Case Series: Mucinous Adenocarcinoma of the Prostatic Urethra After Brachytherapy for Prostatic Adenocarcinoma

In 2011, physicians at Massachusetts General Hospital reported the first case of mucinous adenocarcinoma of the prostatic urethra after brachytherapy for prostate cancer (published in The New England Journal of Medicine). Any mucinous adenocarcinoma of the urethra is extremely rare. To date, only two more brachytherapy-associated cases have been published, one in the Canadian Journal of Urology and one in SAGE Open Medical Case Reports.

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In Human Pathology, Ting Zhao, MD, a resident and research fellow in the Mass General Department of Pathology, Chin-Lee Wu, MD, PhD, director of Genitourinary Pathology Services at Mass General and the Mass General Cancer Center, and colleagues recently presented long-term follow-up on the previously reported case and describe three additional cases at Mass General, with brief comparisons to the two cases reported by other groups.

The authors conclude the symptoms and immunohistochemical (IHC) characteristics of brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra differ from its radiation-independent counterpart, and it is associated with lower stage and less aggressive behavior.

Clinical Characteristics

The four cases of the rare disease entity at Mass General occurred over 15 years (2008–2022), according to a review of surgical pathology records. At the time of presentation, the patients had a mean age of 72 (range 63–87). Key clinical characteristics were:

• Original Gleason score—3 + 3 (grade group 1) in three patients and unknown in one
• The interval from brachytherapy to the new tumor—Mean, 14.8 years (range, 9–22 years)
• Brachytherapy regimen—All patients received brachytherapy at outside institutions; details were available on two patients and showed their treatment complied with current guidelines (94 Iodine-125 seeds with a total radiation dose of 145 Gy or total radiation dose of 110 Gy)
• Symptoms—Hematuria in three patients and urinary retention in one
• Cystoscopy—Performed on three patients; two had papillary lesions, and one had irregular white tissue
• Colonoscopy—Performed on three patients; findings were normal
• Surgery—Three patients underwent radical surgery (cystoprostatourethrectomy with pelvic lymph node dissection), and one had transurethral resection of the prostate
• Survival—All patients were alive without disease after a mean follow-up period of 4.9 years (range, 0.5–14 years)

Pathology Findings

Pathology reports provided evidence the tumors were primary adenocarcinoma of the prostatic urethra, histologically distinct from the original prostatic adenocarcinoma. There was prominent intestinal-type urethritis glandularis with low-grade dysplasia and a transition between benign urothelium and adenocarcinoma in situ.

Radiation treatment-induced changes in the prostate were seen, including atrophy, reduced glandular epithelium, diffuse epithelial atypia of residual glands, and prominent stromal fibrosis around brachytherapy seeds.

Of the three patients who underwent radical surgery, two had pT2N0 tumors (confined to the prostatic urethra and prostate), and one had a pT3N0 tumor with seminal vesicle involvement.

On IHC staining, tumor cells were negative for PSA, PSAP, and NKX3.1 but were diffusely positive for CK20, CDX2, and AMACR.

Differential Diagnosis

The differential diagnosis for primary mucinous adenocarcinoma of the prostatic urethra includes:

• Secondary involvement by colon adenocarcinoma—Excluded in these cases because of normal findings on colonoscopy and lack of gastrointestinal symptoms
• Secondary involvement by bladder adenocarcinoma—Ruled out clinically by cystoscopy and pathologically in the cystoprostatourethrectomy specimens
• Mucinous adenocarcinoma of other parts of the urethra—No tumors were noted in other parts of the urethra, such as the membranous or penile urethra
• Prostatic adenocarcinoma with mucin production—Excluded by the IHC findings

An Enigma

It's unclear why brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra behaves less aggressively and has a better prognosis than non–brachytherapy-associated cases. In addition to resulting in carcinogenesis in the prostatic urethra, brachytherapy seeds implanted in the prostatic stroma might alter the gene expression involved in tumor invasion and metastasis, ultimately containing the disease.

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