Carcinoma of the urethra

Abstract

Primary carcinomas of the urethra are rare and poorly understood lesions; hence, their clinical and pathologic spectrum is not completely defined. We analyzed a series of 130 primary urethral tumors and classified 106 of them as primary urethral carcinomas. The age at diagnosis of patients with primary urethral carcinomas ranged from 42 to 97 years (mean, 69.4 years; median, 70 years). There were 73 male and 33 female patients with a ratio of 2.2:1. In male patients, the tumors most frequently developed in the bulbous-membranous segment of the urethra. In female patients, the entire length of the urethra was typically involved. Microscopically, they were poorly differentiated carcinomas with hybrid squamous and urothelial features and developed from precursor intraepithelial conditions such as dysplasia and carcinoma in situ, which were frequently present in the adjacent urethral mucosa. High-risk human papilloma virus infection could be documented in 31.6% of these tumors. Follow-up information was available for 95 patients. Twenty-three patients died of the disease with a mean and median survival of 39 and 21 months, respectively. Urethral carcinomas are aggressive tumors with a high propensity for regional and distant metastases with mean and median survival of 39 and 21 months, respectively. Our observations have important implications for the management of patients with primary carcinoma of the urethra by defining them as a unique entity linked to human papilloma virus infection.

Keywords: Carcinoma in situ of the urethra; Carcinoma with hybrid squamous and urothelial features; HPV-related cancer; MRI imaging of urethral carcinomas; Squamous urothelial; Urethral carcinoma.

Fig. 1. Radiographic imaging and gross morphology of carcinoma developing in the male urethra

(A) Sagittal MRI T2 weighted image of the pelvis showing a mass with intermediate signal intensity involving the bulbous urethra (asterix). (B) Total urethral and prostate resection specimen showing a fungating mass in the bulbous urethra (arrows). (C) Higher magnification of B showing the irregular cobbled and partially papillary surface of the fungating tumor in the bulbous segment of the urethra. (D) The axial MRI image at the level of the base of the penis showing the involvement of both corpora cavernosa (arrows).

Fig. 2. Microscopic images of poorly differentiated urethral carcinoma with basaloid features

(A and B) Intermediate and high power views of poorly differentiated tumor cells infiltrating stroma with a somewhat palisading arrangement of cells at the periphery of the tumor nests referred to as basaloid features. (C and D) Intermediate and high power views of poorly differentiated tumor cells infiltrating stroma and showing a palisading arrangement of tumor cells at the periphery of the tumor nests. (A–D hematoxylin and eosin; A and D, ×200; B, ×400; C, ×100)

Fig. 3. Microscopic images of urethral carcinoma showing squamous and urothelial differentiation

(A and B) Irregular clusters of tumor cells showing features of squamous differentiation. (C and D) Papillary configuration of the tumor surface showing urothelium-like stratification in the epithelial layer. Note that in contrast to conventional urothelial carcinomas, these are irregular, short papillary structures with broad fibrovascular cores. (A–D: hematoxylin and eosin; A, ×200; B, ×400; C and D, ×100)

Fig. 4. Microscopic images of precursor intraepithelial lesions in the urethral mucosa adjacent to invasive cancer

(A and B) Proliferation of atypical epithelial cells with high N/C ratio and brisk mitotic activity showing some degree of differentiation and stratification towards the luminal layer of epithelium consistent with severe dysplasia. (C and D) Proliferation of atypical undifferentiated cells, with a high N/C ratio throughout the epithelium, which show brisk mitotic activity consistent with carcinoma in situ. (A–D: hematoxylin and eosin; A–D, ×400)

Fig. 5. Immunohistochemical features of urethral carcinoma

(A) Strong positivity for KRT5/6 in tumor cells. (B) Strong and diffuse staining for P16 in tumor cells. (C) Strong nuclear staining for P63 in tumor cells. (D) Strong membranous staining for thrombmodulin in tumor cells. Inset, Positive RNA hybridization signal for HPV HR7 (RNA scope analysis) in tumor cells. (A–D: DAB and hematoxylin; A–D and inset, ×200).

Fig. 6. Kaplan Meier survival analyses of patients with urethral carcinoma

(A) Overall survival analysis. Shaded area indicates the confidence interval. (B) Survival by gender. (C) Survival by histologic grade. (D) Survival by stage.