Carcinoma of the urinary bladder is the most common malignancy involving the urinary tract system. Urothelial carcinomas can also occur in the renal pelvis, ureter, or urethra but their occurrence is far less common than in the urinary bladder. The histology of urothelial carcinoma is variable. On the whole about 70% of urothelial carcinomas of the urinary bladder are noninvasive or superficially invasive and these tumours are usually papillary and exhibit different degrees of differentiation; on the other hand, most muscle-invasive urothelial carcinomas are nonpapillary and usually exhibit high-grade cytomorphology. These types of classic urothelial carcinomas can be easily diagnosed histologically and they do not pose a problem to the pathologist.
A number of systems have been utilized to grade and classify urinary bladder tumours. In 1972, the World Health Organization (WHO) adopted a system which distinguished papillomas from grades I, II, and III papillary transitional cell carcinomas. Subsequently in 1998, The World Health Organization in a collaborative effort conjointly with the International Society of Urological Pathologists (ISUP) published a consensus opinion classification system for urothelial (transitional cell) tumours. Studies that were carried out after 1998 were supportive of/validated the clinical significance of the classification scheme, and in view of this in 2004, the classification system was accepted as the standard classification system. According to this classification system, urothelial carcinoma has been classified into (a) low grade and (b) high grade depending upon the degree of nuclear anaplasia and architectural abnormalities with exception of some tumours, for example, tubular or nested/tubular variant. Invasive urothelial carcinoma is of high grade.
A number of variants of urothelial carcinoma were added to the World Health Organization classification in 2004 and some of these include lymphoepithelioma-like cell variant, sarcomatoid variant, plasmacytoid variant, microcystic variant, micropapillary variant, nested variant, and small cell type. These variants of urothelial carcinoma have varied biological behaviours but small cell carcinoma of the urinary bladder is a very aggressive tumour with very poor prognosis. Nested variant of urothelial carcinoma is characterized by an unusual, bland morphology which mimics some benign urinary bladder lesions and it has a clinical behaviour which simulates the clinical behaviour of high-grade conventional urothelial carcinomas. Nested variant of urothelial carcinoma was first reported by Stern [
Extensive literature search was done using various internet search engines to identify case reports, case series, and review manuscripts as well as conference abstracts on nested variant of urothelial carcinoma using the following terms: nested variant of urothelial carcinoma and nested variant of transitional cell carcinoma. The identified documentations were thoroughly read in order to ascertain the presentation, investigation, diagnostic features, tumour stage, management, and outcome of nested variant of urothelial carcinoma. Details of diagnostic features, tumour details and outcome were not detailed in few of the identified documentations on nested variant of urothelial carcinoma; however, enough information was gathered to summarize the presentation, diagnosis, management, and outcome of patients in most cases (see Tables
A list of some of the reported cases of nested variant of urothelial carcinoma and their outcome.
Patient | Reference | Age/sex | Pathologic stage | AJCC stage | Treatment | Status | Follow-up | Associated CUC (WHO/ISUP 1998) |
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1 | Lin et al. [ |
90/F | pT1 | 1 | Cystectomy | NED | 30 | No |
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2 | Lin et al. [ |
73/F | pT3b | III | Cystectomy + chemotherapy | NED | 5 | No |
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3 | Lin et al. [ |
65/M | pT2b | IV | Cystectomy + chemotherapy | AWM | 16 | Flat CIS |
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4 | Lin et al. [ |
70/M | pT3b | III | Cystectomy + chemotherapy | AWM | 15 | Flat CIS |
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5 | Lin et al. [ |
61/M | pT3b | IV | Cystectomy + chemotherapy | NED | 19 | Flat CIS |
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6 | Lin et al. [ |
80/M | pT3b | III | Cystectomy | NED | 27 | Flat CIS |
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7 | Lin et al. [ |
66/M | pT1 | I | Cystectomy | NED | 22 | No |
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8 | Lin et al. [ |
53/M | pT1 | I | Cystectomy | NED | 19 | No |
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9 | Lin et al. [ |
51/M | pT2 | IV | Radiotherapy | DOD | 3 | No |
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10 | Lin et al. [ |
59/M | pT2a | II | Cystectomy | NED | 24 | No |
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11 | Lin et al. [ |
42/F | pT2a | II | Cystectomy | NED | 20 | No |
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12 | Lin et al. [ |
75/M | pT2a | I | TUR | NED | 12 | Low-grade papillary UC |
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13 | Wang et al. [ |
