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UROLOGICAL DIAGNOSIS AND IMAGING

Official Journal of S.I.E.U.N. EDITOR in CHIEF Andrea B. Galosi, Ancona (IT)

CO-EDITOR Pasquale Martino, Bari (IT)

ASSISTANT EDITOR Lucio Dell’Atti, Ancona (IT)

EDITORIAL BOARD Urology Ahmed Hashim, London (GB), Artibani Walter, Verona (IT) Battaglia Michele, Bari (IT), Bucci Stefano, Trieste (IT) Carini Marco, Firenze (IT), Carrieri Giuseppe, Foggia (IT) De Nunzio Cosimo, Roma (IT), Fandella Andrea, Treviso (IT) Ficarra Vincenzo, Messina (IT), Finazzi Agrò Enrico, Roma (IT) Franzese Corrado, Nola (IT), Gunelli Roberta, Forlì (IT) Kastner Christof, Cambridge (GB), Lapini Alberto, Firenze (IT) Miano Roberto, Roma (IT), Mirone Vincenzo, Napoli (IT) Montorsi Francesco, Milano (IT), Morgia Giuseppe, Catania (IT) Muller Stefan, Bonn (GE), Palazzo Silvano, Bari (IT) Pavlovich Christian, Baltimore, Maryland (USA) Pepe Pietro, Catania (IT), Rocco Bernardo, Modena (IT) Salomon George, Hamburg (GE) Schiavina Riccardo, Bologna (IT), Scattoni Vincenzo, Milano (IT) Volpe Alessandro, Novara (IT), Waltz Joachen, Marseille (FR)

Andrology Bettocchi Carlo, Bari (IT), Bitelli Marco, Roma (IT) Cai Tommaso, Trento (IT), Cormio Luigi, Foggia (IT) Fusco Ferdinando, Napoli (IT), Gontero Paolo, Torino (IT) Liguori Giovanni, Trieste (IT), Lotti Francesco, Firenze (IT) Pizzocaro Alessandro, Milano (IT), Trombetta Carlo, Trieste (IT)

Nephrology Boscutti Giuliano, Trieste (IT), D’Amelio Alessandro, Lecce (IT), Fiorini Fulvio, Rovigo (IT), Gesualdo Loreto, Bari (IT), Granata Antonio, Agrigento (IT), Ranghino Andrea, Ancona (IT)

Radiology Barozzi Libero, Bologna (IT), Bertolotto Michele, Trieste (IT) Giuseppetti Gian Marco, Ancona (IT), Giovagnoni Andrea, Ancona (IT), Valentino Massimo, Tolmezzo (IT)

Pathology Beltran Antonio Lopez, Lisbon (PT) Fiorentino Michelangelo, Bologna (IT) Liang Cheng, Indianapolis (USA), Montironi Rodolfo, Ancona (IT)

Bio-Medical Engineering Wijkstra Hessel, Eindhoven (NL) Advances in Urological Diagnosis and Imaging - 2020; 3, 2

Official Journal of S.I.E.U.N.

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Contents 47

Lucio Dell’Atti

The emerging role of high-resolution transrectal micro-ultrasound in prostate cancer detection: A narrative review Simone Scarcella, Lucio Dell’Atti, Giulio Milanese, Gianluca Giannarini, Andrea Galosi

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Imaging study of acute renal colic in Emergency Department during the COVID-19 pandemic

Incidental diagnosis of primary lung cancer with choline PET/CT in a patient affected by prostate cancer: Changing of treatment strategies Cristina Mariucci, Fabiola Patani, Francesco Fenu, Andrea Benedetto Galosi, Giovanna Mantello

Pararectal lymph node metastases in prostate cancer patients: Report of two cases Fabiola Patani, Cristina Mariucci, Francesco Fenu, Andrea Benedetto Galosi, Giovanna Mantello

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Advances in Urological Diagnosis and Imaging - 2020; 3, 2

EDITORIAL

Imaging study of acute renal colic in Emergency Department during the COVID-19 pandemic Lucio Dellâ&#x20AC;&#x2122;Atti Department of Urology, University Hospital â&#x20AC;&#x153;Ospedali Riunitiâ&#x20AC;?, Marche Polytechnic University, Ancona, Italy.

