Kristen R. Scarpato, MD, MPH

(provided by Raoul S. Concepcion, MD, FACS)

To contextualize the rapidly evolving landscape of evaluation of patients with prostate cancer, consider a case example: A 62-year-old White man presents for consultation due to an elevated prostate-specific antigen (PSA) of 8.2 ng/dL that was confirmed on repeat testing. He has no prior values available for comparison.

Symptomatically, he has an American Urological Association symptom score of 11 without other complaints. His past medical history is unremarkable with only hypertension, for which he takes amlodipine 5 mg daily and a baby aspirin. He’s undergone a laparoscopic cholecystectomy. He has no known drug allergies and is married with 2 healthy adult male children. Notably, his family history includes prostate cancer in his father (diagnosed at aged 58 years and alive) and breast cancer in his paternal grandmother (diagnosed at aged 50 years and now deceased from the disease).

On physical examination, the prostate is estimated at 50 grams, symmetric, and without nodules or induration. The patient undergoes a prebiopsy multiparametric MRI scan, which demonstrates a prostate volume of 65.3 cc and a PI-RADS (Prostate Imaging Reporting and Data System) 4 lesion at the right peripheral zone (base, 1.2 cm). He then undergoes a fusion biopsy; the pathologic results show:

Target lesion: 2/3 cores (+), grade group (GG) 4, approximately 65% involved

R base: 2/2 cores (+), GG 4, approximately 70% involved

R mid: 1/2 cores (+, GG 4, < 50% involved

R apex: 1/2 cores (+), GG 3, < 50% involved

L base: 2/2 cores (+) GG 3, approximately 60% involved

This patient has newly diagnosed cT1c prostate cancer, which is very high risk—according to the National Comprehensive Cancer Network (NCCN) criteria—because of the presence of more than 4 cores of GG 4 disease.

As we evaluate this patient, our goal is to accurately determine his current and future risk of disease spread to inform treatment, prognosis, and counseling. Current guidelines recommend staging with conventional imaging (CT or MRI, and bone scan) as well as genetic testing. However, advances in staging imaging are allowing more accurate detection of metastatic disease and play an increasingly large role in other parts of the world, with adoption in the United States expected to follow.

Guideline-concordant conventional imaging in patients with high- and very high–risk disease includes abdominopelvic cross-sectional imaging, often a CT scan, and a technetium-99m methylene diphosphonate bone scintigraphy scan. Multiparametric MRI (mpMRI) has emerged in the past 5 to 10 years as a common staging imaging modality, and NCCN guidelines endorse the superiority of mpMRI compared with abdominopelvic CT for staging.1

For this patient, we would follow a current guideline–based approach and complete his staging with a nuclear medicine bone scan to complement his mpMRI. If the bone scan is negative for evidence of metastasis, he falls into a group of men with apparently localized disease who are at high risk for recurrence despite appropriate primary therapy, likely due to the inability of conventional imaging to identify small metastases at low PSA. Closing this gap in diagnostic accuracy is an area of active research.

Newly published data suggest that advanced imaging techniques using PET-CT may complement or supplant conventional imaging in the near future. The use of PET-CT
in prostate cancer in the US has been led, to date, by the approval of 3 radiotracers in the management of recurrent or metastatic prostate cancer: choline C 11, sodium fluoride F 18, and fluciclovine F 18 (Axumin). Newer prostate-specific membrane antigen (PSMA)–based tracers including gallium 68 (68Ga) and DCFPyL F 18 are increasingly being used, first in Australia and Europe and now in the US. These PSMA-based tracers are the subject of several recent clinical trials that support the diagnostic superiority of PSMA PET-CT over conventional and previously approved advanced imaging modalities.

PSMA is a cell surface glycoprotein that is highly overexpressed in most prostate cancer cells. Multiple recent studies have added to the growing body of evidence supporting the use of PSMA PET-CT across the prostate cancer disease spectrum. The proPSMA study was a multicenter clinical trial of patients with high-risk prostate cancer who were randomized to receive conventional imaging vs 68Ga PSMA PET-CT for the purposes of pretreatment staging.

