Types of Urothelial Carcinoma
Urothelial carcinoma is classified by anatomical location, morphological patterns (flat vs. papillary), grade (low vs. high), invasion status (non-muscle-invasive vs. muscle-invasive), and histologic subtypes, with the 2022 WHO Classification now using "subtype" terminology instead of "variant" to describe distinct morphologic categories. 1
Anatomical Distribution
Urothelial carcinoma can develop anywhere urothelium is present, from the renal pelvis to the proximal two-thirds of the urethra 1:
- Bladder origin: >90% of urothelial tumors 1
- Renal pelvis: Approximately 8% 1, 2
- Ureter and urethra: Remaining 2% 1, 2
Morphological Patterns
Flat Lesions 1
- Urothelial carcinoma in situ (CIS): High-grade noninvasive urothelial carcinoma characterized by replacement of urothelium with malignant cells showing nuclear pleomorphism, hyperchromasia, and prominent nucleoli 1, 3
- Urothelial dysplasia: Used in rare circumstances when morphologic features fall short of CIS diagnosis 1
Papillary Lesions 1
Benign papillary lesions 1:
- Urothelial papilloma
- Inverted papilloma
Malignant papillary lesions 1:
- Papillary urothelial neoplasm of low malignant potential (PUNLMP)
- Papillary urothelial carcinoma, low-grade
- Papillary urothelial carcinoma, high-grade
Inverted Lesions 1
The WHO/ISUP criteria can be extrapolated to inverted neoplasia 1:
- Inverted papilloma
- Inverted PUNLMP
- Inverted urothelial carcinoma, low-grade, non-invasive
- Inverted urothelial carcinoma, high-grade, non-invasive
- Inverted urothelial carcinoma, high-grade, invasive
Grading System
The WHO (2004)/ISUP System is the grading system of choice for papillary and flat non-invasive urothelial neoplasia 1:
- Low-grade: Defined by lesser extent of cytologic and architectural atypia 1
- High-grade: Defined by greater extent of cytologic and architectural atypia 1
Important grading principle: Invasive urothelial carcinoma should generally be graded as high-grade, irrespective of depth of invasion 1. For tumors with grade heterogeneity, assign grade by the highest grade component 1.
Histologic Subtypes (Previously Called "Variants")
Critical terminology update: The 2022 WHO Classification adopted "subtype" to replace "variant" histology when referring to distinct morphologic categories, reserving "variant" for genomic alterations 1. Documentation of histologic subtypes is essential because they define natural history, risk of progression, genetic etiology, and guide treatment aggressiveness 1.
Recognized Histologic Subtypes 1
The following subtypes have been identified (not exhaustive):
- Micropapillary urothelial carcinoma: Key diagnostic features include "multiple nests in the same lacuna" and "epithelial ring forms" 1
- Large nested variant 1
- Urothelial carcinoma with small tubules 1
- Undifferentiated carcinoma with rhabdoid features 1
- Urothelial carcinoma with chordoid features 1
Approximately 15-25% of invasive urothelial carcinomas exhibit divergent differentiation along other epithelial lineages or different subtypes of urothelial or sarcomatoid differentiation 4.
Molecular Subtypes
Recent mRNA expression profiling studies have revealed biologically relevant molecular subtypes of urothelial carcinoma 5, 6:
- Luminal subtypes: More common in CIS and associated with specific molecular features 3
- Basal subtypes: May represent class switch from luminal type during progression to invasive carcinoma 3
A consensus molecular classification has categorized urothelial carcinomas into 6 subclasses, though this has not yet been sufficiently validated for routine clinical application 6. These molecular subclasses appear associated with prognosis and response to chemotherapy or immune checkpoint inhibitor therapy 6.
Clinical Staging Categories
Non-muscle-invasive bladder cancer (NMIBC) 1:
- Ta or T1 tumors, which may have associated CIS component
- May have flat and/or papillary histology
Muscle-invasive bladder cancer (MIBC) 5:
- Exhibits different prognosis, survival, progression, and treatment outcomes compared to NMIBC
Common Pitfalls
When evaluating equivocal cases, consider key clinicopathologic data including focality/multifocality, grade of prior diagnoses, lesion size, recurrence frequency, presence/absence of concurrent CIS, and cytologic impressions to help decide whether to upgrade an equivocal lesion 1. There is no established role for immunohistochemical or molecular assays in routine grading decisions 1.
For incipient papillary lesions not accurately classifiable under the current system in patients under surveillance, use terminology such as "dysplasia with early papillary formations" or "carcinoma in situ with early papillary formations," but correlation with cystoscopic findings is mandatory 1.