Disclosures I have nothing to disclose APPLICATION OF - - PowerPoint PPT Presentation

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APPLICATION OF IMMUNOHISTOCHEMISTRY TO CHALLENGING UROLOGIC PATHOLOGY CASES

Bradley Stohr, MD, PhD Assistant Professor, UCSF Pathology

Disclosures

I have nothing to disclose

bradley.stohr@ucsf.edu

Outline

The prostate/bladder interface Advanced prostate cancer Another urothelial mimic

Bladder Prostate Urethra

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Urinary bladder TUR from 70-year-old man

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Diagnosis

Urothelial carcinoma, with invasion of lamina

propria and muscularis propria

IHC panel

Urothelial markers Prostate markers 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 p63 Benign urothelium Tumor

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High molecular weight keratin Benign urothelium Tumor GATA-3 Benign urothelium Tumor PSAP Benign urothelium Tumor P501S Benign urothelium Tumor

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Diagnosis

Poorly differentiated carcinoma Comment: Most consistent with prostatic

adenocarcinoma

Points of emphasis

History is essential as prostate cancer, especially

post treatment, can exhibit a variety of morphologic appearances

Staining for prostate-specific markers such as PSA,

PSAP , and P501S can be decreased or absent in poorly differentiated prostate cancer

Points of emphasis

High sensitivity antibody (90% positive across all prostatic adenocarcinomas) Typical use case TUR from 67-year-old man

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p63 High molecular weight keratin

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PSA

Diagnosis

High-grade urothelial carcinoma with squamous

differentiation, invasive into muscularis propria

New information after signout

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…

UCSF500 Tumor Sequencing

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UCSF500 Results for this Patient

TMPRSS2/ERG fusion FOXA1 frameshift CDKN2A/B deletion

UCSF500 Results for this Patient

First sequencing round Second sequencing round

Diagnosis

Prostatic carcinoma with extensive squamous

differentiation

Prostate cancer with squamous features

Parwani et al. AJSP 2004;28:651. 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

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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

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Benign prostate Tumor CK7 Benign prostate Tumor CK20 Benign prostate Tumor p63 Benign prostate Tumor

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GATA-3 Benign prostate Tumor uroplakin II Benign prostate Tumor PSAP Benign prostate Tumor

Diagnosis

High-grade urothelial carcinoma

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Points of emphasis

The clinical presentation of prostatic

adenocarcinoma and urothelial carcinoma can

• verlap

TURP from 67-year-old man

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p63 Benign prostate Tumor High molecular weight keratin Benign prostate Tumor PSA Benign prostate Tumor

Diagnosis

Ductal adenocarcinoma of the prostate, Gleason

score 4+5=9

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Subsequent course

Patient received definitive therapy for prostate

cancer (external beam radiation plus hormone therapy)

Bladder biopsies showed high-grade papillary

urothelial carcinoma GATA-3 Benign prostate Tumor

Diagnosis

Urothelial carcinoma in situ colonizing prostatic

ducts, with focal invasion into prostatic stroma

Clinical follow-up

Patient subsequently underwent cystoprostatectomy,

which showed urothelial carcinoma involving the bladder, prostate, and multiple regional lymph nodes

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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

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Points of emphasis

Beware the prostate/bladder interface IHC can be useful IHC can also be misleading, particularly in the

setting of aberrant differentiation (e.g. squamous)

Outline

The prostate/bladder interface Advanced prostate cancer Another urothelial mimic

Prostate TUR from 50-year-old man GATA-3 P501S NKX3.1

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Liver biopsy from same patient TTF-1 Synaptophysin Chromogranin NKX3.1

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Diagnosis

Prostate: Prostatic adenocarcinoma, Gleason score

4+5=9

Liver: Metastatic small cell lung carcinoma

Subsequent findings

Clinician noted the absence of a lung mass and

requested additional pathology review

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P501S PSAP chromogranin

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synaptophysin

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

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

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PSA PSAP P501S chromogranin synaptophysin TTF-1

UCSF500 Results for this Patient

TMPRSS2/ERG fusion

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TURP from 67-year-old man

Diagnosis

Prostatic adenocarcinoma PSA staining was very strong, urothelial markers were

weak to absent

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MSH2 MSH6 MLH1 PMS2

Diagnosis

Prostatic adenocarcinoma with mismatch repair

deficiency

MMR-deficient prostate cancer

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 loss – UCSF500

MSH2/MSH6

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Checkpoint inhibitors

Tumor cell T cell TCR MHC PD-1 PD-L1

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

immunotherapy response

Points of emphasis

Advanced prostate cancer can develop an MMR-

deficient, microsatellite unstable phenotype

These tumors are likely to show improved response

to immunotherapy

IHC can identify many of these tumors, but unclear

when to use (reportedly no characteristic morphologic pattern)

Outline

The prostate/bladder interface Advanced prostate cancer Another urothelial mimic

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TURBT from 56-year-old woman

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Diagnosis

High-grade urothelial carcinoma with

micropapillary features and invasion of muscularis propria

Subsequent findings

UCSF urologist mentioned that the original urologist

who performed the TUR felt that the mass was not typical for urothelial carcinoma

We requested block for additional work-up

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p63

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pankeratin chromogranin synaptophysin GATA-3

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Diagnosis

Bladder paraganglioma

Clinical follow-up

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

Very rare tumor (<0.05% of bladder tumors) ~10% show malignant behavior A well-recognized mimic of urothelial carcinoma

(Zhou et al. AJSP 2004;28:94)

Muscularis propria involvement Nuclear atypia Cautery artifact

Points of emphasis

Clinical history can be essential Beware cautery artifact Don’t forget the rare diagnoses GATA-3 can be helpful but stains a lot of entities,

including paraganglioma

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