49/F | G3pT4M1 | Partial cystectomy; en bloc resection of distal ileum, caecum; resection of transplanted pancreas; right salpingo-oophorectomy; repair of ileocolostomy anastomosis; chemotherapy | DOD | 12 months | Plus conventional high-grade TCC | |
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14 | Tatsura et al. [ |
70/M | G3pT3b Nx M0 | >III | Bladder adherent and cystectomy abandoned; open bladder total layer biopsy + bilateral ureterocutaneostomy; chemotherapy | Alive with disease | 12 months | Small tumour atypical cells positive for cytokeratin |
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15 | Terada [ |
80/F | pT1 | TUR | Alive with no tumour | 6 months | Atypical cells forming nests and tubules in lamina propria without surface urothelial involvement | |
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16 |
Terada [ |
78/M | pT1 | TUR | Alive with no tumour | 15 months | Atypical cells forming nests and tubules in lamina propria without surface urothelial involvement | |
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17 | De Berardinis et al. [ |
70/M | pT2aN+ | TUR twice + BCG for initial conventional G3pT1b tumour and cystectomy + lymphadenectomy + chemotherapy for nested variant was started | Alive 12 months after initial diagnosis of conventional urothelial carcinoma | 12 months after initial diagnosis and exact duration of follow-up after cystectomy not stated but patient just started on chemotherapy after cystectomy | ||
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18, 19, 20, 21, 22, 23, 24 | Cardillo et al. [ |
5 M |
3 stage 1; |
6 patients with stages I to III tumours underwent cystectomy; |
Follow-up outcome data not provided | Follow-up outcome data not provided in paper | ||
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25 | Dundar et al. [ |
78/M | pT4N1 | Cystoprostatectomy and chemotherapy planned but not given at time of publication | Alive | Follow-up data not available at time of publication | ||
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26 | Dundar et al. [ |
56/M | pT2 at least | TURBT he refused radical cystoprostatectomy | Alive but had 3 recurrences of nested variant urothelial carcinoma resected over 23 months | 23 months | ||
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27 | Badoual et al. [ |
Details not available | Details not available in English | Details not available | Details not available to author | Details not available | Details not available | Details not available |
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28 | Badoual et al. [ |
Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available |
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29 | Krishnamoorthy et al. [ |
45 F | pT1 | TUR | Alive | No follow-up paper soon after TUR | ||
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30 | Ozdemir et al. [ |
65 M | pT2 at least | TUR biopsy |
Alive no data provided on follow-up case reported after biopsy | Data not available | ||
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31 |
Holmäng and Johansson 2001 [ |
10 patients | Details not available to author | Details not available to author | 7 died of disease or treatment complications (4 months–40 months); 1 died of unrelated cause after 90 months; follow-up ≤1 year for the remaining 2 | |||
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32 | Ooi et al. [ |
74/M | Bladder tumour with ureteric involvement | TUR + bilateral local resection of ureter and chemotherapy | Alive with tumour (partial response) | 12 months | ||
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33–86 | Linder et al. [ |
52 patients |
36 (69%) with pT3-T4 |
All had radical cystectomy |
Analysis in the comparison of patients with nested variant matched with a cohort of conventional urothelial carcinoma showed no significant differences in the 10-year local recurrence free survival (83% versus 80%, |
Median follow-up 10.8 months |
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87 | Tripodi et al. [ |
49/F | Renal pelvis pT1 | Nephrectomy and upper ureterectomy | Alive | No long-term follow-up at time of publication | ||
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88 | Cerda et al. [ |
53/M | pT3b pN1 | TUR and radical cystoprostatectomy, radiotherapy, and chemotherapy | Died due to advanced metastatic disease | 12 months | ||
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89 | Cerda et al. [ |
83/F | pT2 | TUR (surgical procedure not done due to advanced age) | Died of disease | 3 years (36 months) | ||
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90 |
Yildiz et al. [ |
60/M | T2 at least (muscle invasion) | TUR further details in Turkish language | Not found in data | |||
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91 |
Pusztaszeri et al. [ |
Renal pelvis and ureter | Details not available to author | Details not available to author | Details not available to author | |||
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92 | Lau [ |
Renal pelvis | Locally advanced | Details not available to author | Details not available to author | Details not available to author | ||
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93 | Stern [ |
45/M | Details not available to author | Details not available to author | TUR | Alive tumour recurred 18 months later | 18 months | |
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94, 95, 96 | Talbert and Young [ |
3 men |
