Inverted Urothelial (Transitional Cell) Carcinoma

Definition

• Urothelial carcinoma that looks invasive but is not

Note

• Usual papillary urothelial carcinoma is covered separately

Diagnostic Criteria

• Features diagnostic of carcinoma must be present
  • Disorderly maturation and loss of polarity
  • Nuclear atypia/pleomorphism and mitotic activity
• At least 25% of tumor is composed of inverted growth patterns extending into submucosa
  • Two main patterns, may be mixed
    • Anastomosing cords and trabeculae
    • Bulbous invaginations
  • Nodules of carcinoma are smoothly circumscribed
    • Basement membrane may be identifiable
    • Peripheral cells may palisade
• Any of the following are evidence of invasion and exclude the diagnosis of inverted pattern
  • Irregular, jagged nest shapes
  • Single cell infiltration
  • Disruption of basement membrane
  • Desmoplastic stromal response

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 10/20/12

Supplemental studies

Immunohistology

• A keratin stain may be helpful for the identification of invasion

Differential Diagnosis

• Nested variant of urothelial carcinoma
• Inverted papilloma
• Florid von Brunn nests
• Florid cystitis cystica/glandularis
  

Nested Variant Urothelial Carcinoma	Transitional/Urothelial Carcinoma with Inverted Pattern
Invasive carcinoma that looks deceptively non-invasive due to predominantly nested pattern	Non-invasive inverted pattern of carcinoma that looks deceptively invasive
Overall invasive pattern, not circumscribed	Lacks clearly invasive pattern
May involve muscularis propria	Does not involve muscularis propria
Varying sizes and shapes of nests	Frequently formed by fusion of trabeculae and cords (inverted papilloma like pattern)
Desmoplastic stroma may be present	No desmoplasia

Urothelial Carcinoma with Inverted Growth Pattern	Inverted Papilloma
Usually has a surface papillary component	Surface everted papillary component absent or minimal
Cytologic features and disorder of carcinoma, appropriate to grade	Bland, uniform, orderly cells
Mitotic figures present, appropriate to grade	No mitotic figures

These may represent a spectrum, with an intermediate PUNLUMP with inverted pattern

Urothelial Carcinoma with Inverted Growth Pattern	Florid von Brunn Nests, Cystitis Cystica/Glandularis
Usually has a surface papillary component	Surface normal
Cytologic features and disorder of carcinoma, appropriate to grade	Bland, uniform, orderly cells
Mitotic figures present, appropriate to grade	No mitotic figures

Grading / Staging

Grading

• Usual rules apply, see Papillary Carcinoma criteria

Staging

• Presence of an inverted component is not considered submucosal invasion
• Although non-invasive papillary urothelial neoplasms are technically in situ, they are staged as Ta and are not referred to as carcinoma in situ

Clinical

• Same prognosis as usual noninvasive urothelial carcinoma, grade for grade

Classification / Lists

Flat Lesions of the Urinary Bladder

• Flat urothelial hyperplasia
• Reactive urothelial atypia
• Atypa of unknown significance
• Dysplasia
• Urothelial carcinoma in situ

Papillary Lesions of the Urinary Bladder

• Nephrogenic adenoma
• Fibroepithelial polyp
• Polypoid/papillary cystitis
• Papillary urothelial hyperplasia
• Urothelial papilloma
• Papillary urothelial neoplasm of uncertain malignant potential (PUNLUMP)
• Low grade urothelial carcinoma
• High grade urothelial carcinoma

Subtypes of High Grade Urothelial Carcinoma

• Micropapillary urothelial carcinoma
  
• Plasmacytoid urothelial carcinoma
• Small cell carcinoma
• Urothelial carcinoma with chordoid features
• Urothelial carcinoma with sarcomatoid differentiation
• Urothelial carcinoma with squamous differentiation
  

Inverted Lesions of the Urinary Bladder

• Florid hyperplasia of von Brunn nests
• Cystitis cystica/glandularis
• Inverted urothelial papilloma
• Inverted urothelial carcinoma
• Nested variant urothelial carcinoma
• Verrucous squamous carcinoma

Glandular Lesions of the Urinary Bladder

• Nephrogenic adenoma
• Cystitis cystica/glandularis
• Intestinal Metaplasia
• Villous adenoma
• Urothelial carcinoma with glandular differentiation
• Nested urothelial carcinoma with cystic structures
• Non-urachal adenocarcinoma
• Mulllerian lesions
  • Endometriosis
  • Endocervicosis
  • Endosalpingosis
• Urachal lesions
  • Urachal remnant
  • Urachal adenocarcinoma
• Metastatic/direct spread of non-bladder adenocarcinomas

Bibliography

• Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
• Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004.
• Cox R, Epstein JI. Large nested variant of urothelial carcinoma: 23 cases mimicking von Brunn nests and inverted growth pattern of noninvasive papillary urothelial carcinoma. Am J Surg Pathol. 2011 Sep;35(9):1337-42.
• Hodges KB, Lopez-Beltran A, Maclennan GT, Montironi R, Cheng L. Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic findings, differential diagnosis and clinical management. BJU Int. 2011 Feb;107(4):532-7.
• Jones TD, Zhang S, Lopez-Beltran A, Eble JN, Sung MT, MacLennan GT, Montironi R, Tan PH, Zheng S, Baldridge LA, Cheng L. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol. 2007 Dec;31(12):1861-7.
• Amin MB, Gómez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol. 1997 Sep;21(9):1057-68.
• Shanks JH, Iczkowski KA. Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics. Histopathology. 2009