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5/25/2017 Disclosures � I have nothing to disclose APPLICATION OF IMMUNOHISTOCHEMISTRY TO CHALLENGING UROLOGIC PATHOLOGY CASES bradley.stohr@ucsf.edu Bradley Stohr, MD, PhD Assistant Professor, UCSF Pathology Outline Bladder � The prostate/bladder interface � Advanced prostate cancer � Another urothelial mimic Prostate Urethra 1

5/25/2017 Urinary bladder TUR from 70-year-old man 2

5/25/2017 Diagnosis IHC panel � Urothelial carcinoma, with invasion of lamina Urothelial markers Prostate markers propria and muscularis propria p63 PSA HMWK (34BE12, CK903) PSAP GATA-3 P501S Uroplakin (NKX3.1) Thrombomodulin Useful reference: Amin et al. Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology Consensus Conference. AJSP 2014;38:1017-1022. Benign urothelium Tumor Benign urothelium Tumor p63 3

5/25/2017 Benign urothelium Tumor Benign urothelium Tumor High molecular weight keratin GATA-3 Benign urothelium Tumor Benign urothelium Tumor PSAP P501S 4

5/25/2017 Diagnosis Points of emphasis � Poorly differentiated carcinoma � History is essential as prostate cancer, especially post treatment, can exhibit a variety of morphologic � Comment: Most consistent with prostatic appearances adenocarcinoma � Staining for prostate-specific markers such as PSA, PSAP , and P501S can be decreased or absent in poorly differentiated prostate cancer Points of emphasis Typical use case High sensitivity antibody (90% positive across all prostatic adenocarcinomas) TUR from 67-year-old man 5

5/25/2017 p63 High molecular weight keratin 6

5/25/2017 Diagnosis � High-grade urothelial carcinoma with squamous differentiation, invasive into muscularis propria PSA New information after signout UCSF500 Tumor Sequencing � First, clinician immediately called – no papillary tumor seen at cystoscopy, seemed to be mass pushing into bladder � Second, the tumor was sent for UCSF500 sequencing… 7

5/25/2017 UCSF500 Results for this Patient UCSF500 Results for this Patient FOXA1 frameshift CDKN2A/B deletion TMPRSS2/ERG fusion First sequencing round Second sequencing round Diagnosis Prostate cancer with squamous features � Prostatic carcinoma with extensive squamous � Parwani et al. AJSP 2004;28:651. differentiation � Often post-treatment � Can show pure squamous morphology or mixed adenosquamous morphology � “Whereas the adenocarcinoma component is typically high grade, the squamous component has a wide range of differentiation.” � Squamous component usually negative for PSA and PSAP and positive for HMWK 8

5/25/2017 Points of emphasis � Clinical history is essential � Clinical impression can be helpful � In cases with aberrant differentiation, IHC patterns can be dramatically altered Prostate biopsy from 69-year-old man 9

5/25/2017 Benign prostate Tumor Benign prostate Tumor CK7 Benign prostate Tumor Benign prostate Tumor CK20 p63 10

5/25/2017 Benign prostate Tumor Benign prostate Tumor GATA-3 uroplakin II Benign prostate Tumor Diagnosis � High-grade urothelial carcinoma PSAP 11

5/25/2017 Points of emphasis � The clinical presentation of prostatic adenocarcinoma and urothelial carcinoma can overlap TURP from 67-year-old man 12

5/25/2017 Benign prostate Tumor Benign prostate Tumor p63 High molecular weight keratin Benign prostate Tumor Diagnosis � Ductal adenocarcinoma of the prostate, Gleason score 4+5=9 PSA 13

5/25/2017 Subsequent course Benign prostate Tumor � Patient received definitive therapy for prostate cancer (external beam radiation plus hormone therapy) � Bladder biopsies showed high-grade papillary urothelial carcinoma GATA-3 Diagnosis Clinical follow-up � Urothelial carcinoma in situ colonizing prostatic � Patient subsequently underwent cystoprostatectomy, ducts, with focal invasion into prostatic stroma which showed urothelial carcinoma involving the bladder, prostate, and multiple regional lymph nodes 14

5/25/2017 Points of emphasis � Urothelial carcinoma can spread through the prostatic ducts and simulate high-grade prostatic adenocarcinoma � An extended IHC panel may be warranted, as staining can be patchy � The treatment options for urothelial and prostate carcinoma are very different Cystoprostatectomy from 67-year-old man Prostate triple stain (HMWK, p63, AMACR) P501S 15

