title: Immunohistochemical study of neuroendocrine differentiation in primary glandular lesions and tumors of the urinary bladder.
abstract: OBJECTIVE
  Neuroendocrine (NE) cells are uncommon in primary adenocarcinoma (AC) and other glandular lesions of the bladder, with no recent study series concerning its significance in differential diagnosis, prognosis or biologic significance.
  
  
  METHODS
  Sixteen primary bladder AC (enteric-type [n = 71, mucinous [n = 6] and not otherwise specified [NOS] [n = 31), 4 cases of urothelial carcinoma with glandular differentiation, 20 cases of glandular cystitis and 3 urachal remnants with intestinal metaplasia constituted the study series. In addition, 20 specimens of normal-looking urothelium, 15 conventional urothelial carcinomas and 5 small cell carcinoma (SCC) cases were included for comparison. NE differentiation included detection of chromogranin A, neuron-specific enolase (NSE) and synaptophysin by immunohistochemistry. The statistical analysis included the chi2 or Fisher exact test.
  
  
  RESULTS
  Chromogranin A-positive cells were present in 60% (11 of 16) of primary AC, all of enteric or mucinous type, but not in any of the 3 NOS-type AC investigated. NE differentiation in bladder AC subtypes resulted in highly significant differences between enteric or mucinous vs. NOS type (p = 0.0023). NE differentiation was also different in urachal vs. nonurachal AC (p = 0.020) and primary bladder AC vs. conventional invasive urothelial carcinoma (p < 0.001). Synaptophysin-positive cells were seen in 2 (12.5%) of the 16 primary AC cases, and NSE was negative in the 16 primary bladder AC. All urachal remnants and 70% of glandular cystitis examples had chromogranin A-immunoreactive cells. One of 4 urothelial carcinomas with glandular differentiation had chromogranin A-immunoreactive cells, but this was not significant when compared with primary AC (p = 0.1). Normal-looking bladder urothelium and conventional urothelial carcinoma specimens had no chromogranin A-immunoreactive cells. The 5 SCC cases investigated were positive for chromogranin A. No correlation was found between NE differentiation and outcome of primary bladder AC or urothelial carcinoma with glandular differentiation.
  
  
  CONCLUSIONS
  Primary bladder AC, cystitis glandularis and urachal remnants with intestinal metaplasia showed variable degrees of NE differentiation, with no apparent clinical correlation or prognostic significance. However, the absence of NE differentiation in NOS-type primary bladder AC may help in better defining this uncommon subtype of primary bladder AC.
authors.affiliation: Division of Pathology, San Luigi Gonzaga Hospital, Orbassano, Italy. e.bollito@libero.it
authors.forename: Enrico R
authors.initials: ER
authors.lastname: Bollito
authors.forename: Donatella
authors.initials: D
authors.lastname: Pacchioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Beltran
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Carlo
authors.initials: C
authors.lastname: Terrone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casetta
authors.forename: Mauro
authors.initials: M
authors.lastname: Mari
authors.forename: Roberta
authors.initials: R
authors.lastname: DePompa
authors.forename: Susanna
authors.initials: S
authors.lastname: Cappia
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000737:chemistry* / Q000473:pathology* / Q000648:ultrastructure; D018278:Carcinoma, Neuroendocrine / Q000737:chemistry* / Q000473:pathology* / Q000648:ultrastructure; D002454:Cell Differentiation / Q000502:physiology*; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D011379:Prognosis; D016708:Synaptophysin / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D053379:Chromogranin A; D002864:Chromogranins; D016708:Synaptophysin; D010751:Phosphopyruvate Hydratase