 The investigators found that 68Ga PSMA PET-CT had a 27% greater area under the curve for diagnostic accuracy when compared with conventional imaging, driven by its improved sensitivity (85% vs 38%) and specificity (98% vs 91%). Use of PSMA PET-CT was more likely to effect a significant change in management versus conventional imaging (28% vs 15%, respectively). For this patient, PSMA PET-CT may be more likely to identify small regional or distant metastatic disease that, if found, may influence our treatment decision.

Although proPSMA compared 68Ga PSMA PET-CT to conventional imaging, Calais et al compared fluciclovine F 18 PET-CT with 68Ga PSMA PET-CT in the biochemical recurrence setting among men with PSA lower than 2 ng/mL.

 The indication for imaging in this study was different from proPSMA. Here, imaging was used to detect recurrent disease, whereas proPSMA examined the pretreatment staging setting. The investigators demonstrated that PSMA PET-CT had higher detection rates at low PSA compared with fluciclovine F 18, adding to the evidence of the superior sensitivity of PSMA-based PET-CT over fluciclovine F 18 PET-CT.

A pair of recently published trials, OSPREY and CONDOR, led to the recent FDA approval of F18-DCFPyL (Pylarify), another novel radiotracer used for PSMA-targeted PET-CT, for both initial staging and biochemically recurrent disease.

The multicenter phase 2/3 OSPREY study enrolled 2 cohorts to evaluate the diagnostic performance of DCFPyL F 18 PET-CT: Cohort A—most relevant to our patient—enrolled men with high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy to assess its accuracy detecting prostate cancer in the pelvic lymph nodes; cohort B enrolled patients with suspected recurrent or metastatic disease on conventional imaging who then underwent tissue biopsy. In cohort A, DCFPyL F 18 PET-CT had a median specificity of 98%, sensitivity of 40%, positive predictive value (PPV) of 87%, and negative predictive value (NPV) of 83% for detecting pelvic nodal involvement. The performance of DCFPyl F 18 PET-CT was superior compared to conventional imaging with CT/MRI by most measures (3-fold higher PPV: 87% vs 28%, respectively), higher specificity (98% vs 65%), slightly higher NPV (83% vs 78%), and similar sensitivity (40% vs 43%).

The multicenter phase 3 CONDOR study enrolled men with biochemical recurrence after definitive therapy with negative or equivocal conventional imaging and again found that DCFPyL F 18 PET-CT had PPV of 80% to 90% and that 64% of participants experienced a change in intended management after undergoing DCFPyL F 18 PET-CT.

There are some advantages and disadvantages to the different radiotracers from a technical perspective that may guide their real-world adoption. First, as highlighted in the data from Calais and colleagues, 68Ga PSMA PET-CT outperforms fluciclovine F 18 PET-CT.

 Further, 68Ga was the first well-described PSMA-based radiotracer and has, therefore, garnered significant research interest. However, 68Ga requires specialized generators with batch production of 2 to 4 patient doses per generator elution and has a physical half-life of approximately 1 hour, which requires studies to be performed locally because central production with delivery to remote centers would be challenging. On the other hand, F 18–labeled PSMA tracers such as DCFPyL F 18 offer some advantages over 68Ga, namely large-scale radiosynthesis, allowing for a larger number of patient studies; a longer half-life of nearly 2 hours, which could enable centralized production with delivery to more remote centers; and increased maximum spatial resolution due to its lower positron energy than 68Ga.

On December 1, 2020, the FDA approved 68Ga PSMA PET-CT for staging in men with prostate cancer with suspected metastasis before initial definitive therapy and in men with biochemical recurrence, although the approval is, at this time, limited to UCLA and UCSF. DCFPyL F 18 (Pylarify) received FDA approval in May 27, 2021. Although, at this time, NCCN guidelines would not recommend the use of these advanced imaging techniques until after conventional imaging is performed and found to be negative, this may be rapidly changing. The dissemination and availability of DCFPyL F 18, expected to reach routine clinical use towards the end of 2021 dependent on identification of regional radiopharmacies to provide radiotracer, is expected to rapidly bring PSMA imaging from sparse research and clinical trial settings to routine clinical use though this will, as always in US health care, depend on insurer reimbursement decisions.

