Immunohistochemistry and Fluorescence In Situ Hybridization Can Inform the Differential Diagnosis of Low-Grade Noninvasive Urothelial Carcinoma with an Inverted Growth Pattern and Inverted Urothelial Papilloma

Abstract

Urothelial carcinoma (UC) comprises a heterogeneous group of epithelial neoplasms with diverse biological behaviors and variable clinical outcomes. Distinguishing UC histological subtypes has become increasingly important because prognoses and therapy can dramatically differ among subtypes. In clinical work, overlapping morphological findings between low-grade noninvasive UC (LGNUC), which exhibits an inverted growth pattern, and inverted urothelial papilloma (IUP) can make subclassification difficult. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping these clinical entities. In our study, tissue microarray immunohistochemical profiles of Ki-67, p53, cytokeratin 20 (CK20) and cyclinD1 were assessed. Molecular genetic alterations such as the gain of chromosomes 3, 7 or 17 or the homozygous loss of 9p21 were also assessed for their usefulness in differentiating these conditions. Based on our analysis, Ki-67 and CK20 may be useful for the differential diagnosis of these two tumor types. Fluorescence in situ hybridization (FISH) can also provide important data in cases in which the malignant nature of an inverted urothelial neoplasm is unclear. LGNUC with an inverted growth pattern that is negative for both Ki-67 and CK20 can be positively detected using FISH.

Fig 1. Clinicopathological features of inverted papilloma.

IUPs were mainly comprised anastomosing cords, which were thin and congruous in width (A), or nests (C). Cysts were occasionally observed in the interiors of the nests (B). Peripheral palisading nuclei were observed (D).

Fig 2. Clinicopathological features of low-grade noninvasive UC with an inverted growth pattern.

The cords of LGNUC with an inverted growth pattern were usually thick and irregular (A), and definite fibrovascular cores were observed (B). Nests were usually large and inordinate (C), and mitotic figures, which were common in the superficial or middle layers, were easy to detect (D).

Fig 3. IHC results for the two tumor types.

Ki-67 was negative for IUP (A) but positive for LGNUC with an inverted growth pattern (B). CK20 was negative for IUP (C) but positive for LGNUC with an inverted growth pattern (D). IUP (E) and LGNUC with an inverted growth pattern (F) were both positive for P53. IUP (G) and LGNUC with an inverted growth pattern (H) were both positive for CyclinD1.

Fig 4. FISH results for the two tumor types.

The cases that exhibited a gain of at least 2 of chromosomes 3 (B), 7 (B) and 17 (A, B) or a homozygous loss of 9p21 (B) were defined as UroVysion FISH positive.

Fig 5. Comparison between the DFS of the IUP group and that of the LGNUC with an inverted growth pattern group.