Details not available to author | Details not available to author | Details not available to author | |||
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97, 98, 99, 100 | Murphy and Deana [ |
4 cases | Details not available to author | Details not available to author | Details not available to author | Tumours persisted/recurred | Details not available to author | |
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101–130 | Wasco et al. [ |
30 cases |
All but 1 invasive tumours (9% pT1; pT2-3a; 65% pT3b; 17% pT4) | All had cystectomy and 15 had cystectomy and chemotherapy | 3 (10%) died of disease; 16 (55%) alive with persistent or recurrent disease; 10 (34%) alive without disease |
Follow-up in 29 patients (97%) with median 12 months (range 1–31 months) | Focal atypia in 90% and focal high-grade cytological atypia at tumour base in 40% | |
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131–134 | Young and Oliva [ |
4 patients |
Details not available to author | Details not available to author | Details not available to author | 1 or more specimens were misinterpreted as benign | ||
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135–150 | Drew et al. [ |
16 cases with marked male predominance | Details not available to author | Details not available to author | 3 with no disease | Average follow-up 16.6 months | A few cells in every case with cytological atypia | |
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151 and |
Xiao et al. [ |
69/M |
pT4 N1 |
Radical cystoprostatectomy and chemotherapy |
Developed bone and soft tissue metastases in 4 months | 4 months |
Focal urothelial CIS and multiple foci of urothelial atypia | |
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153 | Huang et al. [ |
83/M | G3pT2-3 | Cystoprostatectomy | Alive no long-term follow-up data available to author | |||
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154–164 | Volmar et al. [ |
11 patients | 5 pT2-3 N0 |
Details not available to author | Details not available | |||
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165–174 |
Holmäng and Johansson [ |
10 patients | Details not available | Locoregional therapy | 7 died of disease or treatment complications 4–40 months after diagnosis; |
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175–177 | Liedberg et al. [ |
3 patients | Advanced muscle-invasive 2 with lymph node involvement | Final outcome not available | ||||
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178–200 | Cox and Epstein [ |
23 cases |
20 T2-T3 |
18 had TURBT |
3 of 17 patients developed metastasis 2 lung 1 unknown with 2 of the 3 dead of disease; 1 patient died of disease with no known details |
Follow-up for 17 patients |
Abbreviations: M: male; F: female; NED: alive with no evidence of disease; AWM: alive with metastasis; DOD: dead of disease; CIS: carcinoma
Nested variant of urothelial carcinoma: example of results and geographic distribution of several markers in nested variant of urothelial carcinoma taken from Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, and Reuter V E. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases. Modern Pathology 2003; 16(12): 1289–1298.
Case | Ref. | P21 result | P21 location | P27 result | P27 location | P53 result | P53 location | EGF-R result | Bc12 result | Bc12 location | MIB-1% | MIB1 location | Other comments |
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1 | Lin et al. [ |
+ | Diffuse | + | Surface | − | − | − | 20 | Diffuse | |||
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2 | Lin et al. [ |
+ | Diffuse | + | Diffuse | − | − | − | 15 | Diffuse | |||
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3 | Lin et al. [ |
+ | Diffuse | − | − | − | − | 35 | Diffuse | ||||
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4 | Lin et al.[ |
+ | Diffuse | + | Surface | − | − | − | 35 | Diffuse | |||
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5 | Lin et al. [ |
+ | Base | + | Surface | + | Base | − | + | Surface | 2 | Base | |
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6 | Lin et al. [ |
− | + | Surface | − | − | − | 20 | Diffuse | ||||
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7 | Lin et al. [ |
+ | Base | + | Surface | − | − | + | Surface | 35 | Diffuse | ||
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8 | Lin et al. [ |
+ | Base | + | Surface | − | − | − | 15 | Base | |||
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9 | Lin et al. [ |
− | + | Surface | + | Diffuse | − | − | 30 | Diffuse | |||
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10 | Lin et al. [ |
+ | Diffuse | + | Surface | − | − | − | 30 | Base | |||
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11 | Lin et al. [ |
+ | Base | + | Surface | − | − | − | 20 | Diffuse | |||
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12 | Lin et al. [ |
+ | Base | + | Surface | + | Base | − | − | 15 | Base | ||
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13 | Wang et al. [ |
Not done | Not done | − | Not done | Not done | Not done | ||||||
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14 | Tatsura et al. [ |
Not done | Not done | Not done | Not done | Not done | Not done | Cytokeratin+ | |||||
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15 | Terada [ |
Not done | + | Not done | Ki-67 labeling = 15%; +cytokeratins; +EMA; | ||||||||
