LELC is a rare variant of infiltrating urothelial carcinoma, first described by Zuckerberg et al in 1991.
1 Since then there have been only a few relatively small studies on LELC of urinary bladder.
2–8 The largest study was reported by Tamas et al
8 who described 17 pure 13 mixed LELC. Prior to that Lopez-Beltran et al
5 reported 3 pure, 6 predominant and 4 focal LELCs of the urinary bladder. Amin et al
3 reported 3 pure, 5 predominant and 3 focal LELCs and Holmang et al
6 described 3 pure, 5 predominant and 3 focal cases of LELC. To our knowledge, LELC of the urinary bladder has not been reported from the Middle East to date.
The exact pathogenesis of this tumor is not well established. Epstein-Barr virus (EBV) is frequently associated with lymphoepithelioma of the nasopharynx and LELC arising in the lung, stomach, thymus and salivary gland.
1,2,8,9 However, such an association has not been documented for LELC of the urinary bladder. Hybridization with EBV-encoded RNA (EBER) has been reported to be negative.
5,8,9 It has been suggested that abnormalities of p53 regulation might be crucial in the pathogenesis of LELC of the urinary bladder.
10 Though the exact origin of these carcinomas is not well known, the expression of common urothelial markers suggest that they are probably modified urothelial cells that have derived from stem cells.
5,6The tumor usually presents in late adulthood. Most patients present with painless hematuria and are stage T2-T3 at diagnosis.
5,6,8 Histological features of LELC closely resemble lymphoepithelioma of the nasopharynx, with the tumor growing in nests, sheets or cords of large undifferentiated malignant epithelial cells within a dense inflammatory background, comprising mature lymphocytes, plasma cells, and rarely neutrophils and eosinophils. The background lymphocytes are usually an admixture of B and T lymphocytes.
11 Amin et al
3 categorized the LELC of bladder into three subgroups as pure, predominant (more than 50% lymphoepithelial component) and focal (less than 50% lymphoepithelial component). Invasive urothelial carcinoma usually accompanies predominant or focal LELC.
3,5,8 Though uncommon, the tumor may have accompanying adenocarcinoma and squamous cell carcinoma as well.
5,8 The overlying or adjacent urothelium may show urothelial dysplasia or carcinoma in situ.
2,8 The present case was a pure LELC. A correct diagnosis on a urine cytology specimen can be particularly challenging, considering the rarity of the tumor. Cai and Parwani
12 reported cytologic findings in two cases of LELC of the bladder, which were confirmed by histopathological examination of the resected tumor. Useful cytomorphologic features include the presence of large tumor cells with a high nuclear-to-cytoplasmic ratio, vesicular chromatin and prominent nucleoli, presenting as single cells or intermixed with inflammatory cells.
12Pure LELC must be distinguished from reactive inflammatory lesions or lymphoma. Primary lymphoma of the bladder is extremely rare, and has an entirely different therapeutic approach.
3 Immunohistochemistry for cytokeratin and lymphoid markers can help in resolving this differential diagnosis. Owing to the presence of a prominent inflammatory background, the neoplastic cells may be assumed to be reactive histiocytes and the lesion may be misdiagnosed as chronic cystitis.
1,3 Hence, a dense lymphoid infiltrate in a urinary bladder biopsy should alert the pathologist to closely look for neoplastic cells. Immunohistochemistry for epithelial markers can be helpful in highlighting the neoplastic cells in such instances. Other important differential diagnoses include poorly differentiated invasive transitional cell carcinoma or poorly differentiated squamous cell carcinoma with associated dense lymphoplasmacytic infiltrate.
3,13 Sometimes, it might be problematic to differentiate LELC from small cell carcinoma of the urinary bladder or prostate in small, improperly fixed biopsy specimens with crush artifacts.
1,3Most of the previous studies have suggested that LELC has a relatively favorable prognosis when in pure or predominant forms with reported rates of metastasis ranging from only 12% to 15%.
2,3,5 Amin et al
3 reported on three patients having pure LELC and five patients having predominant LELC, all of whom showed no evidence of disease (2-72 months). In contrast, the two patients with focal LELC succumbed to metastatic disease 6 and 84 months after diagnosis. Similarly all the three patients in the study by Holmang et al
6 with focal LELC died of the disease (9-68 months), compared to none of the six patients with pure or predominant LELC (13 months to 18 years). In the study by Lopez-Beltran et al,
5 all three patients with pure and 4/6 patients with predominant LELC were alive, while all four patients having focal LELC died of disease. However, Tamas et al
8 did not find any difference in prognosis between pure and mixed LELC. Their study demonstrated that LELC treated by cystectomy has a similar prognosis to ordinary urothelial carcinoma and does not differ between pure and mixed cases. In cases with cystectomy, the overall 5-year actuarial recurrence-free risk was 59% (62% and 57%, for pure and mixed LELC, respectively). The rationale behind this apparent better prognosis, however, has not been well investigated. It is known that tumors with lymphoid infiltration have a comparatively better prognosis than those without it. Intense immune response generated by these lymphoid cells against the tumor may play an important role in this regard.
3The paucity of published literature suggests that there is limited experience in therapeutic approaches to LELC of the bladder. The pure/predominant form may respond to chemotherapy.
3–5,8 In the study by Amin et al,
3 four of the pure/predominant LELC were treated with transurethral resection and chemotherapy and all showed no evidence of disease. Dinney et al
4 has shown a complete response to chemotherapy and transurethral resection of the bladder tumor in 3 cases of muscle invasive LELC. In another study by Lopez-Beltran et al
5 2 of their 13 patients received chemotherapy and both showed no evidence of disease at 21 and 47 months. In a recent study by Tamas et al,
8 of the three pure cases treated by chemotherapy, two were free of disease at 4 and 65 months and the third had recurrent disease at 17 months. Our case underwent radical cystectomy without chemotherapy and was free of disease 12 months after surgery.
In conclusion, LELC of the bladder is rare and should be ruled out in bladder biopsies that show dense lymphoid infiltrate. The differential diagnosis is usually lymphoma, poorly differentiated invasive transitional cell carcinoma and poorly differentiated squamous cell carcinoma with lymphoplasmacytic background. Existing data suggest the pure form responds well to chemotherapy and has a better prognosis.
