Review: Urinary Bladder Carcinoma Variants, a conversational discussion (0:28:00)

List of bladder cancer variants discussed in the review:

• Squamous Cell Bladder Carcinoma (SCC)
• Non-bilharzial-associated SCC (NB-SCC)
• Bladder adenocarcinomas
  • Primary bladder adenocarcinoma
  • Secondary bladder adenocarcinoma
  • Intestinal/enteric bladder adenocarcinoma
  • Clear cell adenocarcinoma
  • Signet-ring cell adenocarcinoma
• Urachal adenocarcinoma
  • Mucinous urachal adenocarcinoma
  • Enteric urachal adenocarcinoma
  • Signet-ring cell urachal adenocarcinoma
  • Non-urachal bladder adenocarcinoma
• High-grade neuroendocrine carcinoma
  • Pure small cell carcinoma (SmCC)
  • Mixed histology SmCC (with UC, adenocarcinoma, or SCC)
• Bladder sarcomas
  • Leiomyosarcoma of the bladder
  • Rhabdomyosarcoma
  • Angiosarcomas
• Urothelial Carcinoma (UC) variants
  • Urothelial with squamous differentiation
  • Urothelial with glandular differentiation
  • Nested variant
  • Microcystic variant
  • Micropapillary variant
  • Plasmacytoid/signet ring and lymphoma-like
  • Undifferentiated
  • Lymphoepithelioma-like
  • Clear cell variant
  • Lipid cell variant
  • Sarcomatoid or carcinosarcoma variants
• Plasmacytoid Urothelial Carcinoma (pUC)
• Lymphoepithelioma-Like Carcinomas
• Micropapillary Urothelial Carcinoma (mUC)
• Nested Urothelial Carcinoma (nUC)
• Nested Variant of Urothelial Carcinoma (NVUC)
• Large Nested Urothelial Carcinoma (LNUC)
• Carcinosarcoma (CS)

Content solely for training and education purposes.

Transcript

Understanding Bladder Cancer Variant Histology: A Comprehensive Review 

Bladder cancer represents a significant public health concern, with Urothelial Carcinoma (UC) dominating as the most prevalent histological subtype. While the diagnosis and treatment of UC have witnessed significant advancements, the realm of non-urothelial bladder cancers and urothelial variants, collectively termed as Bladder Cancer Variant Histology (BCVH), demands focused attention. BCVH accounts for 5-25% of all bladder cancer cases, posing unique challenges due to their aggressive nature and often late-stage presentation at the time of diagnosis. [1, 2] This review provides a comprehensive exploration of the clinicopathological characteristics of the most common BCVH, organized by specific variants and drawing from the provided sources.

1. Squamous Cell Bladder Cancer (SCC)

Squamous Cell Bladder Cancer (SCC) comprises around 5% of bladder cancers in Western nations. [3-5] It is distinguished histologically by the presence of keratin pearls, intercellular bridges, and intracellular keratohyalin granules. [3, 6] Notably, pure SCC is defined by the absence of any urothelial component, setting it apart from UC exhibiting mixed histology. [3] While often presenting as solitary lesions accompanied by leukoplakia upon cystoscopy, SCCs can demonstrate a range of appearances, including exophytic, ulcerated, or nodular, frequently with keratin debris and necrotic material on their surface. [3, 6-8]

In Western countries, the prevalent subtype is non-bilharzial-associated SCC (NB-SCC). Risk factors associated with NB-SCC encompass spinal cord injury, neurogenic bladder, chronic indwelling urinary catheter use, tobacco use, and recurrent urinary tract infections (UTIs). [6, 9-11] Additionally, non-invasive bladder malignancies like keratinizing squamous metaplasia or verrucous squamous hyperplasia can elevate the risk of developing invasive SCCs. [12, 13]

2. Glandular Neoplasms (Bladder Adenocarcinomas)

Bladder adenocarcinomas make up 0.5-2% of all bladder cancer diagnoses. [14] While they can occur as either primary or secondary tumors, secondary bladder adenocarcinomas are more common. [14] It's crucial to differentiate primary bladder adenocarcinomas from those originating in other organs, such as the colon or prostate, which can spread to the bladder through contiguous local extension. [14-16] A thorough and extensive workup is essential to accurately determine the tumor's origin. [14]

