Mucin‐producing urothelial‐type adenocarcinoma of the prostate with sarcomatoid features and novel molecular phenotype

Introduction Mucin‐producing urothelial‐type adenocarcinoma of the prostate is a rare tumor that may not elevate serum prostate‐specific antigen, creating significant diagnostic and monitoring challenges. We evaluate our case in detail and review prior studies to demonstrate that the pathologic and molecular features of this tumor are distinct from conventional prostate adenocarcinoma. Case presentation Our patient had a remote history of radiation‐treated conventional prostate adenocarcinoma and presented many years later with an abscess‐like prostate mass leading to urinary obstruction and hematuria. Biopsy revealed mucin‐producing urothelial‐type adenocarcinoma of the prostate with concurrent sarcomatoid features. Molecular studies showed a unique phenotype involving alterations in the KRAS, PTEN, RAD21, and TP53 genes. Conclusions To our knowledge, this is the first report that describes sarcomatoid features and molecular mutations in mucin‐producing urothelial‐type adenocarcinoma of the prostate.


Introduction
Mucin-producing urothelial-type adenocarcinoma of the prostate is a very rare entity that typically develops in the prostatic urethra or proximal large ducts of the prostate. 1Appropriate workup of these tumors is important on limited biopsy samples, mainly because they do not express PSA and have significant morphologic and immunohistochemical overlap with the more commonly seen entities like conventional prostate adenocarcinoma with mucin production and secondary adenocarcinoma from urinary bladder or colorectal origin.
Our patient had a remote history of radiation-treated conventional prostate adenocarcinoma and presented years later with obstructive urinary symptoms and hematuria due to an abscess-like prostate mass.Upon clinical suspicion of recurrent prostate adenocarcinoma, the mass was biopsied and revealed mucin-producing urothelial-type adenocarcinoma of the prostate showing infiltrative atypical glandular cells containing intracytoplasmic mucin, sarcomatoid areas of tumor cells, negative PSA and NKX3.1, and alterations in the KRAS, PTEN, RAD21, and TP53 genes.levels presented with hematuria and obstructive urinary retention which required catheterization.Imaging studies showed an abscess-like mass involving the prostate gland bilaterally and rapidly rising PSA (4.39 ng/mL), suspicious for locally/ regionally recurrent prostate cancer (Fig. 1).The colon and urinary bladder showed no evidence of masses.
Following androgen deprivation therapy (ADT), he had an undetectable serum PSA, but his pelvic/urethral pain and discomfort had worsened.Given the lack of clinical improvement after a favorable PSA response, a restaging CT scan of the abdomen and pelvis demonstrated an increased size of the prostate mass.Overall, the findings were worrisome for a non-conventional malignancy-the differential diagnoses included small cell carcinoma, sarcoma, and secondary metastasis to the prostate gland.

Pathologic evaluation
A transrectal ultrasound-guided biopsy targeting six different areas of the prostate gland (bilateral apex, mid, and base) along with the designated lesion was obtained.The tumor involving all the above sites was consistent with mucinproducing urothelial-type adenocarcinoma of the prostate.Atypical columnar to cuboidal glandular cells containing intracytoplasmic mucin were seen infiltrating the prostate gland (Fig. 2a,b-arrows).Occasional complex glandular forms, pleomorphic single cells with hyperchromatic nuclei, and apoptotic bodies were seen (Fig. 2c, arrows).Interestingly, multifocal areas of differentiation into sarcomatoid morphology closely mixed with the adenocarcinoma were noted (Fig. 2a, arrowheads and inset box).A minor component (<5%) of conventional prostate adenocarcinoma with therapy-related effect was seen focally, which was morphologically and immunohistochemically distinct from the dominant tumor.Notably, no urothelial carcinoma in situ or urothelial carcinoma was identified.On immunohistochemistry, the adenocarcinoma cells from the dominant tumor were positive for keratin AE1/AE3, cytokeratin 7 (CK7), carcinoembryonic antigen (CEA), and CK20 (rare positive), whereas they were negative for PSA and NKX3.1.Secondary metastases from other organs like colon, lung, and kidneys were excluded by negative staining for CDX2, SATB2, TTF-1, and PAX8.The sarcomatoid areas were negative for all the cytokeratin immunostains.The expanded immunohistochemical staining performed is summarized in Table 1.Molecular studies performed on the tumor revealed microsatellite stability and alterations involving the following genes-KRAS (Q61L missense substitution; variant allele frequency 39.7%), PTEN (splice site 210-2A > C; variant allele frequency 41.6%), RAD21 amplification, and TP53 (C135fs*35 deletion-frameshift; variant allele frequency 41.7%).

Follow-up
By four cycles of chemotherapy, he had radiologic improvement of tumor.At 12 months, the patient's scan redemonstrated local progression that led to a transurethral resection (TUR) of the tumor which showed predominant high-grade sarcomatoid areas (Fig. 2d), morphologically like the previous biopsy.The patient is currently treated with pembrolizumab (anti-PD1 antibody) with stable disease, subject to regular surveillance (radiologic and cystoscopic) and supportive care.

