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The case

A 57-year-old man presented with a 4-week history of intermittent, painless, macroscopic hematuria. Blood was mixed through the urinary stream, with occasional clots. He described no significant previous lower urinary tract symptoms. He was a nonsmoker with no significant occupational risk factors. There was no family history of urinary tract malignancy and there had been no recent foreign travel. He had experienced no previous urologic diseases or surgery. The patient had no significant comorbidities and was taking no regular medication.

On presentation, he was apyrexial and hemodynamically stable, with no signs of clinical anemia. Examination of the abdominal system and external genitalia revealed nothing out of the ordinary. A urine dipstick test was positive for blood only.

There was no growth of organisms on culture of midstream urine. Microscopy confirmed the presence of more than 5 red blood cells per high-power field, but there was no evidence of malignant cells on cytologic assessment. Ultrasound of the urinary tract and intravenous urogram were unremarkable. A flexible cystoscopy demonstrated a partially solid, solitary lesion of 3 cm in diameter on the right lateral wall of the bladder. Rigid cystoscopy confirmed the findings of flexible cystoscopy and the tumor was macroscopically adequately resected. Histopathologic examination of the specimen revealed a G3 pT1 transitional cell carcinoma (TCC) of the bladder.

He underwent an early second-look transurethral resection at 6 weeks for accurate pathologic staging, and a G3pTa solitary recurrence at the old resection site was found. A standard 6-week course of intravesical bacillus Calmette–Guérin was administered on the recommendation of the multidisciplinary urology team. At the 3-month-check cystoscopy, the tumor recurred as a lymphoepithelioma-like carcinoma (LELC) of at least grade G3pT1. In the presence of disease progression, despite intravesical bacillus Calmette–Guérin therapy, it was felt appropriate to offer the patient a radical cystoprostatectomy with ileal conduit formation. The patient was considered for neobladder formation but declined.

There were no intraoperative or postoperative complications and the patient was discharged on the ninth postoperative day. Pathologic examination of the specimen demonstrated negative resection margins with no perineural, vascular, or lymph-node invasion. The tumor had recurred as a G3pT2b pure LELC. Histologically, it bore close resemblance to lymphoepithelioma of the nasopharynx, and was characterized by nests of undifferentiated malignant cells with ill-defined cytoplasmic borders, prominent nucleoli, and numerous mitoses growing in a typical syncytial pattern (Figures 1 and 2). The neoplastic cells were positive for cytokeratin (AE1 or AE3; Figure 3), and the lymphoid infiltrate comprised mixed B and T cells (CD3 and CD79a) with many admixed CD68-positive macrophages.

Figure 1 Low-power view of pure lymphoepithelioma-like-carcinoma pattern showing tumor cells arranged in solid sheets and nests and intimately associated with a mixed lymphoid infiltrate

 

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Figure 2 High-power view showing glassy-appearing, pleomorphic neoplastic cells with irregular nuclei, prominent nucleoli, ill-defined cytoplasmic borders, and numerous mitoses

Neoplastic cells are arranged in syncytia with a dense lymphocytic infiltrate, comprising of mixed B and T cells with admixed macrophages.

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Figure 3 The neoplastic cells show intense positivity for cytokeratin (AE1 or AE3), indicating epithelial origin

 

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The team concluded that the patient would receive no benefit from adjuvant therapy in the context of complete tumor resection. The patient remains under close surveillance with regular clinical and radiologic follow-up, and remains well 36 months postoperatively, with no evidence of disease recurrence.

Discussion of diagnosis

Lymphoepithelioma is an undifferentiated, malignant, epithelial tumor of the nasopharynx that is histologically distinct by virtue of a prominent lymphoid infiltrate suggestive of malignant lymphoma.^{1, 2} Tumors of similar histologic type have been described at sites other than the nasopharynx, including the lung,³ stomach,⁴ cervix,⁵ and bladder,⁶ and are known as LELC. Primary LELC was first described in 1991, with less than 50 cases reported to date. It is typically diagnosed in the sixth to eighth decades of life (mean age at diagnosis 68 years) and represents 0.4–1.3% of all bladder carcinomas.⁷

LELC has a strong association with the Epstein–Barr virus (EBV) in nasopharyngeal carcinomas and, likewise, a causal relationship has been demonstrated between EBV and cancers at other anatomic sites.⁸ Lopez et al. investigated the possible oncogenic role of EBV in 13 cases of LELC of the bladder, using in situ hybridisation and the EBV-encoded latent membrane protein 1. Their results failed to demonstrate the presence of EBV in any of the LELC cases.⁸ This finding corroborated the results of prior studies,⁹ suggesting an alternative etiology for LELC in the bladder, such as an exaggerated host immune response.