The prevailing hypothesis is that primary bladder adenocarcinoma arises from urothelium that has undergone glandular metaplasia, a process often associated with chronic bladder irritation. [14, 17, 18] There are several subtypes of bladder adenocarcinomas, with the intestinal or enteric type being the most common. [14] This subtype exhibits infiltrating glands closely resembling colonic carcinoma, frequently accompanied by luminal necrosis, mucinous production, and inflammation with cystitis cystica. [14, 19] Immunohistochemical staining reveals strong and diffuse positivity for CDX2 and CK20, while negativity for CK-7, p63, and GATA-3 is observed. [14] Beta-catenin exhibits membranous staining in this subtype. [14]

Clear cell adenocarcinoma, a less common subtype, often originates in or near the urethra. [20, 21] Cytopathological examination reveals abundant cells in round clusters with plentiful clear vacuolated cytoplasm due to glycogenation, hence its name. [21]

Signet-ring cell adenocarcinoma constitutes the most aggressive subtype of bladder adenocarcinoma, typically presenting with infiltrative bladder thickening. [20] Cytopathology demonstrates small, dissociated mucin-filled cytoplasmic vacuoles. [20] Distinguishing this subtype from adenocarcinomas originating outside the bladder is of paramount importance. [20]

3. Urachal Carcinomas

Urachal adenocarcinoma arises from the urachal remnant, a structure derived from the allantoic fibrous connection between the bladder and the umbilical cord. [22] While this remnant usually regresses and is obliterated by birth, some individuals retain a persistent remnant, manifesting as a tubular or cystic structure in the midline area. [22, 23] While urachal adenocarcinoma is not technically considered a bladder cancer, it frequently involves the bladder through direct invasion. [22]

Given its origin outside the bladder, urachal adenocarcinoma invades the outer muscular wall of the bladder, and sparing of the superficial urothelium is sometimes observed. [8, 22] The most frequently observed subtype is the mucinous type. [22] Other subtypes include the enteric type, resembling colorectal adenocarcinoma, and the signet-ring cell type. [22]

Differentiating between urachal and non-urachal bladder adenocarcinoma can be challenging. [7] The immunohistochemical pattern in most urachal adenocarcinomas includes expression of CK-20 and CDX-2, with negativity for CK-7. [7, 24] However, this pattern can also be observed in non-urachal bladder adenocarcinomas. [7] Several comprehensive diagnostic models have been proposed to aid in differentiation, incorporating criteria such as tumor location in the bladder dome, presence of a urachal remnant, extension to the Retzius space, and absence of cystitis cystica et glandularis. [7, 25, 26]

4. Small Cell (High-Grade Neuroendocrine) Carcinoma of the Bladder

Small cell carcinoma (SmCC), alternatively referred to as high-grade neuroendocrine carcinoma, represents approximately 0.5-1% of bladder cancers. [27-29] In an analysis of 243 cases of small cell carcinomas affecting the bladder, 62% were classified as pure SmCC, while the remaining 38% exhibited mixed histology with UC, adenocarcinoma, or SCC. [30, 31] The precise cell of origin for bladder small cell carcinoma remains elusive, though it is postulated to potentially originate from totipotent stem cells within the urinary tract submucosa. [32, 33]

Patients with bladder SmCC may present with microscopic or gross hematuria, urinary frequency, and dysuria, similar to other bladder cancers. [27, 28, 34] These carcinomas can develop anywhere along the bladder mucosa, with a predilection for the lateral walls, dome, and posterior wall. [27] Cystoscopy is used for identification, and their appearance can vary significantly, ranging from a submucosal nodule to a broad-based solid mass measuring 2-10 centimeters in diameter. [27] They can be polypoid, ulcerated, or hemorrhagic and may be locally extensive, involving the perivesical fat. [6, 27, 28, 35]

Small cell neuroendocrine tumors are characterized microscopically by large, irregular nests or sheets of small tumor cells with scant cytoplasm and hyperchromatic nuclei. [28, 32, 34] These nests and sheets are separated by fibrovascular stroma with sparse lymphocytic infiltration. [32] The nucleoli of the malignant cells are not prominent, and chromatin dispersion is observed. [32] Features like extensive necrosis, mitotic figures, and apoptotic bodies are frequently noted. [28, 32, 34]

Similar to small cell tumors arising in other organs, bladder small cell carcinomas exhibit positive staining for neuroendocrine markers on immunohistochemistry (IHC), including synaptophysin, chromogranin, neuron-specific enolase, and CD56. [28, 32, 34] These cells also frequently demonstrate immunoreactivity for epithelial markers like pancytokeratin, CAM5.2, and high molecular weight cytokeratin. [28, 32, 34] Approximately half of bladder small cell carcinomas express TTF-1, while about a third show nuclear GATA-3 expression, ranging from focal to diffuse positivity. [32, 36, 37]

