What's known on the subject? and What does the study add?
Urologists are often confronted with cystoscopic appearances that at times are abnormal but non-specific, may mimic urothelial carcinoma or in some instances are quite bizarre given the clinical scenarios in which they occur (e.g. changes associated with a catheter will be more obvious than a de-novo presentation of cystitis cystica). Metaplasias of the bladder urothelium make up the majority of such cases. Furthermore, when confronted with a pathological diagnosis of a metaplasia within the bladder- what are the implications for the patient and how should they be followed-up?
This review provides a concise summary of the pathological features of the various metaplasias that occur in the bladder and briefly describes their current treatment and requirement for follow-up.
Metaplasia of the bladder urothelium occurs commonly in response to local injury. Usually the changes are reversible, but some conditions may be premalignant. This review describes the different metaplastic entities and their clinical significance. Most importantly, keratinising squamous metaplasia is a precursor to the development of bladder cancer, and requires treatment and long term follow up. The role of intestinal metaplasia in the development of cancer is uncertain, and these patients require follow-up until further evidence is obtained on the outcome of this entity.
The urothelium lines the entire urinary excretory passage. The urothelium shows histologic features intermediate between squamous and glandular epithelium, hence the designation as transitional epithelium. It shows pronounced ability to transform morphologically into squamous or glandular epithelium in response to injury, and this constitutes the basis of metaplasia. Metaplasia (Greek: “Change in form”) is the transformation of one differentiated cell type into another, usually in response to a normal maturation process or in response to an abnormal external stimulus. The change in cell type is part of the accommodation of the cell to a new environment. It is important to note that metaplasia is reversible and is distinct from dysplasia which is a change in cell morphology due to genetic changes in the cell as part of a neoplastic process. In metaplasia, if the eliciting stimulus is removed, the tissue may return to a normal pattern of differentiation.
In general, transformation or metaplasia of the urothelium tends to occur in response to local stimulus, with a variety of benign morphologic variants. In this review, the different types of metaplasia will be discussed, with reference to their clinical significance.
von Brunn's Nests
von Brunn's nests (Brunn nests) are nests of urothelial cells which show no atypia. They develop as an invagination of the surface urothelium into the lamina propria which subsequently disconnect from the surface, and occur as a reaction to catheterisation, infection and calculi. von Brunn's nests are virtually a normal condition and are present in up to 90% of bladders in autopsy studies. As with any normal urothelium, carcinoma may develop. A special circumstance is where florid von Brunn nests may mimic the nested variant of urothelial carcinoma and this must be excluded using strict pathological crtieria . Finally von Brunn's nests should not be confused with an inverted papilloma which is a benign proliferative lesion associated with chronic inflammation or bladder outlet obstruction. Inverted papilloma is most often located on the trigone and comprise less than 1% of all bladder tumours .
Cystitis Cystica et Glandularis
Cystitis cystica occurs with cystic dilatation of von Brunn's nests, where the nests acquire a luminal space and may become markedly dilated. In cystitis glandularis, the luminal epithelium of these cysts is replaced by mucin secreting cuboidal or columnar cells (Figures 1 and 2). Cystitis cystica et glandularis is common. It occurs as a proliferative/reactive change due to local injury such as recurrent urinary tract infection (UTI) although it can be seen with no associated inflammation. It is often seen in association with carcinoma but no causal link with carcinoma has been demonstrated. The condition is most often diagnosed after endoscopy and biopsy in a patient with irritative bladder symptoms or haematuria . It is likely to represent a reactive condition adjacent to, and possibly secondary to inflammation associated with, carcinoma rather than a premalignant condition. Despite only a few instances of transformation to malignancy in the literature, some advocate repeat cystoscopy and follow-up, particularly in florid cases or where risk factors for urothelial cancer exist .
When this condition occurs in the ureter, it is known as uretreitis cystica or ureteritis glandularis depending on the predominant proliferation. It is notable as it may mimic other conditions on imaging, such as urothelial carcinoma, blood clots, air bubbles, radiolucent stones, fibroepithelial polyps, and sloughed renal papillae .
Intestinal Metaplasia (Cystitis Glandularis with Intestinal Differentiation)
Intestinal metaplasia (Cystitis glandularis of intestinal type, “colonic metaplasia”) occurs when the epithelium acquires intestinal type goblet cells interspersed among the columnar cells and morphologically resembles colonic mucosa (Figure 1). Rarely Paneth cells (large eosinophilic cells of normal small intestinal epithelium) may be seen. Intestinal metaplasia has a different immunoprofile from cystitis glandularis. The cells of intestinal metaplasia have a more “colonic” immunoprofile, expressing CDX2 and CK20 and containing colonic mucins MUC5AC and MUC2, while cystitis glandularis is more “urothelial”, with CK7 expression and containing the urothelial mucin MUC1.