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16 | Terada [ |
Not done | Not done | + | Not done | Ki-67 labeling = 30%; +cytokeratins; +EMA, +p63, +p53, +C10, +CEA, +MUC1 | |||||||
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17 | De Berardinis et al. [ |
Not done | Not done | Strongly+ | Not done | Ki-67 +high expression | |||||||
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18, 19, 20, 21, 22, 23, 24 | Cardillo et al. [ |
Not done | Not done | Not done | Not done | ||||||||
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25 | Dundar et al. [ |
Not done | +40% | +40% | Not done | Ki-67 20%; 34 | |||||||
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26 | Dundar et al. [ |
Not done | +50% | +40% | Ki-67 15%; +34 | ||||||||
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27 | Badoual et al. [ |
Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available |
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28 | Badoual et al. [ |
Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available |
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29 | Krishnamoorthy et al. [ |
Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Details not available | Irregular nests of tubules in lamina propria |
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30. | Ozdemir et al. [ |
Not done | Not done | Not done | Not done | Not done | Details not available to author | ||||||
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31 |
Holmäng and Johansson [ |
Details not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | Deatials not available to author | |
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32 | Ooi et al. [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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33 to 86 | Linder et al. [ |
52 patients | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | Details not availabe | |
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87 | Tripodi et al. [ |
Not done | Not done | Not done | +P63 | ||||||||
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88 | Cerda et al. [ |
Not done | Not done | Not done | Not done | Not done | Not done | Not done | Not done | +CK7,+CK20, | |||
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89 | Cerda et al. [ |
Not done | Not done | Not done | Not done | Not done | Not done | Not done | Not done | Not done | Not done | +CK7,+CK20, +34 | |
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90 |
Yildiz et al. [ |
Details unavailable | Details unavailable | Details unavailable | Details unavailable | Details unavailable | Details unavailable | ||||||
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91 |
Pusztaszeri et al. [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |||||
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92 | Lau [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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93 | Stern [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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94–96 | Talbert and Young [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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97–100 | Murphy and Deana [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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101–130 | Wasco et al. [ |
CK7+ (93%); CK20+ (68%); P63+ (92%); CK903+ (92%) | |||||||||||
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131–134 | Young and Oliva [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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135–150 | Drew et al. [ |
Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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151 and 152 | Xiao et al. [ |
High +p53 | Both Strongly+ for 63; | ||||||||||
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153 | Huang et al. [ |
+CK7; | |||||||||||
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154–164 | Volmar et al. [ |
8.8% | +p53 4.2%; | ||||||||||
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165–174 |
Holmäng and Johansson [ |
Details not available | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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175–177 | Liedberg et al. [ |
Details not available | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | |
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178–200 | Cox and Epstein [ |
Details not available | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author | Details not available to author |
Nested variant of urothelial carcinoma is one of the variants of urothelial carcinoma that was added to the WHO classification in 2004. This variant of urothelial carcinoma exhibits a deceptively bland-appearing invasion by nests of cells [
Nested variant of urothelial carcinoma usually occurs in men who are older than 60 years which is similar to the occurrence of classic urothelial carcinoma [
Nested variant of urothelial carcinomas has been reported in patients aged between 42 years and 90 years.
Nested variant of urothelial carcinoma is either rare or underreported with a reported incidence of 0.3% of invasive bladder tumours [
It has been stated that the neoplasm resembles von Brunn’s nest [
Radical surgical resection is the treatment of choice [
Quite often there is no evidence of a clearly defined tumour.
