Case 25-2013: A 71-Year-Old Man with Hematuria and a Mass in the Bladder

Dr. Donald S. Kaufman: A 71-year-old man was seen in the outpatient cancer center of this hospital because of gross hematuria and a mass in the bladder. The patient had been well until 6 weeks earlier, when painless hematuria had developed, with passage of clots, while he was traveling in a wilderness area. After 2 days, he saw a nurse practitioner at a local facility. Attempts at passing a catheter into his bladder were unsuccessful, and he was referred to a hospital in a larger city. Computed tomography (CT) performed without the administration of contrast material reportedly revealed a multilobulated mass (isodense to hyperdense and measuring 8 cm by 7.5 cm by 6.5 cm) in the urinary bladder, diffuse fat stranding in the perivesical and left periurethral regions, and bilateral intrarenal calculi and cysts. The next day, cystoscopic examination revealed an open prostatic urethra and brisk bleeding, making visualization of the bladder difficult. A fungating lesion at the anterior bladder neck at the 12 oclock position, with an adherent clot, was partially excised. Laser ablation resulted in hemostasis. Pathological examination of the tissue reportedly showed focal adenocarcinoma in situ that was thought to be of bladder origin and was associated with bland papillary and glandular epithelium, with no evidence of invasion. Five days later, bleeding persisted, and the patient was transferred to a second hospital, near his home. Ultrasonography of the abdomen and pelvis revealed bilateral renal cysts and bilateral nonobstructing nephrolithiasis. The next day, repeat cystoscopy reportedly revealed a large fungating lesion and clot at the anterior bladder neck at the 12 oclock position. Flushing of the bladder and biopsies were performed. Pathological examination of the biopsy specimens reportedly showed adenocarcinoma; consultation with outside experts was pending. CT of the abdomen, performed the next day, reportedly revealed no evidence of metastatic disease. After decompression of the bladder with a catheter, irregular thickening of the bladder wall was seen, with an irregular, multiloculated gas collection, 2.5 cm by 3.5 cm, in the suprapubic region. The patient was discharged on the fifth day to follow up with his urologist.

Nineteen days before this evaluation, transrectal biopsies of the prostate were performed with ultrasonographic guidance. Pathologica examination of the specimens revealed adenocarcinoma in one of two cores from the right base, with a Gleason score of 7 (grade 3 plus grade 4) on a scale of 1 to 10 (with higher scores indicating a worse prognosis), involving 30% of the tissue, and adenocarcinoma in a core from the left lateral midportion, with a Gleason score of 6 (3+3), involving 10% of the tissue. The patient was referred to the cancer center of this hospital. He reported that hematuria and clot passage had resolved and that he felt well. He had a history of lower urinary tract symptoms and urinary retention, for which a transurethral resection of the prostate had been performed elsewhere 12 years earlier. Pathological examination of the tissue reportedly had shown an area of focal high-grade prostate intraepithelial neoplasia. Four subsequent prostatic biopsies, the most recent performed 4 years before this evaluation, were negative for cancer. Levels of prostate-specific antigen (PSA), measured annually, had been normal until 5 days after the second cystoscopy, 1 month before this evaluation, when the level was 13.0 ng per milliliter (reference range, 4.0). The patient also had erectile dysfunction, hypertrophic cardiomyopathy, hypertension, hyperlipidemia, diverticulosis, mild obstructive sleep apnea (for which he used continuous positive air pressure at night), and nephrolithiasis, which was treated with lithotripsy. Results of a

colonoscopy performed 1 year earlier were normal. Medications included atorvastatin and verapamil; other medications (doxazosin, amlodipine, valsartan, telmisartan, hydrochlorothiazide, potassium aminobenzoic acid, oxybutynin chloride, and potassium chloride supplement) had recently been stopped. He was married, had adult children, and was retired from the shipping industry, where he had been exposed to asbestos. He was physically active in outdoor activities. He did not smoke or drink alcohol. There was no family history of urologic cancers. On examination, the pulse was 50 beats per minute and the blood pressure, temperature, respiratory rate, and oxygen saturation were normal. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 30.0. Rectal examination was not performed, and the remainder of the examination was normal. The blood potassium level was 3.3 mmol per liter (reference range, 3.4 to 4.8), the creatinine level 1.3 mg per deciliter (115 mol per liter; reference range, 0.6 to 1.5 mg per deciliter [53 to 133 mol per liter]), and the urea nitrogen level 15 mg per deciliter (5.4 mmol per liter; reference range, 8 to 25 mg per deciliter [2.9 to 8.9 mmol per liter]); the estimated glomerular filtration rate was 59 ml per minute per 1.73 m2 of body-surface area (reference range, 60). The complete blood count and levels of other electrolytes, calcium, and glucose were normal. A diagnostic test was performed, and management decisions were made.

