Editor: Mahmut Akgul (

2022-32/August 15

Contributors: Laurence A. Galea, Ana Cristina Vargas

A male patient in his 70s presented with macroscopic haematuria and underwent transurethral resection of a bladder tumour. He had a history of hypercholesterolaemia and metastatic prostatic carcinoma on androgen deprivation therapy.



a) Granular cell tumor and prostatic adenocarcinoma

b) Bladder xanthoma and urothelial carcinoma

c) Prostatic carcinoma with and without significant treatment effect

d) ALK-positive histiocytosis and urothelial carcinoma

e) Bladder xanthoma and prostatic carcinoma without significant treatment effect

Bladder xanthoma and prostatic adenocarcinoma without significant treatment effect

The bladder mass was situated at the anterior bladder neck (Fig. 1). On microscopic examination of the transurethral resection specimen, most of the tissue was composed of sheets of polygonal cells with small pyknotic nuclei and abundant foamy cytoplasm undermining and entrapping normal urothelium (Figs. 2-3). No significant inflammatory cells and no multinucleated giant cells were seen. The cells were positive for CD68 and negative for S100. They showed patchy cytoplasmic staining with ALK (D5F3) immunohistochemistry (IHC), interpreted as equivocal. ALK FISH showed copy number gain of 3-4 copies of ALK in 60% of the cells examined, however, no ALK (2p23) rearrangement was detected. In addition, scattered amongst the foamy histiocytes were generally fused glands with cells showing round nuclei, conspicuous nucleoli and amphophilic cytoplasm (Figs. 4-5). The cells were positive for NKX3.1 and PSMA. PIN4 stain showed loss of basal staining with p63 and 34Be12 and cytoplasmic positivity with AMACR.

A diagnosis of urinary bladder xanthoma with associated prostatic adenocarcinoma without significant treatment effect, Grade Group 4 (Gleason score 4+4=8) was rendered.

Given the history of androgen deprivation therapy (ADT), the main differential diagnosis of urinary bladder xanthoma was prostatic adenocarcinoma with significant treatment effect. ADT can result in significant cytomorphological changes in prostatic carcinoma, including cells with pyknotic nuclei, loss of nucleolar prominence and foamy cytoplasm resembling histiocytes [1,2]. The cells would be keratin positive and CD68 negative. In this case the reverse was true, excluding this possibility. In granular cell tumour the cytoplasm is eosinophilic and granular rather than pale foamy and the cells would be S100 positive. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasms characterised by rearrangement of the ALK gene mostly with KIF5B, as well as other fusion partner genes. It can involve various organs, but to our knowledge it has not been described in the bladder to date [3]. In this case no ALK rearrangement was detected by FISH, excluding ALK-positive histiocytosis. ALK FISH interpretation follows the guidelines for lung adenocarcinoma regardless of the organ and/or type of cells scored. FISH ALK copy number gain, as identified in this case, should not be interpreted as a positive result [4], however, it likely accounted for the cytoplasmic staining with ALK (D5F3) IHC.

Urinary bladder xanthomas, as xanthomas identified elsewhere in the body, are benign reactive histiocytic proliferations composed of aggregates of lipid-laden histiocytes without an associated inflammatory or stromal host response. Clinical presentation includes haematuria or irritative symptoms, but they can also be incidentally identified at cystoscopy. They can be found in association with urothelial neoplasms, usually low-grade papillary urothelial neoplasms or as an isolated finding [5]. As in this case, they are frequently associated with underlying lipid abnormalities, especially hypercholesterolaemia [5].

1. Amin MB, Berney DM, Compérat, EM, et al. Tumours of the prostate. In: WHO Classification of Tumours Editorial Board. Urinary and male genital tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2022/3/20]. (WHO classification of tumours series, 5th ed.; vol. 8). Available from:

2. Collins K, Cheng L. Morphologic spectrum of treatment-related changes in prostate tissue and prostate cancer: an updated review. Hum Pathol. 2022 Jun; 127:56-66.

3. Kemps PG, Picarsic J, Durham BH, et al. ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood. 2022 Jan; 139(2):256-280.

4. Yoshida A, Varella-Garcia M. Fluorescence in situ Hybridization (FISH). In Tsao MS, Hirsch FR, Yatabe Y eds. IASLC Atlas of ALK Testing in Lung Cancer. Aurora, Colorado: IASLC Press, 2013; 17-28.

5. Yu DC, Patel P, Bonert M, Carlson K, Yilmaz A, Paner G, Magi-Galluzzi C, Lopez-Beltran A, Trpkov K. Urinary bladder xanthoma: a multi-institutional series of 17 cases. Histopathology. 2015 Aug; 67(2):255-261.

Laurence A Galea
Department of Anatomical Pathology, Melbourne Pathology, Sonic Healthcare
Victoria, Australia Ana Cristina Vargas Department of Anatomical Pathology, Douglass Hanly Moir Pathology, Sonic Healthcare
NSW, Australia


Bladder, xanthoma, prostatic carcinoma, therapy-related effect, ALK positive histiocytosis