5/25/2017 Points of emphasis Outline � Beware the prostate/bladder interface � The prostate/bladder interface � IHC can be useful � Advanced prostate cancer � IHC can also be misleading, particularly in the � Another urothelial mimic setting of aberrant differentiation (e.g. squamous) Prostate TUR from 50-year-old man GATA-3 P501S NKX3.1 16

5/25/2017 Liver biopsy from same patient TTF-1 Synaptophysin Chromogranin NKX3.1 17

5/25/2017 Diagnosis Subsequent findings � Prostate: Prostatic adenocarcinoma, Gleason score � Clinician noted the absence of a lung mass and 4+5=9 requested additional pathology review � Liver: Metastatic small cell lung carcinoma 18

5/25/2017 P501S PSAP chromogranin 19

5/25/2017 Diagnosis � Prostate � Prostatic adenocarcinoma, Gleason score 4+5=9 � Small focus of tumor highly suspicious for small cell neuroendocrine carcinoma � Liver � Metastatic small cell neuroendocrine carcinoma � Prostatic origin most likely � Cannot formally exclude another site of origin synaptophysin Points of emphasis � Prostatic small cell carcinoma is rare (~1% of cases), but incidence is much higher in treated patients with advanced disease � It may be a small component of the tumor � Clinically aggressive tumor with poor prognosis � Most cases are negative for PSA, PSAP , and NKX3.1 � More than half are positive for TTF-1 Liver biopsy from 66-year-old man 20

5/25/2017 PSA PSAP P501S UCSF500 Results for this Patient TMPRSS2/ERG fusion chromogranin synaptophysin TTF-1 21

5/25/2017 TURP from 67-year-old man Diagnosis � Prostatic adenocarcinoma � PSA staining was very strong, urothelial markers were weak to absent 22

5/25/2017 Diagnosis � Prostatic adenocarcinoma with mismatch repair deficiency MSH2 MLH1 MSH6 PMS2 MMR-deficient prostate cancer MSH2/MSH6 loss – UCSF500 � 7/60 (12%) advanced prostate cancers are hypermutated, with MMR gene mutations and MSI � Pritchard et al. Nature Communications 2014;5:4988. � Usually due to complex MSH2 and MSH6 mutations MSH2/MSH6 23

5/25/2017 Checkpoint inhibitors Checkpoint inhibitors � Disease control rate with MMR deficiency: ~90% � Le et al. NEJM 2015;372:2509. � Disease control rate with wild-type MMR: ~10% � Putative mechanism: more neoantigens = improved MHC TCR immunotherapy response Tumor cell T cell PD-L1 PD-1 Points of emphasis Outline � Advanced prostate cancer can develop an MMR- � The prostate/bladder interface deficient, microsatellite unstable phenotype � Advanced prostate cancer � These tumors are likely to show improved response � Another urothelial mimic to immunotherapy � IHC can identify many of these tumors, but unclear when to use (reportedly no characteristic morphologic pattern) 24

5/25/2017 TURBT from 56-year-old woman 25

5/25/2017 Diagnosis Subsequent findings � High-grade urothelial carcinoma with � UCSF urologist mentioned that the original urologist micropapillary features and invasion of muscularis who performed the TUR felt that the mass was not propria typical for urothelial carcinoma � We requested block for additional work-up 26

5/25/2017 p63 27

5/25/2017 pankeratin chromogranin synaptophysin GATA-3 28

5/25/2017 Diagnosis Clinical follow-up � Bladder paraganglioma � Neoadjuvant chemotherapy and cystoprostatectomy canceled � Repeat TURBT negative for residual tumor � Patient chose surveillance over partial cystectomy � Resolution of episodic attacks (palpitations, sweating, headaches, heat intolerance) Bladder paraganglioma Points of emphasis � Very rare tumor (<0.05% of bladder tumors) � Clinical history can be essential � ~10% show malignant behavior � Beware cautery artifact � A well-recognized mimic of urothelial carcinoma � Don’t forget the rare diagnoses (Zhou et al. AJSP 2004;28:94) � GATA-3 can be helpful but stains a lot of entities, � Muscularis propria involvement including paraganglioma � Nuclear atypia � Cautery artifact 29

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