Since the first publication of the histologic classification of bladder cancer in 1973 to the most recent in 2016, the World Health Organization classification of urothelial carcinoma (UC) has grown substantially.¹ Up to a third of cystectomy specimens may harbor divergent differentiations, defined as UC present with other morphologies.² Here we discuss the most common carcinoma variants.

Pure Squamous Cell Carcinoma

Pure squamous bladder carcinoma is the most common histologic variant, representing 5% of bladder cancers in Western countries and up to 30% of cancers in endemic countries.³ Risk factors include Schistosomiasis infection, recurrent urinary tract infections, long-term indwelling catheters and recurrent bladder calculi. Histologically, typical squamous features are seen with keratin pearls and intercellular bridges (see figure, part A).¹ More than 70% of patients have muscle-invasive bladder cancer (MIBC) at diagnosis. Radical cystectomy (RC) is the mainstay of treatment in nonmetastatic cases and is superior to radiation.⁴ Unfortunately, patients have a worse prognosis when stage-matched to pure conventional urothelial carcinoma (PUC) due to tendency for locoregional metastasis. Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy have no role in treatment. It should be noted that UC with squamous differentiation, which is found in up to 30% of UC tumors, has different clinicopathological features than pure squamous bladder cancer (see figure, part B). SWOG S8710 showed that patients with UC with squamous or glandular differentiation had a better response to NAC than those with PUC.⁵

Figure. A, pure squamous. B, UC with squamous differentiation. C, UC with glandular differentiation. D, adenocarcinoma. E, nested. F, micropapillary. G, small cell/neuroendocrine. H, plasmacytoid. I, sarcomatoid. J, LELC.

UC with Glandular Differentiation

Glandular differentiation is seen in 8–18% of invasive UC.⁶ Glandular UC can be differentiated from benign glandular lesions, such as villous adenoma and cystitis glandularis, by the TERT promotor mutation, which is seen in two-thirds of UC with glandular differentiation.⁷ Glandular neoplasms include enteric and mucinous types and may be characterized by extravasated mucin with or without signet ring cells (see figure, part C).⁸ While UC with glandular differentiation has similar overall survival (OS) to PUC, it often presents at a more advanced stage.⁹ NAC may downstage prior to RC, and RC is preferred if surgically resectable.⁵

Pure Adenocarcinoma

Primary bladder adenocarcinoma makes up about 2% of bladder cancers.³ It must be clinically differentiated from adenocarcinoma from a different primary organ, such as prostate, endometrium or colon. Like UC with glandular differentiation, these are mucinous tumors that may or may not contain signet ring cells (see figure, part D). Additionally, there are urachal and non-urachal subtypes. Treatment is cystectomy or partial cystectomy. Partial cystectomy, including en bloc removal of the umbilicus, urachus and bladder dome, is appropriate in select cases where the tumor is localized to the bladder dome. Adjuvant radiotherapy is indicated for advanced disease to improve local control.¹⁰

Nested UC

The nested variant is characterized by “nests” or clusters of urothelial cells invading into the lamina propria and muscularis propria (see figure, part E). The bland appearance of these cells makes it difficult to distinguish from benign lesions such as florid von Brunn’s nests or nephrogenic adenoma, although these benign lesions typically do not invade the muscularis propria.³ Similar to PUC, there is a high incidence of TERT promotor mutations in the nested variant that is not present in its benign mimics.⁶ When compared to stage-matched PUC, the nested variant has a higher rate of locally advanced disease (pT3–T4) at RC.^1,3,11 Data on this variant’s response to NAC are limited with one small study showing a 13% response rate.¹²

Micropapillary UC

Micropapillary bladder cancer accounts for 2–5% of UC.³ Histologically, it has small aggregates and filiforms of cells within lacunar spaces (see figure, part F). Genetically it is associated with HER2/ErbB2 amplification and is molecularly classified as the luminal subtype. Unfortunately, these tumors often present at a high pathological stage with lymphovascular invasion.¹ Data indicate that T1 micropapillary carcinoma of the bladder should be treated with prompt RC rather than bacillus Calmette-Guérin given its aggressive nature and poor response rate to intravesical therapy. There are conflicting data regarding the utility of NAC prior to cystectomy for T2 disease. It may downstage tumors and have an OS benefit for patients without tumor-associated hydronephrosis.¹³ Metastatic micropapillary disease has similar OS to PUC.⁹

Small Cell/Neuroendocrine Carcinoma

Small cell/neuroendocrine bladder cancer is a rare variant (<1%) with high metastatic potential, especially to the brain and bone. On histology it is indistinguishable from small cell carcinomas of other organs and is characterized by sheets of infiltrative small blue cells with granular nuclear chromatin (see figure, part G). Genetically it is associated with loss of the TP53 and RB1 genes.¹⁴ Given the propensity for brain metastasis, staging for small cell bladder cancer should include brain imaging. Treatment parallels that of small cell lung cancer with platinum-based chemotherapy as the mainstay (usually with etoposide), even for early localized disease.⁹ RC or radiotherapy should be performed after NAC in nonmetastatic cases. It is not known which treatment modality is superior given the rarity of this variant. Unfortunately, OS for this subtype is worse than any other molecular subtype.^3,14

Plasmacytoid UC

Plasmacytoid urothelial carcinoma, also sometimes called signet ring cell carcinoma or diffuse urothelial carcinoma, is another highly aggressive variant that has poor prognosis. Plasmacytoid features histologically consist of infiltrated discohesive cells resembling plasma cells (see figure, part H).⁸ Genetically, it is associated with CDH1 and E-cadherin loss and is molecularly classified as the luminal subtype. T1 disease requires timely RC due to the high risk of under-staging as well as disease progression. Furthermore, plasmacytoid bladder cancer tends to spread without macroscopic tissue changes, making it difficult for the surgeon to determine surgical margins intraoperatively and necessitating wide surgical margins. While early studies showed benefit to NAC, contemporary data suggest no OS benefit and up-front RC is recommended. Unfortunately, prognosis is worse than PUC, even with prompt treatment.

Sarcomatoid UC

Sarcomatoid bladder cancer represents approximately 0.3% of UC. Risk factors include previous radiotherapy exposure and intravesical cyclophosphamide.³ Histologically, mesenchymal differentiation is noted often with spindle cell morphology (see figure, part I). Molecularly, sarcomatoid UC is closest to the basal subtype.⁶ Genetically, sarcomatoid bladder cancer has mutations in TP53, RB1 and PIK3CA. Unfortunately, 41% of patients present with cT2 disease and 15% present with cT3 disease. Therefore, patients with sarcomatoid UC often have a poor prognosis. These tumors are chemoresistant, and early RC is recommended.

Lymphoepithelioma-Like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) of the bladder accounts for <1% of all UC. It is aptly named as its poorly differentiated tumor cells with large nuclei, prominent nucleoli and syncytial growth resemble nasopharyngeal lymphoepithelioma (see figure, part J).³ Because of the prominence of lymphoid cells, these lesions may be mistaken for a chronic cystitis or lymphoma. A high index of suspicion is necessary for a correct diagnosis. Prognosis does not differ from PUC. RC confers the highest disease-free rate, but platinum-based chemotherapy remains an option as well.^15,16