The described microscopic features of nested variant of urothelial carcinoma include the following. Irregular and confluent small nests and abortive tubules are composed of urothelial cells infiltrating the lamina propria or muscularis propria, usually without surface involvement [ The tumour cells usually exhibit mild atypia (mild pleomorphism, slightly increased nuclear/cytoplasmic ratios, occasional prominent nucleoli, and rare mitotic figures) and resemble cystitis glandularis and cystitis cystica [ Deep tumour-stroma interface is jagged and infiltrative [ Often more atypia and focal anaplasia with increasing depth of invasion are one of the features [ Typical urothelial is often present [ Retraction artefact may be seen [ By definition these tumours cannot be high grade or have overlying surface carcinoma
It has been stated that subtle features are not diagnostic themselves—these subtle features include medium sized round/polygonal cells with abundant, dense, slightly granular basophilic cytoplasm and well-defined cell borders, irregular cell counters, increased nuclear/cytoplasmic ratio, coarse chromatin, and occasional prominent nucleoli [
Nested variants of urothelial carcinoma stain positively for the following: CK7, CK20, p63, Ki-67, and CK903 [ variable P53 [
Nested variants of urothelial carcinoma stain negatively with Bc12, EGFR, and PSA [
Some of the listed differential diagnoses of nested variant of urothelial carcinoma include the following. Adenocarcinoma: colonic differentiation and more prominent atypia [ Cystitis cystica/cystitis glandularis: this has no atypia and no invasion [ Inverted papilloma: this has no deep invasion [ Nephrogenic metaplasia/adenoma: this usually has papillary component, prominent tubular, or cystic structures lined by single layer of cuboidal cells, no atypia, and no invasion [ Adenocarcinoma of prostate: this is centred in the prostate gland and immunohistochemically stains positively with PSA and PSAP [ Urothelial carcinoma with small tubules: this is an invasive carcinoma with small gland-like spaces lined by urothelial cells without intracellular mucin or columnar lining; some authors have considered this as part of nested variant of urothelial carcinoma [ von Brunn’s nests: these have no invasion, no prominent atypia, and no focal anaplasia as stated by some authors [
Rouse [ Infiltrative pattern: it is worth noting that (a) the infiltrative pattern may sometimes be difficult to assess on biopsies that are small; (b) deep foci of classical jagged invasion quite often exist; (c) if present evidence of muscularis propria involvement is definitional (d) the stroma may be desmoplastic or normal. Predominant pattern—variably sized nests are seen and these are most often small sized and fused. Frequent forms of lumens or spaces—(a) the lumens are quite often empty; however, necrotic debris may be found in them or PASd stainable material; (b) the carcinoma cells forming and lining the spaces do not have secretory/glandular cytoplasmic differentiation; (c) the lining cells of the spaces tend to be transitional or squamous PASd negative; (d) There is no absence of goblet cells; and (e) if extensive then the terminology of microcytic urothelial carcinoma can be used. Cytologically predominantly bland—the cytological features of this tumour include the following (a) focal cytologic atypia is almost invariably present but sometimes this is only present in deeper tissues; (b) the overlying mucosa is often normal or there may be a papillary component; (c) nested variant of urothelial carcinoma often involves the ureteric orifices; and (d) despite the bland cytology these tumours are usually aggressive and invasive tumours [
Lin and associates [ Nested variant of urothelial carcinoma is characterized by confluent small nests and abortive tubules of mildly atypical neoplastic cells infiltrating the lamina propria and/or muscularis propria of the bladder. Despite its deceptively bland histomorphologic appearance, the lesion is reported to have an aggressive behaviour. The collective immunohistochemical expression of suppressor genes, growth factor, and proliferation activity marker had not been previously studied in this disease. They had stained formalin-fixed, paraffin-embedded archival tissues from 12 cases of nested variant of urothelial carcinoma with monoclonal antibodies to p21, p27, p53, EGF-R, and bcl-2, as well as the proliferation marker MIB-1. They also evaluated the area of predominant immunoreactivity. They also compared the pattern of immunostaining with the clinical parameters. p21 was positive in 10 of 12 cases and located at the deepest portion of the tumour in 5 of 10 positive cases. Immunoreactivity for p27 was seen in 11 of 12 cases and limited to the superficial portion of the tumor in 9 of 11 positive cases. Only 3 and 2 of 12 cases were positive for p53 and bcl-2, respectively. MIB-1 immunoreactivity ranged from 2 to 35% of the neoplastic cells, with most tumors showing a proliferation index of >15%. Follow-up ranged from 3 to 30 months (mean, 17.6 months). All patients except one were alive, although three patients developed metastases. Nested variant of urothelial carcinoma is a deceptively benign-appearing neoplasm with potential of deep invasion and metastases. Immunohistochemically, nested variant of urothelial carcinoma shares some features with high-risk conventional urothelial carcinomas, such as loss of p27 expression and high proliferation index. Nevertheless, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen.
