Management Of Upper Tract Urothelial Carcinoma

Introduction

Urothelial carcinoma is the fourth most prevalent kind of solid cancer. The majority of situations (90 to 95 percent) occur in the lower urinary tracts (urinary bladder and urethra), with the remaining occurring in the upper urinary tract (renal calyces, renal pelvis, and ureter). Upper tract urothelial carcinomas (UTUC) share a similar histological pattern as lower tract urothelial carcinomas. Still, they have been discovered to exhibit different phenotypic and genotypic (genetic and epigenetic) variances, prompting physicians to refer to them as dissimilar twins. UTUCs are rare, accounting for five to ten percent of urothelial carcinomas (UCs). UTUC has a distinct natural history from UCB (urinary carcinoma of the bladder), and at diagnosis, UTUC has a greater incidence of local invasion. Hereditary nonpolyposis colorectal cancer has been associated with familial or hereditary UTUCs, and these individuals can be tested during screening.

What Are the Risk Factors of Upper Tract Urothelial Carcinoma?

• Several environmental variables influence the development of UTUC. Exposure to tobacco enhances the likelihood from 2.5 to 7. UTUC "amino tumors" were previously linked to occupational exposure to carcinogenic aromatic amines such as benzidine and b-naphthalene.

• The average exposure period required to develop UTUC is seven years, with a delay of up to 20 years following exposure termination.

• Numerous investigations have shown that aristolochic acid, present in Aristolochia fangchi and clematis plants, has carcinogenic potential.

• The aristolochic acid-derivative d-aristolactam is linked to a particular mutation in the p53 gene at codon 139, which is seen in individuals with UTUC who have nephropathy caused by Chinese herbs or Balkan endemic nephropathy.

• Even though the frequency of Balkan endemic nephropathy is decreasing, aristolochic acid serves an important role in the pathogenesis of this nephropathy.

What Are the Underlying Molecular Pathways for UTUC?

• The molecular architecture of UTUC is poorly understood and frequently hypothesized from bladder urothelial carcinoma. Yet, the two have considerable epidemiological and clinicopathological disparities, indicating that distinct genetic traits cause them.

• Understanding these molecular pathways is crucial because it offers the possibility of possible therapeutic targets.

• Sfakianos et al. and colleagues recently developed a unique next-generation sequencing technique to discover somatic mutations and copy number variations in 300 cancer-associated genes in tumor and germline DNA from UTUC (n=83) and bladder urothelial carcinoma (n=102) patients.

• Although the spectrum of mutant genes was comparable, the frequency of variations in certain repeatedly mutated genes, such as FGFR3, HRAS, TP53, and RB1, differed. Compared to high-grade bladder urothelial carcinoma, high-grade UTUC had more FGFR3 and HRAS mutations and less TP53 and RB1.

How Is Upper Tract Urothelial Carcinoma Managed?

• Kidney-Sparing Surgery:

  • Kidney-sparing surgery (KSS) for low-risk UTUC minimizes the morbidity of radical surgery while maintaining oncological results and kidney function.

  • It is the recommended strategy in low-risk tumors, with survival being comparable following kidney-sparing surgery (KSS) versus radical nephroureterectomy (RNU).

  • This approach should thus be considered in all low-risk patients, regardless of the condition of the contralateral kidney. Moreover, it might be explored in individuals with severe renal insufficiency or a single kidney.

• Ureteroscopy:

  • Endoscopic ablation can be explored in individuals with clinically low-risk malignancy in the following cases:

    • For biopsies, laser generators and pliers are provided.

    • If a flexible instead of a rigid ureteroscope is accessible, use it.

    • The patient is warned of needing an early, closer, and strict observation.

    • Complete resection of the tumor or elimination is possible.

    • Yet, there is a danger of understating and under-grading with endoscopic treatment.

• Percutaneous Access:

  • Percutaneous intervention should be performed for low-risk UTUC in the renal pelvis. This procedure may treat low-risk tumors in the lower calyceal system that are not accessible or hard to manage using flexible ureteroscopy.

  • Nevertheless, this procedure is being utilized less frequently due to the advent of better endoscopic equipment, like the distal-tip deflection of modern ureteroscopes. With a percutaneous approach, the possibility of tumor seeding exists.

• Segmental Ureteral Resection:

  • By sparing the ipsilateral (same side) kidney, segmental ureteral resection with broad margins gives appropriate histopathological samples for staging and grading of cancer. Lymphadenectomy (excision of the regional lymph nodes) can also be done during segmental ureteral resection.

  • Total distal ureterectomy with neo-cystostomy (surgical bladder implantation) is appropriate for low-risk distal ureter tumors, which cannot be excised fully endoscopically, and high-risk tumors when KSS for preserving renal function. The iliac and lumbar ureters fail faster than the distal pelvic ureter.

  • Partial pyelotomy or partial nephrectomy is exceedingly unusual. Open excision of tumors of the renal pelvis or calyces has been practically stopped.

• Adjuvant Topical Agents:

  • During kidney-sparing therapy or for the treatment of CIS (carcinoma in situ), antegrade (upwards) administration of bacillus Calmette-Guérin (BCG) vaccine or Mitomycin C in the upper urinary tract by percutaneous nephrostomy using a three-valve system open at 20 cm (after total tumor removal) is possible.

  • Retrograde (downwards) instillation through a ureteric stent is also employed. However, it is risky because of the possibility of a ureteral blockage and subsequent pyelovenous inflow following instillation or perfusion.

  • Reflux from a double-J stent has been employed. However, it is not recommended because it frequently does not reach the renal pelvis.

• Radical Nephroureterectomy (RNU):

  • Irrespective of the tumor site, open radical nephroureterectomy (RNU) with bladder cuff resection is the gold standard for high-risk UTUC. RNU must adhere to oncological principles, such as avoiding tumor seeding by limiting entrance into the urinary system while removing.

  • The distal ureter and its opening are excised since there is a high probability of tumor recurrence in this location. It is difficult to visualize or access the proximal ureter once removed.

  • After RNU, the distal ureter and bladder cuff should be removed. Various procedures, such as plucking, stripping, transurethral resection of the intramural ureter, and intussusception, have been suggested to aid distal ureter excision. Except for ureteral stripping, all of these procedures are equal to bladder cuff excision.

• Laparoscopic RNU:

  • Several examples of retroperitoneal metastatic spread and metastases through the trocar system following the management of massive tumors in a pneumoperitoneum environment have been described.

  • Various measures can be taken to reduce the risk of tumor spillage:

    • Do not penetrate the urinary tract.

    • Avoid putting equipment in direct contact with the tumor.

    • Laparoscopic RNU must be performed within a closed system. To avoid tumor morcellation, utilize an endo bag for tumor resection.

    • The kidney and ureter must be extracted together with the bladder cuff.

    • Until proven otherwise, invasive or huge tumors are contraindicated for laparoscopic RNU.

Conclusion

A complete understanding of the epidemiological variables and molecular mechanisms is necessary for successful UTUC management. For low-risk conditions, kidney-sparing surgery is used, and for high-risk diseases, a radical nephroureterectomy is performed. With increased scientific evidence and research in urothelial carcinoma, perioperative immunotherapy and chemotherapy may be explored.