Differential Diagnosis
Dr. Aria F. Olumi: I am aware of the diagnosis in this case. This patient presented to another hospital with the abrupt onset of gross, painless hematuria. May we see the initial imaging studies? Dr. Mukesh G. Harisinghani: Noncontrast-enhanced CT scans obtained at the first hospital, before the cystoscopic evaluation, show highdensity, lobular filling defects in the bladder that have an appearance that is typical of blood clots or hemorrhage. The high-density material appears to project beyond the outline of the bladder (Fig. 1), a finding consistent with clot or hemorrhage in a diverticulum. There is soft-tissue stranding in the perivesical area. Since no intravenous contrast material was administered, it is difficult to identify an enhancing mass distinct from the clots.

Differential diagnosis of hematuria

Dr. Olumi: Hematuria can be categorized as having a glomerular or nonglomerular cause. In glomerular hematuria, red cells are often dysmorphic, casts are present on light-microscopical examination, and urine dipstick testing shows 2+ to 3+ proteinuria. Often, a renal biopsy is required to discriminate among the different entities associated with glomerular hematuria. In nonglomerular hematuria, the red cells are normal in appearance and casts are absent. Causes of nonglomerular hematuria can be further subcategorized into nonurologic and urologic entities. Nonglomerular, nonurologic hematuria is caused by tubulointerstitial diseases and is often accompanied by proteinuria. Renal papillary necrosis or a vascular disease accounts for many of the underlying causes of nonglomerular, nonurologic hematuria. An absence of proteinuria distinguishes urologic causes of nonglomerular hematuria from the other diseases associated with hematuria. Urologic causes of hematuria can be further subcategorized as painless versus painful and microscopic versus gross. Often, painful hematuria is associated with infectious causes, nephrolithiasis, or both, whereas painless hematuria is associated with urologic cancers. However, benign entities, such as benign prostatic hyperplasia or supratherapeutic anticoagulation, can also lead to painless hematuria. This patient has gross, painless hematuria; therefore, a urologic cancer must be suspected.

Differential diagnosis of a bladder mass

This patient had filling defects in the bladder on imaging, and a mass was seen on cystoscopy. Bladder masses can be benign (epithelial hyperplasia or metaplasia), dysplastic (inverted papilloma, nephrogenic adenoma, or vesical leukoplakia), or cancerous (transitionalcell, squamous-cell, or adenocarcinoma). Cystoscopic evaluation was repeated at this hospital. On digital rectal examination during the procedure, the rectal tone was intact, the pelvic organs were mobile, the prostate weight was estimated to be 40 to 50 g, and there was no palpable prostate nodule or rectal mass. Cystoscopy revealed an irregular posterior bladder neck and

trigone. The anterior bladder neck contained small diverticula at its junction with the prostate, with mucosal abnormalities that were worrisome for cancer. In view of the patients presentation, our clinical diagnosis was urothelial carcinoma of the bladder neck, the prostatic urethra, or both. DR. Aria F. OLUMIS DIAGNOSIS Urothelial carcinoma of the bladder neck, the prostatic urethra, or both.