Wang and associates [
Wang and associates [
Nested variant of urothelial carcinoma was classified by the World Health Organization in 2004 as an “uncommon aggressive tumor,” with few reported cases and a 70% mortality rate 4 to 40 months after diagnosis despite therapy [
While the degree of cytologic atypia noted in this case is not typically described in NVUC, this feature can be seen in these lesions and NVUC is associated with areas of conventional high-grade urothelial carcinoma in the majority of instances [
Wang and associates [
Some authors [
Wang and associates [
Cox and associates [
Three of 17 patients developed metastatic disease (2 in the lung, 1 unknown) with 2 of these dead due to disease; another patient died of disease with un known details. Of the aforementioned 3 patients who died of disease, 2 had no and 1 had focal (<5%) conventional invasive urothelial carcinoma on transurethral resection. Cox and associates [ These cases, which posed great diagnostic difficulty both for the contributing pathologists and for the consultant, represent the first formal description of a large nested pattern of urothelial carcinoma. This pattern is distinguished from an inverted growth pattern of noninvasive urothelial carcinoma and from von Brunn nests by either muscularis propria invasion, irregularly infiltrating nests, or a stromal reaction. Despite the bland cytological features of these neoplasms, they have well-documented metastatic potential.
Wasco and associates [ The nested component demonstrated an immunophenotype which was identical to the usual urothelial carcinoma, with CK7, CK20, p63, and CK903 expression in 93%, 68%, 92%, and 92% of cases, respectively. At resection, all of the cases except 1 case were demonstrated to be invasive—9% into lamina propria, 4% into muscularis propria, 65% into perivesical fat, and 17% into adjacent organ(s). In comparison with pure high-grade urothelial carcinoma, nested variant of urothelial carcinoma was associated with muscleinvasion at transurethral resection (31% versus 70%; Follow-up was available for 29 patients (97%) with a median of 12 months (range, 1 month to 31 months) of follow-up; 3 (10%) died of disease, 16 (55%) were alive with persistent or recurrent disease, and 10 (34%) were alive without disease. Response to neoadjuvant chemotherapy was observed in 2 (13%) of 15 patients. Nested variant of urothelial carcinoma which was seen either in pure form or with a component of usual urothelial carcinoma had similarly unfavourable outcome (
Wasco and associates [
Dundar and associates [
Low-power view showing closely packed, irregularly spaced, glandular, and cystic urothelial nests somewhat resembling von Brunn nests. Note that the overlying urothelium appears uninvolved (hematoxylin-eosin, original magnification ×100). Nested variant of urothelial carcinoma taken from Dhall et al. [
Low-power view showing bland tumor cells in the nested pattern infiltrating the muscularis propria (hematoxylin-eosin, original magnification ×100). Nested variant of urothelial carcinoma taken from Dhall et al. [
Immunohistochemical studies of the tumour were undertaken and these showed that the percentages of cells that were positive for Ki-67, p53, and p27 were 20%, 40%, and 40% in Case 1 and 15%, 40%, and 50% in Case 2, respectively (Figure
On high-power view, the tumour cells show no significant cytologic atypia (hematoxylin-eosin, original magnification ×400). Nested variant of urothelial carcinoma taken from Dhall et al. [
Terada [ Both cases were positive with P53 and high Ki7 labeling, which suggested that both cases were malignant. One case was characterized by positive cytokeratins, EMA, p53, Ki-67 (labeling = 15%), CD10, CEA, and MUC1. The patients were free of tumour 6 months and at 15 months pursuant to transurethral resection of their bladder tumours.
Cardillo and associates [ The cytologic features of nested variant of urothelial carcinoma are subtle but distinct. A primary diagnosis of nested variant of urothelial carcinoma is not recommended in view of the subtleness of the findings. However, the presence of cells with the aforedescribed features should warrant a cystoscopic examination with histological confirmation in a patient with a previous history of nested variant of urothelial carcinoma.
