Correspondence *James P Wilmot Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA

Email supriya_mohile@urmc.rochester.edu

The case

A 67-year-old woman presented to her primary care physician having experienced abdominal pain, dysuria, and episodic gross hematuria for 1 month. Her medical history was unexceptional except for a 40-pack-year smoking history. With regard to family history, the patient reported that her brother had died of bladder cancer at the age of 55 years. Physical examination revealed a palpable suprapubic pelvic mass. The rest of her examination including pelvic and complete lymph-node examinations was unremarkable. Initial laboratory tests were all normal. A urinalysis was consistent with gross hematuria, but culture and cytology were negative.

A CT scan of the abdomen and pelvis performed 1 month after presentation showed an 8 cm calcified pelvic mass associated with the dome of the bladder, which extended from the urachus. No obvious sites of distant metastases were noted. A chest X-ray and bone scan were negative. The patient underwent a cystoscopy, which revealed an indentation at the dome of the bladder and normal mucosa, but no biopsy was performed. One month later, the patient underwent a planned radical cystectomy, but during the surgery an extensive area of fibrous tissue, in continuity with the primary tumor and extending to the pelvic sidewall directly below the obturator internus, interfered with its completion. Instead, a gross tumor resection, partial cystectomy with en bloc removal of the attached urachus and umbilicus, and bilateral pelvic lymph-node dissection were performed. The area of fibrous tissue and a mass on the left pelvic sidewall were also resected. Intraoperative pathology consultation revealed poorly differentiated carcinoma with no invasive carcinoma on the margins. On gross examination, a partially necrotic mass measuring 6.4 3.4 3.2 cm originating from the dome of the bladder was observed. The left pelvic side-wall mass was 0.6 cm. The histologic features of the tumor as assessed by hematoxylin and eosin staining ranged from sheets of poorly differentiated carcinoma to areas with poorly differentiated 'signet-ring' cells (Figure 1A). In addition, the tumor had a mucinous appearance with nests of neoplastic cells floating in pools of extracellular mucin (Figure 1B). The left pelvic mass showed proliferating spindle cells interspersed with pleomorphic tumor cells. Immunohistochemical staining revealed that these pleomorphic cells were positive for cytokeratin 20 but negative for calretinin—consistent with metastatic carcinoma. Mucicarmine staining of the pelvic-wall specimen revealed that the poorly differentiated cells resembled the 'signet-ring' cells of the primary tumor. A diagnosis of urachal carcinoma with locoregional extension to the left pelvic wall was made.

Figure 1 Histological examination of the tumor.

(A) Sheets of poorly differentiated 'signet-ring' cells (arrows). (B) Nests of neoplastic cells floating in pools of extracellular mucin.

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At 6 weeks after surgery, no evidence of gross metastatic disease was noted on CT scans of the chest or on MRI of the abdomen and pelvis. After a discussion about the risks and benefits of further treatment such as radiation or adjuvant chemotherapy, the patient opted for observation. An MRI of the abdomen and pelvis obtained 3 months after surgery revealed a lobulated left pelvic mass measuring 7.8 6.6 cm in the area of the prior pelvic-sidewall mass (Figure 2). The patient began chemotherapy 2 weeks after the MRI with irinotecan at 125 mg/m², bolus 5-fluorouracil (5-FU) at 500 mg/m², and leucovorin at 20 mg/m² (IFL) delivered weekly for 4 weeks over a 6-week cycle. Owing to significant diarrhea, the chemotherapy dose was reduced by 25% after the first cycle and the patient tolerated this dose for the subsequent cycles. MRI of the abdomen and pelvis performed after 4 cycles of standard IFL treatment revealed no evidence of disease (Figure 3). The patient received one additional cycle of chemotherapy and did well without any further treatment for the next 6 months when she developed sciatic pain that radiated down her left leg. She was found to have an L3 pathologic compression fracture and underwent radiation therapy to L2–L5 (3,000 Gy) for 2 weeks. Radiation therapy was minimally effective and she continued to have considerable sciatic pain. At 2 months after the completion of radiation therapy the patient restarted chemotherapy with IFL at the original doses and after one cycle her pain had completely resolved. At the last follow-up, no new sites of metastatic disease were noted on imaging scans. Follow-up visits and imaging are currently scheduled every 8 weeks.

Figure 2 Extent of disease before therapy.

(A) Cross-sectional view of lobulated left pelvic mass measuring 7.8 6.6 cm (arrow) in the area of the prior pelvic-sidewall mass. (B) Axial view of the same mass (arrow).

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Figure 3 Extent of disease after therapy.

(A) Resolution of the left pelvic mass after chemotherapy (cross-sectional view). (B) Resolution of the left pelvic mass after chemotherapy (axial view).

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Discussion of diagnosis

Primary adenocarcinomas of the bladder and urachus are extremely rare, accounting for 0.5–2.0% of all bladder malignancies. Although single-institution series have suggested that urachal adenocarcinomas account for 25–30% of primary adenocarcinomas of the bladder, a recent population-based analysis indicated that urachal adenocarcinomas represent approximately 10% of this group.¹

The urachus is a musculofibrous band that extends from the dome of the bladder to the umbilicus. During fetal development, the urachus develops into the median umbilical ligament that stretches from the umbilicus to the bladder. Urachal carcinoma stems from the epithelium of the remnant of this structure and adenocarcinoma accounts for 90% of all cases. Pathological examination of specimens of urachal carcinoma can reveal fragments of adenocarcinoma that float within 'pools' or 'lakes' of mucin (Figure 1).