5. Mesenchymal Tumors

Bladder sarcomas represent an uncommon and rare type of mesenchymal neoplasm affecting the genitourinary tract. [11] They constitute 2% of all soft tissue sarcomas but account for only 1-2% of all malignant genitourinary tumors. [11, 38]

Leiomyosarcoma of the bladder stands out as one of the more common subtypes, alongside rhabdomyosarcoma. [11, 39, 40] Other subtypes include angiosarcomas. [11, 41, 42] Similar to typical UC, bladder sarcomas predominantly affect men. [11] Risk factors associated with bladder sarcomas include cigarette smoking, occupational exposure to vinyl chlorides, and prior history of prostate or gynecologic cancer requiring radiation therapy. [11]

6. Bladder Cancer Variant Histology (BCVH)

The realm of BCVH includes rare urothelial variants with distinct characteristics and aggressive behavior. [12] These variants are noteworthy for their clinical implications and warrant specific attention. According to the World Health Organization (WHO) classification of urothelial cancers, there are 13 different histologic variants, encompassing: urothelial with squamous differentiation, glandular differentiation, nested variant, microcystic variant, micropapillary variant, plasmacytoid/signet ring and lymphoma-like, undifferentiated, lymphoepithelioma-like, clear cell variant, lipid cell variant, and sarcomatoid or carcinosarcoma variants. [6, 12, 43]

• Plasmacytoid Urothelial Carcinoma (pUC) is characterized by tumor cells that resemble plasma cells and/or monocytes and exhibit overexpression of CDH1. [12, 44] It tends to present in advanced stages and may lead to a peculiar pattern of metastases, with peritoneal spread being a prominent feature. [12, 45-47]
• Lymphoepithelioma-Like Carcinomas exhibit syncytial invasive growth patterns with accompanying lymphocytic reactions, predominantly composed of T cells, a key feature reflected in its name. [12, 48]
• Micropapillary Urothelial Carcinoma (mUC) derives its name from the microscopic feature of papillary configurations observed in ovarian tumors. [12, 49] It typically presents as a high-grade cancer. [12, 49, 50]
• Nested Urothelial Carcinoma (nUC) is notable for its deceptively benign appearance, histologically characterized by confluent, irregularly arranged nests of bland-looking cells. [12, 51-54] These nests infiltrate deeper layers of the superficial or muscular layers of the bladder. [12] Clinically, nUC behaves aggressively, mimicking the behavior of UC. [12] Nested Variant of Urothelial Carcinoma (NVUC) and Large Nested Urothelial Carcinoma (LNUC) are rare subtypes of Urothelial Carcinoma that present specific diagnostic and molecular characteristics. [55]
  •  NVUC is characterized by the expression of luminal markers, including CD24, FOXA1, GATA3, and CK20. [55, 56] This places NVUC within the luminal molecular subtype of UC. [55, 56]
  •  LNUC is distinguished by its inverted growth pattern and bland cytology, making diagnosis difficult, especially in transurethral resection (TUR) materials. [2, 55]

7. Carcinosarcoma

Carcinosarcoma (CS) of the bladder is a rare and aggressive tumor, representing only 0.11% of all bladder tumor cases. [13, 57] It comprises both mesenchymal and sarcomatous components. [13] The clinical presentation of CS is similar to that of other bladder tumors. [13, 58] It is twice as common in males compared to females and is more prevalent among white patients. [13] CS is frequently diagnosed in elderly individuals, and risk factors include smoking, diabetes, recurrent cystitis, a history of cyclophosphamide therapy, and prior bladder radiotherapy. [13, 59-61]

Diagnosis Role of Biomarkers & Future Directions

Significant progress has been made in utilizing gene expression profiling for bladder UC, with groups from institutions like The University of North Carolina, The Cancer Genome Atlas (TCGA), and The MD Anderson Cancer Center defining distinct signatures. [62] These signatures, including luminal and basal subtypes, offer prognostic insights. [62-65] However, the application of genomics in diagnosing and prognosticating non-urothelial bladder cancer remains limited, especially in comparison to the extensive genomic information available for UC. [66, 67]

The advancement in genomic profiling of non-urothelial bladder cancers holds immense potential for identifying therapeutic targets and improving treatment outcomes for these challenging tumors. [68] Further research in this area is essential to translate genomic discoveries into clinically relevant interventions and enhance personalized treatment strategies.

Conclusion

Non-urothelial cancers and BCVH represent a diverse and aggressive subset of bladder cancers. [69] Their rarity, coupled with their complex presentation, necessitates a multidisciplinary approach involving pathologists, clinicians, and researchers to ensure accurate diagnosis, prompt intervention, and ultimately, improved patient outcomes.