Urothelial Carcinoma in Situ of the Bladder with Glandular Differentiation

Urothelial carcinoma in situ (CIS) of the bladder with glandular differentiation (CIS-GL) is rare with some showing an association with small cell carcinoma. There is a paucity of data on whether CIS-GL diagnosed in the absence of invasive carcinoma is associated with an increased risk of developing small cell carcinoma of the bladder. Twenty-seven cases of CIS-GL were identified from the consult files of one of the authors from 2008 to 2015 without prior or coexisting invasive carcinoma at the time of diagnosis. Sixty-five additional cases were identified with concurrent CIS-GL and invasive carcinoma to assess the nature of the association. Of the 27 cases with only CIS-GL without invasive carcinoma at the time of diagnosis, follow-up time ranged from 11 to 91 months (mean, 41.1 mo). Of 24/27 cases with follow-up information: 13 (54.2%) had no evidence of disease at last follow-up, typically treated with induction and maintenance Bacillus Calmette-Guerin; 3 (12.5%) patients underwent radical cystectomy due to disease progression; 2 (8.3%) patients had recurrent CIS, and 1 (4.2%) had recurrent noninvasive low-grade papillary urothelial carcinoma (UC) (these patients underwent transurethral resection of the bladder and Bacillus Calmette-Guerin treatment); 2 (8.3%) patients died of metastatic UC; and 3 (12.5%) died of other or unknown causes. Of note, none of these 24 patients developed small cell carcinoma. Of the 65 cases with concurrent CIS-GL and invasive carcinoma, the invasive carcinoma was: pure UC in 29/65 (45%); invasive UC with GL in 13/65 (20%); coexisting small cell carcinoma and invasive UC in 8/65 (12%); plasmacytoid UC in 7/65 (11%); sarcomatoid UC in 3/65 (5%); micropapillary UC in 2/65 (3%); squamous in 2/65 (3%); and signet ring with colloid features in 1/65 (1%). Patients with CIS-GL without invasive carcinoma are at significant risk for cancer progression and in a minority of cases at risk for death from bladder carcinoma, similar to usual CIS. Typically, subsequent invasive carcinoma is UC rather than adenocarcinoma. Similarly, the largest fraction of concurrent invasive carcinoma and CIS-GL is UC. However, this study for the first time demonstrates the wide spectrum of other UC variants that coexist with CIS-GL, including a sizeable minority of cases with invasive UC with GL. Although there is a disproportionately high fraction of CIS-GL with coexisting small cell carcinoma, small cell carcinoma does not seem to develop at high frequency following the diagnosis and treatment of CIS-GL.