Years published: 2023
NORD gratefully acknowledges Gregory Cichon, MD candidate at Creighton University School of Medicine, Kevin McMahon, MD candidate at Creighton University School of Medicine, and Juan Chipollini, MD, FACS, Clinical Associate Professor, Urologic Oncology, The University of Arizona College of Medicine, for the preparation of this report.
Urothelial cell (UC) cancers of the renal pelvis and ureter are relatively rare (approximately 2 per 100,000 people) and make up approximately 5% of transitional cell cancers in the urinary tract. Of these 2 locations – the renal pelvis (located in the kidney) and the ureters (which connect the kidney to the bladder) – UC occurs twice as often in the renal pelvis. The most common initial symptom for these types of cancer is blood in the urine (hematuria). Risk factors for UC include smoking, genetics, painkiller abuse, excessive coffee drinking, and cyclophosphamide (a drug used in chemotherapy). Surgery is the most common treatment for these cancers, however higher stage cancers may also require chemotherapy or radiation. These cancers may most commonly spread down towards the bladder and can spread (metastasize) to other organs. The prognosis after surgery varies and highly depends on the cancer stage and a patients’ risk factors.
Cancer can arise from the transitional layer, also known as urothelial layer, of cells in the renal pelvis or ureter, which are parts of the upper urinary tract. These cancers may first present with blood in the urine and are most associated with a history of cigarette smoking. The current treatment for these cancers is surgery to remove the upper urinary tract and surveillance afterwards to ensure there is no recurrence. More research is ongoing into different treatments, diagnostic tools, and screening modalities for these types of cancer.
The renal pelvis is located inside the kidney and acts as a collecting system for urine which then flows into the ureters. The ureters are 20-30 cm S-shaped tubes connecting the kidneys to the bladder which collects and stores the newly formed urine until urination. The inner layers (which directly contact urine) of both the renal pelvis and ureter are lined by a transitional cell epithelium (aka: urothelium) that are then surrounded by multiple layers of connective tissue and muscle. This specialized type of epithelium functions as an impermeable yet flexible barrier that allows both structures to stretch or shorten depending on urine flow. When this layer of epithelium becomes cancerous, it is damaged and may have abnormal blood vessel formation, resulting in painless red urine.
Although cancers of the renal pelvis and ureters make up only 5% of urinary tract cancers, nearly all cancers that occur here (95%) are the urothelial cell type. Cigarette smoking is strongly associated with these types of cancers, increasing a patient’s risk 2.5 to 7 fold.
Painless blood in the urine (hematuria) is the most common symptom in patients with transitional cancers of the upper urinary tract. Other less common symptoms include lower back pain, pain with urination, or unexplained weight loss.
Urothelial cell cancer is thought to be caused by a mutation leading to the loss of a tumor suppressor gene. Losing a tumor suppressor gene is like taking the brakes off a car, allowing cells to replicate uncontrollably, resulting in cancer. Cancers may be classified as low-grade or high-grade. Low-grade cancers are associated with mutations leading to a loss of functioning tumor suppressor genes such as p53, p19 and p16. High-grade cancers have additional mutations such as the loss of the RB1 tumor suppressor gene. More aggressive cancers tend to spread initially towards the bladder and may metastasize (spread) to other organs. Notably, loss of certain tumor suppressor genes (such as those listed above) does not reflect the patient prognosis (predicted outcome) and scientists are still studying how the loss of certain genes can affect prognosis in patients with different mutations. Due to family genetics, some people may be predisposed to loss of these tumor suppressor genes compared to others. Patients with Lynch syndrome are at an increased risk for transitional cell cancers.
Cigarette smoking is the most well-documented contributor to urothelial cell cancer. Painkiller abuse, caffeine, cyclophosphamide, and occupational exposure to agents used in the plastic and tar industries may all increase one’s risk to transitional cell cancer as well. These agents may induce mutations that cause the loss of tumor suppressor genes (as listed above) in the transitional (urothelial) cells lining the inside of the renal pelvis or ureter. More research is being done on these agents to determine the level of risk.