Discussion
Mucin-producing urothelial-type adenocarcinoma of the prostate arises from the prostatic urethra and large prostatic ducts. 1 Other entities in the differential diagnosis like primary prostatic adenocarcinoma with mucin production and secondary metastasis from primary bladder or colonic origin are more commonly encountered.Data on these cases are very limited, and ongoing effort via case studies provides an improved understanding of this entity [1][2][3][4][5][6][7][8][9][10][11] (Table 2).Most patients with this tumor present with urinary obstruction, dysuria, hematuria, and mucosuria.Serum PSA values are generally less than 1.5 ng/mL, [12][13][14] a sign of the tumor's origin from prostatic urethral epithelium rather than prostatic luminal cells, although some patients have shown elevated serum PSA (greater than 10 ng/mL). 4,5Our case also showed elevated PSA with a favorable biochemical response to ADT, which is explained by co-existing minor foci of conventional prostate adenocarcinoma demonstrating therapy-related change, a finding that has been reported before. 8istologically, the tumor shows atypical, tall, pseudostratified columnar cells (likely arising from glandular metaplasia of the prostatic urethra or proximal prostatic ducts) infiltrating the stroma.5][6][7] The traditional Gleason scoring system used for prostatic adenocarcinoma does not apply to this entity as it is not derived from prostatic ducts or acini.It differs from mucinous adenocarcinoma of the prostate which often shows cords of cuboidal epithelium and cribriform glands with low-intermediate grade cytology and tumor cells floating in pools of extracellular mucin. 9Differentiating non-urachal adenocarcinoma of the bladder is a greater challenge, and involves relying on clinical, radiological, and cystoscopic examination. 2In our case, radiologic studies ruled out any bladder masses, and histologically we did not encounter areas of urothelial carcinoma in situ or urothelial carcinoma that may have diverged or differentiated into glands.
Our case validates the previously described morphology, immunophenotype, and reports novel molecular alterations.While most prior cases have diagnosed this entity on resection specimens, the morphologic and immunohistochemical features seen in our case were supportive of the diagnosis on a biopsy and TUR specimen.Additionally, alterations involving the KRAS, PTEN, RAD21, and TP53 genes were identified.KRAS mutations are commonly seen in gastrointestinal, lung, and a subset of bladder adenocarcinomas, 15 while PTEN alterations are seen in gynecologic tumors (breast, ovaries, and endometrium) and inherited PTEN hamartoma tumor syndromes. 16RAD21 amplification is shown to correlate with poor prognosis in breast, endometrial, KRAS-mutant colorectal, and hormone-resistant prostate cancers, [17][18][19] while TP53 mutations are common in many advanced cancers. 20It was interesting to note that the molecular phenotype of this tumor aligned with bladder or colorectal adenocarcinomas and was comparatively distinct from reported phenotypes in conventional prostate adenocarcinoma.
Prognosis, optimal therapy, and survival data in patients diagnosed with this tumor are under-studied.Hormonal therapy may be valuable in cases that have concomitant conventional prostate cancer; however, our patient's dominant tumor did not respond to ADT.Surgical resection, chemoradiation, and targeted therapies remain viable options.Of the identified alterations, KRAS, PTEN, and TP53 have potential targeted therapies, and ongoing clinical trials in different tumors continue to assess the efficacy of these agents.KRAS Table 1 Extended immunohistochemistry panel performed on the patient's tumor to establish a diagnosis of mucin-producing urothelial-type adenocarcinoma of the prostate NP, not performed; P, patchy; R, rare; RE, retained; SC, sarcomatoid areas; UTA, mucin-producing urothelial-type adenocarcinoma.mutations may predict sensitivity to MEK inhibitors, leading to better response rates in lung tumors. 21Tumors with PTEN alterations may respond to mTOR and PARP inhibitors, which have demonstrated benefits in gynecologic tumors. 22,23Head and neck, gynecologic, and gastrointestinal tumors with TP53 mutations have shown benefit with chemotherapy regimens combined with WEE1 inhibitor. 24,25astly, immunotherapy agents like anti-PD1 antibodies have shown promise in advanced/high-grade urothelial tumors 26 and are currently being explored as therapeutic options in our case.Given that ours is the first report to describe the molecular phenotype of this rare entity, the above-targeted therapies are of potential value, however, the effectiveness remains to be known.

Conclusions
Diagnosis, optimal therapy, and survival data in mucinproducing urothelial-type adenocarcinoma of the prostate are under-studied.We contribute to the understanding of its clinical features, histologic spectrum, and unique molecular characteristics.

Fig. 1
Fig.1Radiological assessment of the prostate gland mass.PET scans in sagittal, axial, and coronal (left to right) planes demonstrate radiotracer uptake in the prostate gland.

Fig. 2
Fig. 2 Morphology of mucin-producing urothelial-type adenocarcinoma of the prostate.Atypical columnar to cuboidal glandular cells containing intracytoplasmic mucin were seen infiltrating the prostate gland (a,b-arrows).The area with sarcomatoid differentiation was closely mixed with the adenocarcinoma (a, arrowheads and inset box).Pleomorphic areas of tumor cells were noted (c, arrows).Subsequent transurethral resection of the tumor demonstrating sarcomatoid areas is shown in (d).Digitally scanned H&E stained slides, 209 magnification; (a) inset box and (d), 409 magnification (Aperio GT 450, Leica Biosystems).

Table 2
Review of the findings from prior case studies on mucin-producing urothelial-type adenocarcinoma of the prostate

Table 2 (
Continued) , immunohistochemistry; N/A, not available.*Chemotherapeuticagents used in the above studies: Current study-carboplatin and paclitaxel, Sebesta et al.-capecitabine, Kawasaki et al.-gemcitabine and cisplatin, Shimizu et al.-capecitabine and oxaliplatin.**Oneprior study (Peak et al.) reported that their patient was treated with radiation therapy for conventional prostate cancer and developed mucin-producing urothelial-type adenocarcinoma of the prostate many years later. IHC