Pathological Discussion
Dr. Chin-Lee Wu: Examination of the specimens obtained by transurethral resection of the ladderneck tumor performed at the two other hospitals shows a tumor with cystic glandular and papillary structures that are lined by pseudostratified tall columnar cells (Fig. 2A and 2B). Mucinous differentiation is not seen. The differential diagnosis included adenocarcinoma of the bladder, involvement by a colonic adenocarcinoma, and ductal adenocarcinoma of the prostate. Immunohistochemical staining showed that the tumor cells were positive for the epithelial markers CK7 and EMA and for the prostatic markers PSA, PSAP, PSMA, and P501S. The tumor cells were negative for thrombomodulin, CK20, CEA, and CDX2. CEA and CDX2 are commonly expressed in colonic adenocarcinoma. On the basis of the combined immunologic and morphologic features, Dr. Jonathan Epstein, at Johns Hopkins Medical Institutions, who was the outside consulting pathologist, favored the diagnosis of ductal adenocarcinoma of the prostate. Because the tumor was described as being located in the bladder neck, which is very unusual for prostatic ductal adenocarcinoma, we suggested that a biopsy of the prostatic urethra be performed to determine whether there was a connection between the tumor and the prostate. Therefore, a biopsy specimen of the prostatic urethra was obtained on cystoscopy in this hospital and showed a tumor with identical morphologic features, supporting the diagnosis of duc-tal adenocarcinoma of the prostate. In addition, examination at this hospital of a transrectal biopsy specimen of the prostate obtained at the second hospital revealed acinar adenocarcinoma of the prostate, Gleason score 6 (3+3), involving 40% of the core from the right base of the prostate gland and 10% of the core from the left lateral midportion (Fig. 2C). Ductal adenocarcinoma of the prostate accounts for approximately 0.8% of all adenocarcinomas of the prostate.1,2 The usual (acinar) type of prostatic adenocarcinoma has a single layer of cuboidal cells. In contrast, ductal adenocarcinoma of the prostate is typified by tall columnar cells forming cribriform or papillary structures and has been called endometrial or endometrioid carcinoma because it is reminiscent of endometrioid carcinoma of the uterus.3 To avoid confusion, the terms endometrial and endometrioid are no longer used to describe ductal adenocarcinoma of the prostate. Prostatic ductal adenocarcinoma was initially described as a polypoid or papillary mass in the prostatic urethra or large periurethral ducts.3 In some cases, the carcinoma has also been shown to be present in the peripheral zone and is commonly associated with high-grade, acinartype prostatic adenocarcinoma. 4,5 Ultrastructural and immunologic examination has shown that such tumor cells have a prostatic origin.1,2 Prostatic ductal adenocarcinoma analyzed in specimens from radical prostatectomies was shown to have a higher pathological stage and an

associated higher rate of positive margins and nodal metastasis. These findings are consistent with reports of aggressive clinical outcomes of the disease.4,5

Discussion of Management Surgical Management of Ductal Adenocarcinoma of the Prostate

Dr. Olumi: Management strategies for ductal adenocarcinoma of the prostate are poorly developed, in view of the rarity of the disease. Prostatic ductal adenocarcinoma is diagnosed in approximately 1% of all radical prostatectomies. Often, the PSA levels in patients with prostatic ductal adenocarcinoma are lower than those in patients with prostatic acinar adenocarcinoma. According to the Surveillance, Epidemiology, and End Results database, patients with prostatic ductal adenocarcinomas typically receive a diagnosis at an older age, have more locally advanced disease, often require adjuvant therapies, and have a higher disease-specific mortality rate, as compared with those with the more common prostatic acinar adenocarcinoma.6 Although experience with the management of ductal adenocarcinoma of the prostate remains limited, a majority of the published material reports the use of radical prostatectomy or externalbeam radiotherapy and adjuvant hormonal-ablation therapies. However, in this patient, the cystoscopic evaluation revealed that the tumor margin was not well-delineated between the anterior bladder neck and the prostatic urethra; therefore, it was not clear whether prostatectomy alone would result in complete resection of the tumor. In this otherwise healthy and vigorous man, we considered the size of the tumor, the possibility that it had invaded the bladder, and our sense that aggressive surgery had a far greater chance of curing him, and we decided to proceed with cystoprostatectomy.

Medical Oncologic Management of Ductal Adenocarcinoma of the Prostate

Dr. Kaufman: Androgen-deprivation therapy (ADT) was not used in this variant of prostatic cancer in the past, when it was considered to be of mllerian- duct origin. However, once it was established that this type of cancer was of prostatic origin, trials of hormones, often in conjunction with radiation treatment, were used in small series and single case reports.7-10 Several trials showed that tumors were hormone-responsive, although cure was almost never attained. Pooled data from the Rare Cancer Network identified 31 patients with ductal adenocarcinoma of the prostate, with a mean follow-up of 56 months. Thirteen of 17 patients who were treated with ADT, either at diagnosis, as an adjuvant to radiation, or at relapse, had a good response. Thus, there was clear evidence that these tumors can be shrunk by the use of ADT.11

Management of Ductal Adenocarcinoma of the Prostate with Radiation Therapy

Dr. Anthony Zietman: We considered the use of radiation and adjuvant ADT in this patient on the basis of the few small reports in the literature. This literature is much less robust than that pertaining to the far more common acinar adenocarcinoma of the prostate. In the Rare Cancer primarily with radiation, and 16 with prostatectomy (including 7 with adjuvant radiation). The recurrence- free survival rate (median follow-up, 56 months) was 57% (3-year biochemical recurrencefree survival [i.e., survival free from rising PSA levels], 79%) among patients treated with radiation and 75% (3-year biochemical recurrence-free survival, 65%) among those treated with surgery. A report of 6 patients treated with external-beam radiation and adjuvant ADT (in 5 patients) showed that 2 patients died from metastatic disease, at 1.4 years and 7.1 years; 3 patients had no evidence of disease at 3.2 to 4.8 years of followup; and there were no local recurrences.12 These results suggest that local radiation may be effective in the treatment of this disease. Dr. Olumi: We believed that the best surgical treatment strategy would be radical cystoprostatectomy, bilateral pelvic-node dissection, and urinary diversion (ileal loop). The patient underwent surgery, had a smooth recovery, and was discharged home on postoperative day 6.