Patients with urachal carcinoma most commonly present with dysuria, hematuria, abdominal pain, or umbilical discharge.² The diagnostic evaluation for urachal carcinoma should include a careful history and physical examination. An urinalysis with cytology may be helpful. CT or MRI scans of the abdomen and pelvis can provide information on local extent of the disease, pelvic lymph-node involvement, and liver metastases. A cystoscopy is necessary to evaluate whether the carcinoma has penetrated the urothelium of the bladder and a transurethral biopsy should be performed if possible. To evaluate the presence of metastatic disease in the lungs or bone, chest X-rays and/or bone scans should be obtained. The MD Anderson Cancer Center has developed practical criteria for the diagnosis of urachal cancer (Box 1).³ Sheldon et al. has proposed a staging schema for urachal carcinomas (Table 1). While early-stage tumors are localized within the urachal mucosa, advanced-stage lesions can extend into local structures such as the bladder, abdominal wall or peritoneum, and metastases to regional lymph nodes or distant sites.² A staging schema proposed by investigators at the Mayo Clinic highly correlated to the staging system proposed by Sheldon et al. and was advocated for its simplicity (Table 1); however, owing to the limited numbers of cases, no staging system has been validated.⁴

Table 1 Staging systems for urachal carcinomas.

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Differential diagnosis

Persistence of an embryonic urachal remnant can cause various clinical problems. Congenital urachal abnormalities such as patent urachus, umbilical urachal sinus, and urachal cyst could cause urinary symptoms and abdominal pain if infected. Abscesses can also develop in the urachal remnant. Benign urachal neoplasms including fibroadenomas, fibromyomas, and hamartomas are extremely rare but can mimic urachal malignancy.^{2, 3} Isolated case studies have also described transitional-cell carcinoma, squamous-cell carcinoma, rhabdomyosarcoma, and neuroblastoma within the urachal remnant.

Treatment and management

Primary treatment of potentially localized disease includes wide local excision of the urachus, umbilicus, and surrounding soft tissue combined with partial or radical cystectomy and bilateral pelvic lymphadenectomy.^{4, 5} Although radical cystectomy has historically been advocated, several studies have demonstrated long-term survival with extended partial cystectomy including en bloc removal of the umbilicus, urachal tumor mass, the entire urachal ligament, and bladder dome.^{3, 4, 6, 7, 8} Despite primary treatment, a retrospective analysis of 66 patients with primary urachal carcinoma treated at the Mayo Clinic revealed a 5-year overall survival rate of only 49%.^{4, 6} Risk factors for recurrence include lack of en bloc resection of the umbilicus, peritoneal involvement, and positive nodes and/or margins.^{4, 6} Owing to lack of early symptoms, the cancer usually presents at an advanced stage. In a population-based study including 62 individuals with a primary diagnosis of urachal tumor, only one patient had cancer localized to the urachus.⁵ Rates of local recurrence are high, with disease usually reoccurring in the pelvis or bladder within 2 years of surgery.^{2, 4}

Chemotherapy and radiation for urachal adenocarcinoma have resulted in minimal responses with no definitive improvement in survival. The rarity of the cancer has prevented accrual to controlled clinical trials. Case reports describe results with various 5-FU and/or cisplatin-based regimens.^{9, 10, 11, 12} Despite measurable responses to treatment, tumors often recur and the majority of patients die within 2 years of diagnosis. Siefker-Radtke et al. reported the results of a retrospective review of 42 patients treated at the MD Anderson Cancer Center. Among the 26 patients who developed metastases, only 4 had significant responses to chemotherapy, and of the 9 patients who received chemotherapy with 5-FU or cisplatin-containing regimens three responded.⁶ A phase II trial with 5-FU, leucovorin, cisplatin, and gemcitabine for adenocarcinomas of the urachus is ongoing at the MD Anderson Cancer Center.³

Irinotecan is a topoisomerase I inhibitor that disrupts cell division by interfering with DNA replication. Irinotecan has demonstrated preclinical activity in adenocarcinomas from a variety of tumor types including gastric, colorectal, pancreatic, lung and breast carcinomas.¹³ Currently, irinotecan in combination with 5-FU/leucovorin with or without bevacizumab is indicated as first-line therapy for metastatic colorectal cancer.¹⁴ Irinotecan has also demonstrated efficacy for metastatic gastric cancer in combination with 5-FU/leucovorin or cisplatin.^{15, 16} Urachal adenocarcinomas are often histologically similar to adenocarcinomas at other sites of origin, including those in the gastrointestinal tract such as the colon or stomach. The histology from this patient demonstrated the typical 'signet-ring' pattern that is also typical of gastric cancer. There is an additional case study in the literature from Japan that describes a patient with metastatic urachal carcinoma and a history of considerable chemotherapy whose lung lesions had a marked response to irinotecan.¹⁷ The patient described here achieved a complete remission of disease with IFL chemotherapy that lasted for 7 months after discontinuation of treatment. Furthermore, IFL chemotherapy has been clinically effective for 5 months following the initiation of treatment for recurrence. Although the patient described in this case study has benefited from IFL, the long-term efficacy of chemotherapy for systemic urachal cancer is still unknown.

Conclusions

Currently, there is no standard chemotherapy regimen for the treatment of metastatic urachal adenocarcinoma. The demonstration that more recently developed agents have efficacy in adenocarcinomas from other tumor types should inspire treatment options for this difficult disease. In addition, agents that demonstrate efficacy in metastatic disease should be pursued in trials designed to clarify the role of neoadjuvant or adjuvant chemotherapy in urachal adenocarcinoma.

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Subject areas under which this article appears: Chemotherapy