The coronavirus pandemic is an ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak was first noted in Wuhan, Hubei province, China, in December 2019. The World Health Organization (WHO) declared the outbreak to be a Public Health Emergency of International Concern on 30 January 2020 and recognized it as a pandemic on 11 March 2020. As of 15 September 2020, more than 29.2 million cases have been reported across 188 countries and territories with more than 928,000 deaths; more than 19.8 million people have recovered (1). World Health Organization and the major European and American public health organizations, are recommending cancellations of elective surgeries in hospitals in geographic COVID-19 hotspots. De-escalation of surgical activity should depend on the emergency status of individual health care systems and what each hospital requires from urological departments (2, 3). Institutional directives for patient care protocols were adapted to the Emergency Departments. Patients were screened for pertinent symptoms, travel history and exposure to individuals with known COVID-19. Based upon these answers, patients were scheduled for their examinations or directed to the urgent care program (4, 5). There are over 2 million annual emergency department visits for suspected renal colic in the United States, and computed tomography (CT) scanning is now performed in more than 90% of patients diagnosed with kidney stones. Despite a dramatic increase in CT use for diagnosis over the last 2 decades, patient-centered outcomes such as admission and intervention do not seem to have been impacted. The evidence suggests that in many cases, ultrasound, either radiology performed or point-of-care, may provide adequate diagnostic information to guide initial treatment (6). Doctors typically diagnose kidney stones based on a physical exam, signs and symptoms (such as blood in the urine and difficulty urinating, among others), and imaging tests. Imaging tests that examine the kidneys, the bladder, and the ureters help doctors identify stones. For many years the standard of care was a type of abdominal x-ray called an intravenous pyelogram. In most medical hospitals, this

has been replaced by a type of CT called unenhanced helical CT scanning with or without radiocontrast. In some cases, such as when a person has impaired renal function or a contrast dye allergy, abdominal ultrasound may be used as an alternative (7). The primary outcome of Emergency Departments is mixing between healthy patients and patients affected by COVID-19. The secondary outcomes are length of stay, amount of analgesics, proportion of patients with diseases other than ureteral calculus, and proportion of patients with unexpected Emergency Departments revisits within 14 days from the index visit. The use of bedside ultrasonography for renal colic has increased in recent years. Its advantage over other diagnostic imaging modalities is that it has no radiation hazards (8, 9). Ultrasonography (US) has also been considered inferior to CT in the assessment of the size of the stones. US tends to overestimate the size of stones, particularly the smaller stones.This has huge implications in management decisions with respect to smaller calculi. Overestimation of stone size leads to surgery for stones which would have been managed conservatively had the accurate size of the stone known previously. At present, CT is the gold standard for a patient suspected to have stone disease. Accurate estimation of stone size has major implications in clinical decision making. There are factors that can be adjusted to increase the accuracy of stone measurement (10, 11). A new mode in US termed as S mode or stone-specific mode which helps in identifying the difference between the stone and the surrounding structures in an accurate way. The settings for S mode US are increased frequency and a high scanning line density. The S mode US increases the sensitivity compared with the traditional B mode (11). The use of acoustic shadow width has recently been analyzed and has been shown to increase the accuracy of stone dimensions. Some radiologists found that measuring of the width of the stone shadow was a more accurate measure than measuring the actual stone on US, and this method improves the accuracy to near CT images (10). The twinkling artifact shows as a rapidly alternating colorDoppler signal that imitates turbulent flow, often discovered behind a strongly reflecting stationary irregular interface, such as a kidney calculus. It is the appearance of colors Advances in Urological Diagnosis and Imaging - 2020; 3,2

L. Dell’Atti

in a mixed pattern in Doppler. However, a Doppler spectrum of the area of twinkling shows only a heterogeneous broadband aliasing signal consistent with noise produced by the reflected signal. The twinkling artifact occurs with urinary tract calculi and parenchymal calcifications, but it can also be observed with no calcified biliary calculi and any material with an irregular, rough, or reflective surface. Evaluation of the twinkling artifact is a complementary technique to standard gray-scale shadowing of calculi and improves detection of urolithiasis on sonography (12, 13). The main advantage of US over CT is its reduced cost, absence of radiation, and portability in a bedside contest (11). US is an ideal first-line imaging modality for nephrolithiasis due to its advantages such as low cost, absence of radiation, and easy availability in ED. Accurate estimation of stone size has major implications in clinical decision making. There are factors that can be adjusted to increase the accuracy of stone measurement. The main factors that help in improving the accuracy are changes in gain and depth and alternate modes such as flash angle imaging, S mode and twinkling artifact. It is important to reduce the number of hospitalized patients and screen all of them before admission to the urologic department for an urgent care program in COVID-19 era. Hospitals should be prepared to face severe disruptions in their routine. It is very likely that protocols and procedures will require revision and updates on a daily basis.

ow width to determine kidney stone size with ultrasound. J Urol. 2016; 195(1):171-177. 12. Rahmouni A. Bargoin R, Herment A, Bargoin N, Vasile N. Color Doppler twinkling artifact in hyperechoic regions.Radiology.1996; 199:269-271. 13. Vijayakumar M, Ganpule A, Singh A, et al. Review of techniques for ultrasonic determination of kidney stone size. Res Rep Urol. 2018; 10:57-61.