De Berardinis and associates in 2012 stated that nested variant of urothelial carcinoma is a rare histological entity, with about 80 reported cases [
Xiao and associates [
Xiao and associates [
Krishnamoorthy and associates [ Nested variant of urothelial carcinoma can easily be confused with a number of benign lesions; it is very important for the pathologist to consider nested variant of urothelial carcinoma in the differential diagnosis of the lesions that show nested type growth pattern in lesions of the urinary bladder. It is equally important for the treating physician to adopt an aggressive approach towards the management of these lesions. The optimal treatment for nested variant of urothelial carcinoma is yet to be determined and this may be because of the rarity of the tumour, very small number of long-term survivors, and the absence of any randomized studies. The aggressive invasive growth and early metastases are the factors that favour radical cystectomy with adjunctive systemic chemotherapy. Nevertheless, a consensus is yet to be arrived at. They had reported their case in view of its rarity, its unusual histology, and its prognostic significance emphasizing the need to distinguish it from the classic transitional cell carcinoma. The aggressive behaviour of these nested variants underlines the importance of distinguishing them from benign proliferative lesions. Cytologic atypia is not a very good parameter because the mild atypia seen in nested variant of transitional cell carcinoma can be very deceptive, especially at low and medium power magnifications. Though the obvious invasion of the muscularis propria excludes the possibility of a benign lesion, the absence of invasion leads the pathologist onto a diagnostic dilemma.
Ooi and associates [
Holmäng and Johansson [
Tatsura and associates [
Murphy and Deana [
Drew and associates [ Nested variant of transitional cell carcinoma was characterized by the presence of irregular nests and/or tubules of transitional cells infiltrating the lamina propria without surface involvement. The neoplastic cells tended to have innocuous features but at least a few cells in every case are cytologically anaplastic. There was a marked male predominance. Synchronous or metachronous transitional cell carcinomas of more usual histologic make-up may occur. After a follow-up averaging 16.6 months, only three patients were known to be alive with no evidence of disease.
Drew and associates [
Clinicopathologic information from their 16 cases combined with the 8 cases of nested variant of transitional cell carcinoma that were reported before the publication of their paper confirms that nested variant of transitional cell carcinoma is a persistent and aggressive neoplasm that is notable for its innocuous appearance in histologic preparations.
Liedberg and associates [ Nested variant of urothelial carcinoma is a rare but an important histopathologic entity. Nested variant of urothelial carcinoma has a poor prognosis. At an early stage, the tumours might be difficult to differentiate from benign conditions and awareness of this condition is of outermost importance.
Because of the rarity of nested variant of urothelial carcinoma most urologists and pathologists would not have encountered a case of nested variant of urothelial carcinoma before and as a result of this there is the possibility that a case of nested variant of urothelial carcinoma may inadvertently be misdiagnosed. It is therefore pertinent to document iterations of Dhall et al. [ These tumours are characterized histologically by large numbers of small, closely packed, poorly defined, confluent, and irregular nests of uniform urothelial cells infiltrating the lamina propria, reminiscent of von Brunn nests, and also infiltrating the muscularis propria with retained nested pattern (see Figures These nests exhibit an infiltrative base as described by Volmar et al. [ Small tubules and microcysts may be seen as described by Talbert and Young [ The overlying urothelium may be normal in appearance. The cells comprising nested variant of urothelial carcinoma exhibit no significant cytologic atypia; they are mildly pleomorphic and show slightly increased nuclear-cytoplasmic ratio and occasionally prominent nucleoli (see Figure Even though nested variant of urothelial carcinoma cells appears to be histologically bland, a number of authors [ Mitotic figures are not readily seen. Mucin is not identified. The surrounding stroma varies from dense and collagenous to loose and myxoid or even oedematous. Lymphatic invasion may be seen [ In view of their deceptively bland appearance, the tumours are sometimes misdiagnosed as benign lesions, especially in the biopsy material leading in some instances to a significant delay in the establishment of diagnosis as stated by Young and Olive [ Nested variant of urothelial carcinoma must be differentiated from the benign proliferative lesions of the urothelium, such as von Brunn nests, cystitis cystica, cystitis glandularis, nephrogenic adenoma, paraganglioma, and inverted papilloma (see Figure
von Brunn nests in comparison with nested variant of urothelial carcinoma showing regularly spaced urothelial nests with a relatively flat base (hematoxylin-eosin, original magnification ×200). Nested variant of urothelial carcinoma taken from Dhall et al. [
Gross photo of Case 1 shows an edematous urinary bladder mucosa and markedly and diffusely thickened bladder wall Xiao et al. [
The neoplastic cells form ill-defined nests with a diffuse growth pattern. Some tumor cells have clear cytoplasm. The surface mucosa is not involved by the underlying tumor (Case 1) (hematoxylin-eosin, original magnification ×200) Xiao et al. [
The nuclei of the tumor cells are relatively uniform with finely granular chromatin, inconspicuous nucleoli, and rare mitosis (Case 1) (hematoxylin-eosin, original magnification ×400) Xiao et al. [
The neoplastic cells are strongly immunoreactive for p63 (Case 1) (p63, original magnification ×200) Xiao et al. [
The cytologically bland neoplastic cells are arranged in a diffuse pattern of relatively ill-defined and variably sized nests (Case 2) (hematoxylin-eosin, original magnification ×600) Xiao et al. [
The neoplastic cells are strongly immunoreactive for p63 (Case 2) (p63, original magnification ×400) Xiao et al. [
Dhall and associates [ Adjuvant chemotherapy and radiation therapy have not been shown by a number of authors to be significantly beneficial in their reported series [ Nested variant of urothelial carcinoma should be kept in mind as a histologically unique variant which should not be confused with von Brunn’s nest. Any bladder biopsy with tightly packed nests with any degree of architectural or cytological atypia should be evaluated with caution, and the possibility of nested variant of urothelial carcinoma should be raised in such circumstances.