Awareness of this rare variant of bladder carcinoma is necessary in order to avoid erroneous diagnosis. In addition, circumstantial evidence suggests that patients with LELC might have a better prognosis compared with patients with stage-matched TCC.^{8, 9, 10} This better prognosis might allow bladder-preserving treatment strategies augmented with adjuvant cisplatin-based systemic chemotherapy to be performed.

As with any bladder tumor, frank hematuria is a common presenting symptom of LELC.^{9, 10} Patients should be investigated in the usual way with urine culture and cytology, radiologic investigation of the upper tracts, and flexible or rigid cystoscopy. Macroscopically, the appearance of LELC can vary, as the overlying urothelium might be normal or show dysplasia, squamous metaplasia, carcinoma in situ, TCC, or adenocarcinoma.

LELC has a characteristic morphologic appearance comprising tumor cells showing a syncytial growth pattern, with poorly defined cytoplasmic borders. The atypical cells have large, prominent nucleoli and frequent mitosis. A dense cellular infiltrate is present, consisting of mature lymphocytes often admixed with plasma cells and histiocytes. The diagnosis is supported by immunohistochemical staining showing positivity to markers of the lymphoid cells that comprise the inflammatory infiltrate,^{6, 9, 10} the atypical neoplastic cells, and the urothelial component of the tumor.^{6, 8} The tumors are stratified according to the Amin et al.'s classification system; categorization is based on the percentage of LELC pattern within the tumor: pure (100%), predominant (greater than 50%), and focal (less than 50%).⁹

Variations in appearance, however, can lead to difficulties in definitive histologic diagnosis, and differential diagnosis might include chronic cystitis, poorly differentiated TCC with a prominent lymphoid stromal infiltrate, and malignant lymphoma of the bladder.^{6, 9} Accurate diagnosis is important as it has therapeutic implications.

Chronic cystitis is by far the most common of the above differentials, and is characterised by infiltration of the epithelium by polymorph leukocytes and occasional lymphocytes. The underlying oedematous lamina propria is infiltrated by chronic inflammatory cells, mainly consisting of plasma cells and lymphocytes. An overtly dense lymphoid infiltrate, however, should alert the pathologist to search for neoplastic cells, as it is possible to regard these as reactive histiocytes and overlook the LELC pattern.⁶

Primary lymphomas of the bladder are rare, accounting for 0.2% of all bladder neoplasms.¹¹ Only about 100 cases have been described in the literature since 1885. The most common type is extranodal marginal-zone lymphoma of mucosal-associated lymphoid tissue, first described in 1990;¹² they are only rarely Hodgkin's type.¹³ Histologically, these tumors consist of a diffuse, infiltrative proliferation of lymphoid cells surrounding and permeating normal structures, rather than replacing them. They are predominantly localized and of low grade and can, therefore, be managed with radiotherapy, which is associated with good remission and recurrence-free-survival rates.¹⁴ More commonly, lymphoma of the bladder is seen in association with systemic lymphoma; this can manifest either as bladder involvement with active systemic lymphoma (nonlocalized bladder lymphoma), or as lymphoma recurrence in the bladder after a period of remission from previous lymphoma (secondary lymphoma). Immunohistochemistry for cytokeratins is invaluable for distinguishing primary bladder lymphoma from LELC.⁹

Treatment and management

LELC is usually muscle invasive at the time of diagnosis (90% are pT2 or pT3).⁷ The small number of reported cases means that the optimum treatment has yet to be determined. A review of the literature by Porcaro et al.⁷ provides the best insight into the treatment and outcome of patients with LELC of the bladder to date. The majority of patients (93%) have undergone either transurethral resection or radical cystectomy as the treatment modality for local control. It is unclear how patients were stratified for selection of a particular treatment modality, and tumor variability means that direct comparison of the two treatment modalities by adjusted and matched groups is impossible. Aggregated data suggests that oncologic outcome, as defined by the disease-specific survival (DSS) rate, is similar irrespective of the treatment modality. The DSS rate was 93% in the group with predominant LELC, of which 44% of patients underwent transurethral resection and 50% underwent radical cystectomy. The DSS rate for the cohort with focal LELC was 0%, in whom 40% underwent transurethral resection and 60% underwent radical cystectomy. Partial cystectomy for preservation of bladder function in patients with LELC has rarely been performed and the number of patients reported to date who have undergone the procedure is too small to allow for definite conclusions. In the three documented cases identified by Pocaro et al.,⁷ two patients had no evidence of disease at 36 months' and 72 months' follow-up. The third patient, who had stage T3 pure LELC, died of the disease at 41 months' follow-up.

