unwanted proteins from the cancer cells (proteasome inhibitors), as well as drugs that target certain pathways, such as the EZH2 pathway, that may be important for RMC. In addition, drugs that harness the body’s immune system to recognize and kill RMC cells are also being investigated. Clinical trials are needed to determine the effectiveness and safety of these new therapies for patients with RMC. Clinical trials that enroll patients with RMC will normally also enroll patients with the RCCU-MP subtype.
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