Linder and associates [
Tripodi et al. [ Grossly, the calices, renal pelvis, and pelviureteric junction appeared modestly dilated with whitish, thickened, and uneven mucosa. Microscopic examination revealed that the subepithelial connective tissue, the fibromuscular layer, and the renal sinus fat were diffusely infiltrated by small nests of medium to large urothelial cells which were immunohistochemically stained positively with p63 and they had abundant eosinophilic cytoplasm and slightly atypical nuclei.
Tripodi et al. [ On the basis of morphologic and immunohistochemical features, a diagnosis of nested variant of urothelial carcinoma was made. After surgery, the patient recovered from hypertension. Pelvic and upper urothelial tract nested variant of urothelial carcinoma was uncommon, and to the best of their knowledge, their case was the second case of nested variant of urothelial carcinoma with renal pelvis involvement.
Cerda et al. [
With regard to the results, both tumours were reported to have shown similar histological features; the neoplastic cells were grouped in confluent smalls nests and abortive tubules which were composed of urothelial cells with nuclear atypia infiltrating deeply the wall of the urinary bladder and in Case 1, the perivesical tissue, urethra, and one lymph node were invaded. Immunohistochemistry profile revealed positive staining for CK7, CK20, 34
Yildiz et al. [
Pusztaszeri et al. [
Lau [
Nested variant of urothelial carcinoma is a rare tumour and to the author’s knowledge about 200 cases have so far been reported.
The tumour usually manifests at an advanced stage and tends to exhibit a persistent and progressive clinical course.
Death rate from nested variant of urothelial carcinoma can be up to 25% of cases and persistent or progressive disease has been reported in up to 60% of cases which had led some authors [
It is important to keep in mind nested variant of urothelial carcinoma as a unique histologic variant which should not be mistaken for florid von Brunn nest.
In cases where bladder biopsy exhibits tightly packed nests with any degree of cytologic atypia or architectural atypia, the biopsy specimens need to be evaluated with care in order to ascertain and exclude the possibility of nested variant of urothelial carcinoma.
Even though reports from case reports had indicated that the prognosis of nested variant of urothelial carcinoma is poor following treatment results of a recent study revealed that there is no significant difference between patients with nested variant of urothelial carcinoma and those with comparatively staged conventional urothelial carcinoma who had undergone cystectomy.
Nested variant of urothelial carcinoma is a rare tumour with characteristic histopathologic features which must be carefully identified to establish its diagnosis.
Previous case reports and case series indicated that nested variant of urothelial carcinoma tends to be diagnosed at an advanced stage and is associated with poor prognosis; however, results of a recent study revealed no statistically significant difference between the outcome of patients with nested variant of urothelial carcinoma and patients with conventional urothelial carcinoma of similar stages who had undergone cystectomy.
Correct and early diagnosis of this tumour is essential in order to provide early curative treatment in order to avoid diagnosis at an advanced stage.
There is the need for a multicentre trial to validate this recent finding and to identify treatment protocols that would help improve the outcome of the tumour following treatment.
The author declares that there is no conflict of interests regarding the publication of this paper.
The author would like to acknowledge the Editor in Chief and the Editorial Board of Archives of Pathology and Laboratory Medicine for granting him permission to reproduce images from their journal specifically to illustrate features of nested variant of urothelial carcinoma in this paper.