Types of Urothelial Cancer

In order to spread outside of the urinary system, urothelial (bladder and upper tract) carcinoma must invade into the lamina propria and beyond. Prior to becoming invasive, there are two different types of precursor lesions: non-invasive papillary urothelial carcinoma and in-situ urothelial carcinoma.

Precursor lesions   

  1. Non-invasive papillary urothelial carcinoma: These are tumors that form papillary structures that are lined by abnormal urothelial cells with varying degrees of cellular atypia. Those tumors with mild atypia are called “low-grade”, while those tumors with more pronounced atypia are called “high-grade.” Both low- and high-grade tumors can be multifocal and frequently recur after resection.
    1. Low-grade papillary urothelial carcinomas are characterized by orderly appearance of cells that are evenly spaced and cohesive. There is minimal but definitive nuclear atypia that is characterized by hyperchromasia, mild variation of nuclear size and mitoses are infrequent. Only a minority of low-grade tumors become invasive (approximately 10%) and rarely would pose a threat to the patient’s life.
    2. High-grade papillary urothelial carcinomas contains urothelial cells that are dyscohesive, with marked nuclear enlargement, hyperchromasia, variability in nuclear sizes or shapes, and frequent mitoses. The majority of high-grade papillary urothelial carcinomas become invasive (approximately 80%) and can spread to adjacent organs or give distant metastases (lung, liver, bone, brain, etc.).
  2. Urothelial carcinoma in-situ (CIS): In contrast to papillary carcinomas, CIS is a flat high-grade cancer that is difficult to visualize in cystoscopy. CIS is always high-grade as it has a has a 50% to 75% risk of becoming invasive, if left untreated.

Invasive Urothelial Carcinoma   

Invasive urothelial carcinoma may be associated with a papillary carcinoma (most commonly high grade) or CIS. Most invasive urothelial carcinomas are high grade, but grade is not as important for prognosis once the tumor has become invasive. The extent of invasion is the most significant prognostic factor and determines the type of therapy. Understaging a tumor in a bladder biopsy is a common problem. Tumors that invade the lamina propria only are frequently managed conservatively with a combination of transurethral resection and intravesical therapy (BCG and/or intravesical chemotherapy). Tumors that invade the detrusor muscle are managed with more aggressive surgery (cystectomy). Tumors that have spread outside of the urinary system are managed with systemic chemotherapy.

Morphologic Variants of Urothelial Carcinoma   

Some cases of urothelial carcinoma show morphologic patterns that are recognized as variants morphology. Those include nested variant, micropapillary, lymphoepithelioma-like, sarcomatoid, small cell carcinoma, and adenocarcinoma. These are frequently under-recognized in bladder biopsies and could have therapeutic implications with different criteria for surgery and different chemotherapy regimens.

PD-L1 Testing in Urothelial Carcinoma   

With the advent of immunotherapy and FDA approval of immunotherapy in certain patients, testing of PD-L1 expression in urothelial carcinomas has become frequent. PD-L1 expression is tested using immunohistochemistry on the same tissue that has been used for a pathologic diagnosis. Patients with a positive test result are more likely to respond to immunotherapy, but some patients with negative tests can also show some favorable response.

Mesenchymal Tumors

Mesenchymal tumors arise from the connective tissue cells of the bladder. These tumors are much less common than urothelial tumors and can be benign or malignant. Malignant mesenchymal tumors are termed sarcomas. Sarcomas can become large and have the capacity to invade adjacent organs and give rise to distant metastases. The most common sarcoma of infancy is rhabdomyosarcoma and of adults is leiomyosarcomas.