In addition to staging investigations, another important consideration for this patient is the use of genetic testing. For patients with high- or very high–risk disease, NCCN guidelines recommend germline genetic testing, and contemporary testing may offer actionable information for physicians and patients. 

 mutations, if found, may hold prognostic information; studies have demonstrated that prostate cancer patients with 

 mutations have higher Gleason scores, nodal involvement, metastatic disease, and worse survival.

 In patients with metastatic disease, genetic testing for mutations in homologous recombination repair genes is required to determine suitability for treatment with PARP inhibitors, such as olaparib (Lynparza) or rucaparib (Rubraca). In addition, pembrolizumab (Keytruda) is approved for use in tumors with microsatellite instability or mismatch repair–deficiency, so approximately 5% of metastatic castration-resistant prostate cancer cases could qualify.

Genetic testing is also important for family counseling. Relatives of a patient with a known 

 mutation may be at increased risk for breast, ovarian, pancreatic, colon, and prostate cancer. Data from the IMPACT study

 mutations may benefit from annual PSA screening earlier than noncarriers or using a lower PSA cutoff value.

In this case, the patient’s high-risk disease and positive family history of prostate cancer in his father, diagnosed at a relatively young age, may also point toward a genetic predisposition and support the utility of the recommended germline testing. Although access to genetic counseling remains challenging at many centers and has limited broader adoption, its use is guideline recommended and should be a priority for these patients.

The diagnostic and treatment landscape across the spectrum of disease states in prostate cancer continues to rapidly evolve, as highlighted by this case. In the near future, we will hopefully better understand when and how to use these advanced tests as well as the implications for patient outcomes and survival.

 is an assistant professor of urology at the Vanderbilt University Medical Center in Nashville, Tennessee.

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 17, 2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf

2. Hofman MS, Lawrentschuk N, Francis RJ, et al; proPSMA Study Group Collaborators. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. 

2020;395(10231):1208-1216. doi:10.1016/S0140-6736(20)30314-7

3. Calais J, Ceci F, Eiber M, et al. 18 F-fluciclovine PET-CT and 68 Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. 

 2019;20(9):1286-1294. doi:10.1016/S1470-2045(19)30415-2

4. Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate-specific membrane antigen PET/CT with 18 F-DCFPyL in prostate cancer patients (OSPREY). 

 Published online February 26, 2021. doi:10.1097/JU.0000000000001698

5. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic performance of 18 F-DCFPYL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase 3, multicenter study. 

 Published online February 23, 2021. doi:10.1158/1078-0432.CCR-20-4573

6. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.

 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882

7. Eeles RA, Bancroft E, Page E, Castro E, Taylor N. Identification of men with a genetic predisposition to prostate cancer: targeted screening in men at higher genetic risk and controls—The IMPACT study.

. 2013;31(suppl 6):12. doi:10.1200/jco.2013.31.6_suppl.12

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Advances allow for more accurate detection of metastatic disease.

Update on advanced imaging in prostate cancer

For this “Case of the Month” report, 

regarding the usage of renal mass biopsy (RMB) for small renal masses, touching on topics including how to determine the need for an RMB, contraindications to RMB, and how she performs the procedure. Concepcion is chief clinical urologist officer, Integra Connect, West Palm Beach, Florida, and clinical associate professor of urology, Vanderbilt University School of Medicine, Nashville, Tennessee. Scarpato is assistant professor of urology at Vanderbilt University Medical Center, Nashville, Tennessee.

66 y.o. African American male referred for an incidentally discovered solid right renal mass, 2.7 cm, in a work up for back pain. Pre/post contrast 15 HU—> 48 HU. No evidence of fatty attenuation.

PMH: (+) HTN, NIDDM, Atrial Fibrillation, Obesity

Dr Scarpato, this is a scenario we as urologists encounter quite frequently in our everyday practice, the incidentaloma small renal mass (SRM). Would you walk through with us please what is your working definition of a SRM, and what radiographic and clinical factors do you take into account as you are trying to determine the need for a renal mass biopsy (RMB)?

Yes, this is a common scenario in urology clinic, which has coincided with the rise in abdominal cross-sectional imaging. A small renal mass typically refers to growth on the kidney measuring less than 4 cm (T1a),

 and at many centers refers to incidentally detected masses less than 3 cm. The 3-cm cutoff originated in the VHL (von Hippel-Lindau syndrome) literature, which suggests that malignant tumors less than 3 cm have a very low likelihood of metastatic spread. Similarly, data indicate that patients with sporadic tumors less than 3 cm also have a low rate of progression and metastasis.