Pathological Discussion
Dr. Wu: Examination of the cystoprostatectomy specimen showed a cystic mass, 2.5 cm in maximal dimension, in the anterior bladder neck and prostatic urethra, in a diverticulum lined by nonneoplastic urothelial cells (Fig. 3A). Sections of this tumor showed adenocarcinoma with pseudostratified tall columnar cells lining papillary, tubular, or cribriform structures (Fig. 3B). On immunostaining for p63 and CK903, two proteins commonly expressed in the urothelium, the adjacent urothelial cells in the diverticulum were positive and the tumor cells were negative (Fig. 3C), indicating a nonurothelial origin of the tumor. The tumor cells were diffusely positive for PSA, PSAP, and P504S/AMACR; focally positive for CK7 and CK20 (Fig. 3D); and negative for CDX2 and CEA. These findings confirmed the preoperative diagnosis of prostatic ductal adenocarcinoma. Carcinoma cells extended through the muscularis propria to involve extravesical fat (Fig. 3E). Because this prostate cancer involved the bladder, the tumor was staged as pT4. Organ-confined acinar adenocarcinoma of the prostate, Gleason score 7 (3+4), was found in the peripheral zone of the prostate, involving the right lobe and left anterior prostate (Fig. 3F). The seminal vesicles, bilateral pelvic lymph nodes, and all resection margins were free of carcinoma. The final diagnoses were ductal adenocarcinoma of the prostate, Gleason score 8 (4+4), involving the prostatic urethra and anterior bladder neck, invading through muscularis propria into perivesical fat, pT4N0Mx; and acinar adenocarcinoma of the prostate, Gleason score 7 (3+4), involving the right anterior, right posterior, and left anterior quadrants, confined to the prostate, pT2cN0Mx. Ductal adenocarcinoma of the prostate is usually seen in the peripheral or transitional zones of the prostate and is usually physically admixed with acinar-type adenocarcinoma. This patient had a very unusual presentation, in that the prostatic ductal adenocarcinoma arose in a urothelial diverticulum in the prostatic urethra and anterior

bladder neck and was physically separated from the coexisting acinar adenocarcinoma in the peripheral zone. FOLLOW-UP Dr. Zietman: Although this patient had the adverse prognostic finding of tumor invasion of perivesical fat, the surgical margins were negative. Because of the lack of data on externalbeam radiation therapy and hormone suppression as adjuvant therapy after cystoprostatectomy, and in view of the known side effects of hormone suppression, we elected to use neither adjuvant radiation nor hormone therapy and to follow the patient closely. Dr. Kaufman: At the most recent follow-up, 24 months after surgery, the patient felt well and was working full time. Repeat imaging studies showed no evidence of recurrent or metastatic cancer. The PSA level has remained below 0.1 ng per milliliter. Dr. W. Scott McDougal (Urology): The prognosisin this disease is very poor, and if you believe that it may be responsive to ADT, why not treat the patient with it now? Dr. Olumi: His PSA levels have been undetectable. We have no marker laboratory or imaging to assess the efficacy of early ADT in this patient. Dr. Kaufman: When we considered additional treatment, the data on adjuvant radiation and ADT really didnt support an improvement in life expectancy. Conversely, the side effects of ADT would affect the patients quality of life right away. This man is a highly physically active outdoor enthusiast, and we did not want to treat him with agents with little evidence of efficacy and much evidence of substantial potential adverse effects. We think the best time for ADT would be when our hand is forced by a disease recurrence. Dr. McDougal, what do you think about the surgical choice of a cystoprostatectomy? There is almost no basis for this in the literature. Dr. McDougal: I think this was absolutely correct. It is an unusual case requiring unusual management. Dr. Zietman: In the Rare Cancer Network study involving 31 patients,11 liver metastases ultimately developed in a relatively high number of patients, which is unusual in typical acinar carcinoma of the prostate. This observation further supports the idea that prostatic ductal adenocarcinoma is a distinct pathologic entity with its own patterns of spread