Bladder Lesion in a Man

Specimen Type:



A 63-year-old man presented with hematuria and cystoscopy revealed a small lesion on the bladder wall. Specimen consists of a single ovoid fragment of light tan tissue that measures 0.2x0.2x0.1cm in greatest dimention. Totally submitted in 1 cassette.

Pathologic Features:

The biopsy reveals a growth characterized by intramucosal and submucosal nests of urothelium arranged at various angles to the mucosal surface (Fig 1). Papillary structures are noted focally (Fig 2). Scattered cells with abundant eosinophilic granular cytoplasm are identified in the basal portion and superficial layer of the urothelium (Fig 3, 4), randomly distributed within the urothelium (Fig 5), mainly located in the periphery of nests (Fig 6), found in the stroma underneath the urothelium (Fig 7), and even the whole nests are composed of such cells (Fig 8). Immunohistochemically, those cells are positive for chromogranin (Fig 9, 10). There is no significant cytologic atypia associated with these cells.

Differential Diagnosis:

  • Urothelial carcinoma in situ, pagetoid variant

Urothelial carcinoma in situ, pagetoid variant: This is a rare variant of bladder cancer that is characterized by an intraepithelial proliferation of large cells arranged singly or in clusters and randomly distributed (references 1, 2). These neoplasms deserve recognition and attention, chiefly because they may be overlooked or misdiagnosed as urothelial dysplasia, then causing unsuspected tumor recurrence after surgery. Pagetoid CIS is usually a focal lesion occurring in a clinical and histological setting of conventional CIS. In cases with extensive urothelial denudation, pagetoid CIS may be focally present in otherwise normal-looking urothelium, thus alerting the pathologist to search for additional CIS elsewhere in the bladder. Patients manifesting pagetoid CIS have essentially the same progression and survival rates as patients without pagetoid changes and are treated in the same way.

Given that primary extramammary Paget disease of the external genitalia and of the anal canal may extend to the bladder and, conversely, some bladder cases of pagetoid CIS may extend to the urethra, ureter, and beyond to the external genitalia, the differential diagnoses between these two entities represent an important therapeutic consideration. A panel of immunostains including CK7+/CK20+ may assist in differentiating urothelial pagetoid CIS from extramammary Paget disease which is known to be CK7+/CK20- (references 2, 3).


Inverted papilloma with neuroendocrine differentiation and Paneth cell-like metaplasia.

Key Features:

  • Typical features of inverted papilloma.
  • Scattered eosinophilic granular large cells randomly distributed within the urothelium, which are immunoreactive with neuroendocrine markers.

Comment: Several types of metaplasia can occur in human bladder epithelium under certain pathological conditions, of which intestinal metaplasia, squamous metaplasia, nephrogenic metaplasia are commonly reported. Although neuroendocrine differentiation or metaplasia is not commonly reported in practice, it is not an unusual finding according to one study, which showed endocrine cells can be demonstrated between the epithelial cells in 40 out of 50 cases of cystitis glandularis or cystica (reference 4). Our present case represents a rare example of florid neuroendocrine differentiation arising in the setting of benign proliferative urothelium. The scattered distribution pattern of large endocrine cells within the benign urothelium raising the concern for pagetoid variant of urothelial carcinoma in situ. Lack of cytologic atypia and positivity for neuroendocrine markers are useful features that help rule out this consideration.


  1. Orozco RE, et al. The pagetoid variant of urothelial carcinoma in situ. Hum Pathol. 1993 Nov; 24 (11):1199-202.
  2. Lopez-Beltran A, et al. The pagetoid variant of bladder urothelial carcinoma in situ: A clinicopathological study of 11 cases. Virchows Arch. 2002 Aug;441 (2):148-53.
  3. Boardman CH, et al. Transitional cell carcinoma of the bladder mimicking recurrent paget's disease of the vulva: report of two cases, with one occurring in a myocutaneous flap. Gynecol Oncol. 2001 Jul;82(1):200-4.
  4. Hamid QA, et al. Endocrine differentiation in inflamed urinary bladder epithelium with metaplastic changes. Virchows Arch A Pathol Anat Histopathol. 1988; 412 (3):267-72.