 When faced with this scenario, it is important to first consider the patient. What is his overall health, and does he have significant cardiac, pulmonary, renal, or other conditions? Does he have risk factors for RCC (renal cell carcinoma) or history of another primary malignancy that may have metastasized? In this patient, his diabetes and renal failure are important considerations when contemplating future renal mass intervention. When considering the mass, it is important to consider tumor location (central vs. peripheral, anterior vs. posterior, medial vs. lateral), endophytic vs. exophytic, size, solid versus cystic consistency, degree of enhancement and vascularity, as well as any significant necrosis. If prior imaging is available, it is helpful to assess growth kinetics over time.

In your opinion, are there any absolute or relative contraindications to RMB?

When counseling the patient, you need to consider the anatomic complexity of the lesion and the implications of the biopsy result on further management. In some patients, it may not be feasible to perform the biopsy due to truncal obesity and significant skin-to-tumor distance. Similarly, in the case of cystic lesions or solid masses in a challenging location, such as those that are medial and upper pole or perihilar, RMB may be relatively contraindicated.

Also, if results are unlikely to change your management plan, I would recommend against biopsy. Although not necessarily a contraindication, it is important to consider patients requiring anticoagulation for periprocedural management if biopsy is being pursued. And finally, historically, tumor seeding was felt to be a contraindication to the procedure. However, this is more of a theoretical risk as tumor seeding of the biopsy tract has not been significantly demonstrated in practice.

Do you differentiate between a solid SRM versus a Bosniak II, III, or IV in your recommendations for RMB?

Yes. This is important when considering RMB. Cystic masses are more challenging to biopsy. For cystic renal masses with higher malignant potential, those that are Bosniak (classification system) III or IV, biopsy is really only feasible if there is a solid component to target. Even then, there is a risk of a non-diagnostic biopsy result, sampling error, or tumor spillage. Generally, when cystic lesions are suspicious for malignancy, we proceed to surgery without attempted biopsy.

At your institution, when you feel a RMB is indicated, are you personally performing the procedure in an office setting or referring these patients to the interventional radiologist (IR) for percutaneous RMB?

At our institution, all RMB for SRMs concerning for cancer are referred to our interventional radiology colleagues. In the IR suite, the interventionalists provide sedation and local anesthesia unless there is a contraindication in which case an anesthesiologist would be involved.

That said, there are certainly urologists who routinely and successfully perform RMB in the office.

 As a specialty, we are facile with ultrasound and the evolution of ultrasound biopsy platforms makes RMB more accessible for us. It is reasonable for urologists who feel comfortable to offer RMB in the office to appropriately selected candidates, particularly those patients with posterior, subcostal lesions.

Obviously depending on site of service, are these best directed with ultrasound, CT, or MRI guidance?

As with most procedures, it comes down to the comfort and experience of the proceduralist and institution. He or she should perform the biopsy in the manner that is most appropriate for him or her. I don’t think one modality has been shown to be superior to the other. Most commonly RMB is performed with CT or ultrasound guidance. Ultrasound may be advantageous for characterization of some lesions, particularly endophytic renal masses, and it avoids contrast exposure, while perhaps being more convenient and cost-effective.

Would you please walk us through operationally the preferred technique you have adopted?

At our institution, patients are most often given sedation and local anesthesia. We are routinely taking core biopsies rather than FNAs (fine needle aspirations) because of the higher diagnostic yield. FNA is often inadequate unless biopsies are performed in conjunction with a cytopathologist on site who can assess the samples immediately. The number of cores taken depends on the quality of the cores, as assessed by the proceduralist. Often, we see 3 to 5 cores per sample. Following the procedure, patients are observed as an outpatient in the radiology suite with close attention to vital signs including pulse oximetry. Some centers may check urinalysis or renal ultrasound prior to discharge5. For complex patients, an overnight stay may be required for additional monitoring.

What are the major complications that have been reported with RMB?

Fortunately, major complications are rare. The literature indicates about a 2% risk of complication overall, with major complications occurring less than 1% of the time.

