What Is the Cause of This Solid White Lesion in a Ureterocele?

A 68-year-old woman presents to a hospital in Brazil noting a 3-month history of blood in her urine. She tells the clinician taking her history that she has never smoked, and on further questioning notes that she has had no known contact with anilines or other chemicals.

Computed tomography (CT) reveals a duplicated ureter, dilatation of the upper kidney pole, and a ureterocele -- i.e., dilatation of the distal portion of an ectopic ureter -- with an expansive lesion and without metastases. Cystoscopy shows a solid white lesion located in the ureterocele that fills the bladder beyond its midline.

Clinicians perform a transurethral resection without complications, and send a surgical specimen of the mucosal tissue for examination. The histology report describes a high-grade noninvasive papillary urothelial carcinoma.

Based on these findings, clinicians initiate intravesical immunotherapy with bacillus Calmette-Guérin; the patient is slated to receive six weekly sessions (40 mg). After the second application, the patient returns to the emergency department reporting low back pain. Clinicians order another CT scan, which shows multiple metastatic lesions.

Anatomopathological immunohistochemistry is performed, which identifies expression for cytokeratin with a Golgi pattern, CD56, synaptophysin, and with a high proliferation index (Ki67 > 95%), consistent with a diagnosis of small cell bladder cancer (SCBC).

The patient is started on platinum-based chemotherapy for four cycles, but has a poor response and unfortunately dies 3 months later.

Discussion

Clinicians presenting this case of an older woman with SCBC that developed in a ureterocele note that this is a rare site for malignant tumors, and the case is believed to be the first reported case of SCBC located in a ureterocele.

Bladder cancer is the second most common malignancy of the genitourinary system after prostate adenocarcinoma. Urothelial carcinoma represents 90% of all bladder tumors, while SCBC is found in only 0.5% to 1.2% of patients.

Initially characterized in 1981, SCBC typically presents with hematuria (63-88% of cases), with dysuria the second most common presenting symptom (30-79% of cases). Abdominal pain, urinary obstruction, hypercalcemia, and weight loss are seen less often, in 5-29% of cases.

Morphologically and biologically, SCBC is marked by the same rapid progression, early metastasis, and high mortality rates that characterize small cell lung carcinoma.

Ureteroceles are cystic dilatations of the distal ureter that occur due to congenital ureteric wall weakness. They may be located either within the bladder or urethra, and can be associated with a single or duplex system; in patients with duplex ureter, ureteroceles are associated with obstruction of the upper pole ureter.

The case authors note that a duplex ureter and urinary collecting system is a not uncommon anatomical variance, ranging in incidence from 0.7% to 4% of the population, and is more common in females than males. The anomaly may be asymptomatic or associated with vesicoureteral reflux, incontinence, ureterocele, or obstruction.

In cases of complete duplication, there are two collector systems for one kidney and two ureters on the same side that lead to the bladder through separate orifices. The Weigert-Meyer rule states that the ureter that drains the kidney's upper pole inserts below and medially to the normal place insertion, and frequently, this insertion is abnormal and associated with ureterocele.

The ureter of lower pole inserts near the normal site, but normally presents vesicoureteral reflux, caused by the angle that it crosses the urinary bladder wall.

Cancers presenting into a ureterocele are rare; imaging studies may reveal alterations of the ureterocele walls, and only a few cases have been reported in the literature, including pheochromocytoma, leiomyoma, adenocarcinoma, and urothelial carcinoma.

Standardized treatment options for SCBC are limited, the authors note, explaining that in most cases, the cancer will already be locally advanced or metastatic at diagnosis. This applies to about 40% of patients, according to a 2015 review of clinical characteristics and treatment outcomes in 960 patients with advanced SCBC.

The most common sites of metastasis are the regional and distant lymph nodes, the liver, and bones, the case authors write, citing a description of these lesions as macroscopically large, with a polypoid or nodular aspect and superficial necrosis. Macroscopically, these carcinomas do not differ from urothelial carcinoma and may coexist in about 40% of cases.

Immunohistochemical analysis generally reveals both epithelial and neuroendocrine differentiation. Markers that are normally positive include neuron-specific enolase (25-100%), chromogranin A (22-89%), synaptophysin (67-76%), CD 56/57, and protein gene product.

Differential diagnoses to consider include large-cell carcinoma and carcinoid cancer of the bladder, high-grade urothelial carcinoma, lymphoma, lymphoepithelial-like carcinoma from the lung, and metastases from another neuroendocrine tumor, neuroendocrine carcinoma of the prostate infiltrative, and rhabdomyosarcoma, the case authors note.

While treatment options for SCBC are not standardized, the authors suggest that better outcomes may be seen with neoadjuvant platinum-based chemotherapy (four cycles) followed by radical cystectomy, except in patients with existing metastases at diagnosis, when chemotherapy alone offers palliative support (four to six cycles).

While transurethral resection of the bladder tumor is not considered adequate treatment, it may be used for the removal of any large tumor burden before chemotherapy, the authors note.

Data show, they said, that when combining chemotherapeutic and surgical treatment modalities, neoadjuvant chemotherapy with cystectomy is associated with longer median overall survival than does cystectomy followed by adjuvant chemotherapy. Survival for patients with limited disease ranges from 12 to 83 months, while for those with extensive disease, survival usually does not exceed 4-13 months.

Conclusion

In conclusion, the case authors state, the most common sign of SCBC is hematuria, and imaging studies can suggest alterations of the ureterocele walls. While the treatment protocol for SCBC remains undefined, neoadjuvant platinum-based chemotherapy followed by cystectomy offers better outcomes, and the choice of treatment depends on the cancer's tumor-nodes-metastasis status. Patients with this aggressive subtype of bladder cancer generally have a poor prognosis, and palliative therapy is common.

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