On the basis of the reported sensitivity of lymphoepitheliomas of the nasopharynx to chemotherapy, (Figure 4), LELC of the bladder has been successfully treated with a variety of systemic chemotherapy regimes, either as primary multiagent chemotherapy,¹⁵ or as adjuvant therapy following transurethral resection or radical cystectomy. The most favourable outcomes seem to be from cisplatin-based systemic chemotherapy, with two of the three patients treated by Dinney et al. with primary chemotherapy having no evidence of disease recurrence at 5 and 6 years' follow-up; the third patient had insufficient follow-up to assess the response to chemotherapy.¹⁵ Radiotherapy and intravesical chemotherapy have also been used as adjuvant therapies. The limitations described above, which hinder comparisons of the optimal treatment option for local control, also apply to the use of adjuvant therapy. The DSS rate for all grades of LELC of the bladder and irrespective of adjuvant therapy use is 71% with a mean follow-up of nearly 38 months. Again, using aggregate data from the review by Porcaro et al., we can see that the DSS rates for patients with well-differentiated, pure LELC and patients with predominant LELC are equal, at 93%. This is despite 88% of the pure-LELC group receiving adjuvant therapy, compared with only 25% of the predominant-LELC group (mean follow-up 48 months vs 32 months, respectively).⁷ By comparison, the DSS rate for the focal-LELC group was 0%, but only 30% of that group had received adjuvant therapy.

Figure 4 Comparison of disease-free survival of patients with lymphoepithelioma of the nasopharynx who were treated with or without adjuvant chemotherapy in addition to whole-neck irradiation

Permission obtained from John Wiley & Sons © Rahima M et al. (1986) Carcinoma of the nasopharynx. Cancer 58: 843–849. Abbreviations: CTX, chemotherapy; NO CTX, no chemotherapy.

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The favorable outcome associated with pure and predominant LELC of the bladder could be explained in part by the strong host immune response to the tumor cells incited by the inflammatory infiltrate.⁶ It might also be that the inflammatory reaction results in irritative bladder symptoms at an early stage, resulting in tumor detection at a relatively early stage when it is more amenable to local treatments.

The encouraging survival outcome for pure and predominant LELC of the bladder, the better prognosis than TCC of the same stage,⁸ and the sensitivity to systemic cisplatin-based chemotherapy regimes have led authors to suggest that radical cystectomy should be avoided for these forms of LELC.^{8, 9} Local control with transurethral resection of the tumor, with or without systemic chemotherapy, is probably indicated. The apparently more aggressive nature of focal LELC of the bladder means that these patients are probably best managed with radical cystectomyand adjuvant systemic chemotherapy.

The rarity of LELC of the bladder is such that the optimal follow-up for this disease entity has yet to be determined. Pocaro et al. suggest that, following endoscopic resection, cystoscopies every 3 or 6 months for the first 2 years and yearly thereafter are reasonable.⁷ Patients who undergo partial cystectomy might require more frequent cystoscopies, combined with regular radiologic imaging, for a longer period, in light of the notable rates of fatal late recurrences in patients who have undergone partial cystectomy with curative intent for the treatment of muscle-invasive TCC.¹⁶

Conclusion

LELC of the bladder is a distinct clinical entity. Presentation, as for any bladder tumor, is typically with painless hematuria and investigations should be undertaken in the usual way. Definitive diagnosis is reliant on accurate histologic interpretation, which guides both treatment options and prognostic stratification. The tumor's characteristic morphologic appearance and positive immunohistochemical studies are the key to establishing the diagnosis. Chronic cystitis and bladder lymphoma have similar histologic appearances, which could potentially cause diagnostic difficulties.

The optimum treatment has yet to be determined because of the rarity of the disease, but evidence from the literature suggests that patients with pure or predominant LELC of the bladder should undergo complete transurethral resection, with or without adjuvant cisplatin-based systemic chemotherapy, and focal LELC should probably be managed by radical cystectomy with adjuvant cisplatin-based systemic chemotherapy. Follow-up after bladder-preserving treatment should involve regular cystoscopy, as it does for TCC. The role of treatment by partial cystectomy in carefully selected patients with pure or predominant forms of LELC is unclear, but more intense follow-up would be required.

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