 Risks include hematoma, pain, infection, with more significant complications of pseudoaneurysm, pneumothorax, and the one we probably all think of first—bleeding. However, even in the face of anticoagulation or antiplatelet medications, the bleeding risk is still quite low. We can’t forget about the risk of nondiagnostic biopsy either, which can occur in up to 15% of RMBs.

Besides histopathology, do you typically send the tissue for any other type of biomarker/genomic testing?

At this point, we are utilizing RMB histopathology results for distinguishing cancer vs noncancer and 

 sending this tissue for biomarker or genomic testing, although that may be the future state, particularly as we learn more about the genomics of RCC. Recent data highlight the impact of determining histologic subtype at the time of RMB, which may have implications on progression.

 We are practicing in the era of precision medicine and personalized care. We are certainly seeing genomics in management of other urologic cancers, like prostate, and in some cases of advanced RCC. However, even for advanced RCC there is a lack of guidance or consensus about the use of genomic testing given the absence of definitive literature.

In your experience, if a patient undergoes RMB and ultimately proceeds to surgical extirpation, have you found the procedure, whether it be open or minimally invasive, to be more difficult due to the inflammation? If so, do you prefer to wait a set period of time before taking the patient to the operating room in hopes that the inflammation will subside?

I am not aware of any literature demonstrating that renal mass biopsy prevents future partial or radical nephrectomy or that it is associated with a higher complication rate. Generally, I would wait a minimum of 4 to 6 weeks from the time of biopsy to allow the patient time to heal. Anecdotally, if a patient develops a bleed with perinephric hematoma following biopsy, the tissue planes can be distorted and the surgery more challenging. In those patients, I may wait longer—months if possible—before proceeding with surgical extirpation.

For our audience, what would you say are the key take-home messages when contemplating percutaneous biopsy for patients with a SRM?

RMB is an important tool in the management of SRMs and should be utilized for patients in whom the results would impact management decisions, typically not the young and healthy or the old and frail. RMB should be performed following shared decision-making.

RMB may be utilized for differentiating benign from malignant tumors but less readily characterizes low grade from high grade. No biomarker or genomic testing is recommended following biopsy of SRMs, although with advancing technology and increasing knowledge of RCC, this is likely on the near horizon.

RMB can be safely performed in the interventional radiology suite or in the urologist’s office depending on physician comfort and experience and SRM characteristics.

Both CT and ultrasound guidance are effective in RMB, with the benefits of ultrasound being potentially improved characterization of endophytic lesions, more readily accessible technology, and cost savings.

1. Campbell S, Uzzo RG, Allaf ME, et al. Renal mass and localized renal cancer: AUA guideline. 

 2017;198(3):520–529. doi:10.1016/j.juro.2017.04.100

2. Crispen PL, Viterbo R, Boorjian S, et al. Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. 

 2009;115(13);2844-2852. doi:10.1002/cncr.24338

3. Frank I, Blute ML, Cheville JC, et al. Solid renal tumors: an analysis of pathological features related to tumor size.

. 2003;170(6 Pt 1):2217-2220. doi:10.1097/01.ju.0000095475.12515.5e

4. Dave CN, Seifman B, Chennamsetty A, et al. Office-based ultrasound-guided renal core biopsy is safe and efficacious in the management of small renal masses. 

 2017;102:26–30. doi:10.1016/j.urology.2016.12.026

5. Dutta R, Okhunov Z, Vernez SL, et al. Cost comparisons between different techniques of percutaneous renal biopsy for small renal masses. 

 2016;30(suppl 1):S28-33. doi:10.1089/end.2016.0015

6. Posielski NM, Bui A, Wells SA, et al. Risk factors for complications and nondiagnostic results following 1,155 consecutive percutaneous core renal mass biopsies.

 2019;201(6):1080-1087. doi:10.1097/JU.0000000000000113

7. Finelli A, Cheung DC, Al-Matar A, et al. Small renal mass surveillance: histology-specific growth rates in a biopsy characterized cohort. 

2020;78(3):460-467. doi:10.1016/j.eururo.2020.06.053

Renal mass biopsy should be used for patients in whom results would impact management decisions.

Kristen R. Scarpato, MD, MPH

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