The average age of patients who develop upper urinary tract urothelial tumors is 65 years, and one’s risk of this cancer increases to a peak in their 70’s-80’s. Urothelial tumors are 3 times more common in men than women and twice as common in people of European descent compared to people of African descent. Patients with a smoking history are at highest risk for these cancers. A family history of transitional cell cancer, especially when a family member was diagnosed at a young age (<45 years old) without a history of smoking and/or Lynch syndrome may increase the risk for transitional cell cancers as well.
Urothelial carcinoma of the bladder: This cancer originates in the bladder rather than the renal pelvis or ureter. It is much more common and shares similar risk factors and causes. Compared to UC of the ureters or renal pelvis, the majority of bladder cancers are less likely to break through the inner cell layer and metastasize (spread) to other organs. Treatment typically involves surgery or ablation and may also include chemotherapy or immunotherapy.
Doctors will usually start by running urine and blood tests to check kidney function, liver function, bladder function, and assess for infection. They will also usually obtain some imaging such as a CT scan, which may show an irregular mass blocking the ureter or kidney suggestive of cancer. Doctors may get additional imaging tests such as a CT using contrast, known as a CT urogram. If the cancerous mass is small and is not obstructing the renal pelvis or ureters, it may not be initially detected by these imaging tests. A urologist, which is a doctor specializing in the urinary tract, may perform a procedure called a uroscopy, which is the use of a flexible scope inserted through the urethra (opening in the penis or above the vagina through which urine leaves the body) to directly visualize the cancerous mass in the ureter or renal pelvis and may remove small bits of tissue for further testing. Once a diagnosis is confirmed, doctors will stage the cancer by performing more imaging scans to see if it has spread to other parts of the body such as the lungs or lymph nodes. To help with staging, doctors may also perform genetic tests, urine cell tests, and biopsies.
The prognosis for a diagnosed cancer varies greatly. Factors which may improve prognosis include non-smoker, lower-grade, lower-stage, lack of recurrence and younger age. A full work-up of a newly diagnosed transitional cell cancer helps guide the choice of therapy and better clarify the likely prognosis. Researchers are still investigating which factors or tests might provide the best insight into disease progression.
The standard of therapy for transitional cell cancer of the renal pelvis and ureter is surgery. The most common surgery is known as a radical nephroureterectomy in which the kidney, ureter, adrenal gland, and nearby lymph nodes are removed. The surgery may be done laparoscopically via a camera with small incisions or robotically to minimize the complications and decrease hospitalization length, but larger or more aggressive tumors may require an open surgery. Most people fully recover from a nephroureterectomy within 6 weeks. Lower grade tumors may instead undergo an ablation of the tumor using a laser or a ureterectomy in which only a part of the ureter is removed to preserve the kidney function. The major risks associated with these surgeries include injury to major blood vessels or nerves, infection, side effects of anesthesia such as nausea and vomiting, and blood loss. Following radical nephroureterectomies, recurrence of the original cancer is not common but UC may arise in other parts of the urinary system such as the bladder. Patients should follow up with their doctor routinely to check for bladder cancer using a cystoscopy and selective urine cytology. The frequency of follow-up may depend on the stage of the original cancer as well as the likelihood for a recurrence. Most patients should follow-up every 3 months after their surgery during the first year and every six months after that.
Patients with higher grade tumors who are not able to undergo radical therapy may instead receive topical or systemic chemotherapy either through a ureteral catheter or through a nephrostomy tube. In 2020, the FDA approved a treatment for low-grade renal pelvis and ureter transitional cell cancers called mitomycin pyelocalyceal (Jelmyto). This therapy utilizes a ureteral catheter or a nephrostomy tube to medically treat the cancer instead of surgery. Patients with metastasis to other organs may require systemic chemotherapy rather than targeted chemotherapy, but few studies have been done due to the relative rarity of the disease. Studies are also still being done on whether a combination of surgery and chemotherapy (known as adjuvant or neoadjuvant chemotherapy) provides a mortality benefit.
Scientists are still researching alternative medical and surgical ways to treat transitional cell cancer of the renal pelvis and ureter. More research is being done on tumor markers for better diagnosis, prognosis, and surveillance of transitional cell cancer. Molecular and genetic pathways are being studied as possible targets for future medical therapies and tests. Clinical trials are being performed on new therapies to assist in the treatment of these cancers.
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