Intestinal metaplasia usually occurs with long standing inflammation / irritation, such as indwelling catheters, calculi, neurogenic bladder and bladder exstrophy. Intestinal metaplasia may be focal or diffuse, but is usually only seen microscopically. Rarely, it may present clinically with mucinuria when mucin is secreted in the urine, or as a mass lesion when there is extensive mucin extravasation into the surrounding tissues. At cystoscopy, these lesions may be seen as flat, polypoid or have a gelatinous appearance due to the presence of mucin. There is some similarity of intestinal metaplasia to adenocarcinoma with mucinous differentiation. Pathologically, these lesions can be distinguished from adenocarcinoma by the lack of atypia and mitoses in the lining epithelium.
Intestinal metaplasia often co-exists with adenocarcinoma of bladder, and some authors have proposed that intestinal metaplasia may be a precursor lesion. For example, telomere shortening which is associated with carcinogenesis, was shown by Morton et al.  to be present in all 34 cases of intestinal metaplasia tested, together with chromosomal gains in three cases. Telomere shortening was present to a lesser extent in cystitis glandularis, but not seen in the normal urothelium. However, long term clinicopathological studies have failed to demonstrate the development of adenocarcinoma in patients with intestinal metaplasia, including a study of 53 patients with more than 10 years of clinical follow up, in whom none developed adenocarcinoma [7, 8]. While the current evidence suggests that intestinal metaplasia is not a premalignant condition, it may be prudent to continue follow up in these patients until further evidence is obtained. This is especially so in those rare cases of intestinal metaplasia in which there is dysplasia, analogous to colonic adenoma. In this situation, close follow up is recommended although the outcome is unknown.
Squamous metaplasia represents replacement of the urothelium by stratified squamous epithelium. It consists of two forms: non-keratinising squamous metaplasia (“vaginal metaplasia”) and keratinising squamous metaplasia. Approximately 40% of women and 5% of men have squamous metaplasia of the bladder, which is usually related to infection, trauma, and surgery .
Non-keratinising squamous metaplasia (“vaginal metaplasia”) occurs commonly in the trigone of women of pre-menopausal women and is considered to be a normal variant (Figures 1 and 2). It arises de novo with no evidence of previous injury and is hormonally responsive. There is no associated inflammation and the squamous metaplasia in this condition is the same as the squamous mucosa of the vagina or cervix. This condition was often mistakenly diathermied and often repeatedly so, up until twenty years ago.
Keratinising squamous metaplasia occurs more commonly in males in a non-trigone location including bladder diverticula, and may be focal or diffuse. In keratinising squamous metaplasia, the squamous epithelium develops parakeratosis, hyperkeratosis or a granular layer, and can be seen as white or grey plaques at cystoscopy (“leukoplakia”), often with a background erythematous mucosa. The mucosa bleeds easily when the plaques are removed. 80% of cases occur in males who present with haematuria, with or without irritative symptoms.
Keratinising squamous metaplasia arises in response to chronic irritation, most commonly in the setting of recurrent infections (Figure 1). Urinary bacterial infection is identified in between 50 and 100% of patients. Traditionally the eliciting organisms were tuberculosis and Schistosomiasis, but the most common bacterial isolates are E. Coli, Proteus sp. and Streptococcus Faecalis. Other factors include calculi, indwelling catheters, bladder exstrophy, bladder surgery and vitamin A deficiency. Spinal cord injured patients are particularly prone to develop this condition from catheter trauma and/or urinary tract infections and are at risk of cancer .
Keratinising squamous metaplasia is clinically significant and may be associated with the development of bladder cancer, bladder contracture or obstructive uropathy. Khan et al.  described a series of 34 cases with keratinising squamous metaplasia, of which four patients had synchronous carcinomas. In a further 14 patients with extensive keratinising squamous metaplasia (involving 50% of the mucosa), 55% of patients developed bladder cancer. One patient died from obstructive uropathy, two patients developed bladder contracture and one patient developed unilateral loss of renal function. In 16 patients with limited keratinising squamous metaplasia (<50% of the mucosa involved), the prognosis was more favourable, but two patients developed squamous cell carcinoma. From this and other studies, the risk of the development of carcinoma in patients with keratinising squamous metaplasia is estimated to be 21 to 42%, with a latent period ranging from 4 to 28 years. Therefore, any degree of keratinising squamous metaplasia is a significant risk factor for the development of subsequent carcinoma, as well as bladder contractures or obstruction. Complete conservative resection with close follow up is recommended. Cystectomy can be considered for selected patients with extensive bladder involvement and a long life expectancy (>10 years).
Nephrogenic metaplasia/adenoma is a benign condition which can occur at all ages, with 30% in patients less than 30 years of age (Figure 1). It affects males more than females. The lesion has a tubular/papillary architecture, with a single layer of cuboidal to low columnar cells forming papillae across the surface or tubules within the mucosa. It is associated with previous instrumentation/surgery, calculi, foreign bodies, chemical agents and cystitis and is more commonly seen in renal transplant patients (8% of cases). At cystoscopy, the lesion may be flat or polypoid (65%) with friable or velvety lesions and may be single or multifocal. 60% of lesions are <1 cm but range from microscopic foci to lesions which are 7cm. Given the papillary or polypoid architecture, they may simulate cancer cystoscopically.
While nephrogenic metaplasia is currently considered to be a metaplastic condition in response to local injury or inflammation, the histogenesis is controversial. Recent evidence suggests the lesion(s) may be derived from seeding or implantation of renal tubular epithelium into the bladder mucosa, rather than metaplasia of the urothelium. The epithelial cells forming nephrogenic metaplasia are positive for PAX2 and PAX8 which are antigens expressed by renal tubular epithelium not urothelium. Further, Mazal et al.  showed in a study of 29 renal transplant patients with opposite sex donor kidneys that the cells in nephrogenic adenoma in the transplant patients were formed by the donor renal tubular cells, not by the host cells.
Although it morphologically resembles clear cell adenocarcinoma, nephrogenic metaplasia/adenoma is not considered to be a premalignant condition. The most frequent presenting symptom is gross hematuria, often in conjunction with UTI. Management consists of elimination of the chronic irritation and transurethral resection where appropriate to give a pathological diagnosis intitially and to treat.
Epithelial Proliferation Associated with Radiotherapy and Chemotherapy
It has been recently recognised that bizarre and atypical epithelial proliferations may occur following radiotherapy and chemotherapy (“pseudocarcinomatous proliferation”). This is an uncommon reactive cellular proliferation in response to radiation injury in the bladder, and is less commonly seen following chemotherapy and rarely in association with ischaemic events unrelated to radiotherapy or chemotherapy . Patients present with haematuria up to 7 years after therapy, most commonly at 2 years. The bladder often shows radiation changes, with ulceration and congestion at cystoscopy . Microscopically, this lesion shows features which are easily confused for carcinoma pathologically, with small, irregular nests of atypical cells in the lamina propria. Morphologic clues to the correct diagnosis of a reactive proliferation are the presence of ulceration, inflammation, haemorrhage and fibrin deposition through the mucosa with ectatic vessels related to the previous radiotherapy. Also, these epithelial proliferations may show squamous differentiation with abundant glycogen with no atypia in the squamous cells and often the nests of epithelial cells are in close proximity to vessels and surrounding fibrin. No carcinoma insitu is seen away from the lesion. If these features are present, then this should be regarded as a reactive proliferation and not confused with malignancy.
The importance of this condition is that it may be confused with carcinoma pathologically, but it is not a premalignant condition.
Metaplasia is common in the urothelium of the bladder, and in many instances it is a normal finding or is a reversible change in response to injury. The majority of metaplasias are reversible and are not premalignant (Table 1). The exception is keratinizing squamous metaplasia, which has a significant association with the development of carcinoma, and complete resection and continued observation is recommended. The role of intestinal metaplasia in the development of adenocarcinoma is not clear cut, and surveillance is recommended pending the results of further studies. An interesting recent finding is that nephrogenic metaplasia may represent implantation of renal tubular cells in the bladder rather than urothelial metaplasia.
Table 1. Summary of common metaplastic conditions of the bladder and implications
Physiological or pathological
Association with cancer
von Brunn's nests
No but may rarely arise as with any urothelium
Cystitis cystica et glandularis (or ureteritis)
Underlying condition e.g. UTI; Resection/laser in symptomatic cases
Most likely nil; Only in very select cases
Underlying condition e.g. UTI; Resection/laser in symptomatic cases
a. Pathologial (possibly physiological variant)
b. Resection/laser if symptomatic
b. Endoscopic regime
Underlying condition e.g. UTI; Resection/laser in symptomatic cases