REFERENCES 1. https://documenter.getpostman.com/view/1794236/SzYW2f4S?version=latest 2. Carenzo L, Costantini E, Greco M, et al. Hospital surge capacity in a tertiary emergency referral centre during the COVID-19 outbreak in Italy. Anaesthesia. 2020; 75:928-934. 3. Angelico R, Trapani S, Manzia TM, et al. The COVID-19 outbreak in Italy: initial implications for organ transplantation programs. Am J Transplant. 2020; 20:1780-1784. 4. Tolia VM, Chan TC, Castillo EM. Preliminary Results of Initial Testing for Coronavirus (COVID-19) in the Emergency Department. West J Emerg Med. 2020; 27;21:503-506. 5. Cao Y, Li Q, Chen J, et al. Hospital Emergency Management Plan During the COVID-19 Epidemic. Acad Emerg Med. 2020. doi: 10.1111/acem.13951. [Epub ahead of print] 6. Fwu C, Eggers P, Kimmel P, et al. Emergency room visits, use of imaging and drugs for urolithiasis have increased in the United States. Kidney Int. 2013; 83:479-486. 7. Yilmaz S, Sindel T, Arslan G, et al. Renal colic: comparison of spiral CT, US, and IVU in the detection of ureteral calculi. Eur Radiol. 1998; 8:212-217. 8. Schoenfeld EM, Shieh MS, Pekow PS, et al. Association of Patient and Visit Characteristics With Rate and Timing of Urologic Procedures for Patients Discharged From the Emergency Department With Renal Colic. JAMA Netw Open. 2019; 2(12):e1916454.

CORRESPONDENCE

9. Fung SY, Yuen KS, Ye ZW, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020; 9:558-70.

Marche Polytechnic University.

10. Dunmire B, Lee FC, Hsi RS, et al. Tools to improve the accuracy of kidney stone sizing with ultrasound. J Endourol. 2015; 29(2):147-152.

Phone number: +39 071/5966523

11. Dunmire B, Harper JD, Cunitz BW, et al. Use of the acoustic shad-

Advances in Urological Diagnosis and Imaging - 2020; 3,2

Lucio Dell’Atti, MD, PhD Department of Urology, University Hospital “Ospedali Riuniti”, 71 Conca Street, 60126 Torrette, Ancona - Italy. E-mail: dellatti@hotmail.com Fax: +39 071/5963367.

REVIEW

The emerging role of high-resolution transrectal micro-ultrasound in prostate cancer detection: A narrative review Simone Scarcella 1, Lucio Dell’Atti 1, Giulio Milanese 1, Gianluca Giannarini 2, Andrea Galosi 1. 1 2

Department of Urology, Marche Polytechnic University, School of Medicine, United Hospitals, Ancona, Italy; Urology Unit, Academic Medical Centre “Santa Maria della Misericordia”, Udine, Italy.

Objective(s): The ExactVu Micro-Ultrasound system is a novel 29MHz high resolution imaging system for the visualization, systematic sampling and real-time targeting of suspicious regions of the prostate. Its use has been enhanced by the development and validation of the PRIMUS (Prostate Risk Identification for Micro-Ultrasound) protocol that has been demonstrated to correlate with both the risk and severity of prostate cancer. Herein, we present a narrative review of the literature regarding the advantages of this new technique and its possible role in Prostate Cancer detection and management. Material and method(s): Literature search was conducted via PubMed, Web of Science, Embase and Cochrane Library databases before April 2020 using these following key words: “micro-ultrasound” and “prostate cancer”. A total of 8 articles were eligible for this review. Result(s): Micro-ultrasound is an emerging technology with preliminary data that are beginning to build evidence regarding its clinical applications in Prostate Cancer detection, targeting for sampling, Active Surveillance protocols and focal treatment. Conclusion(s): Micro-ultrasound application could improve prostate cancer detection without affecting the existing urological practice defined by its accessibility without any contraindications.

SUMMARY

KEY WORDS: Diagnosis, Prostate Cancer, Ultrasound, Biopsy, Micro-Ultrasound, TRUS, Exact Vu.

INTRODUCTION Prostate cancer (PCa) is the most prevalent cancer diagnosed in men in western countries, representing the third cancer-related death in Europe (1). In Italy an estimated 37000 new diagnosis were made during 2019, with about 7540 PCa-related death recorded (2).Traditional screening protocols rely on PSA blood test alongside with digital rectal examination while, in suspected cases, the definitive diagnosis is made by the uro-pathologist with the examination of tissue samples obtained by transrectal or transperineal ultrasound-guided biopsy (3). Unfortunately, conventional ultrasound-based systematic biopsy is inaccurate, with a cancer detection rate ranging from 20% to 50% (4). Moreover, this technique is affected by a high rate of false-negative outcomes and biopsy-related morbidity such as post procedural haemorrhages, infections and sepsis (5). As a consequence of these limitations, multiparametric MRI (mpMRI) has been widely incorporated in riskadapted diagnostic algorithms for PCa, furthermore international guidelines are promoting its use prior to initial and repeat biopsy (6). Supporting this trend, multiple studies (Precision (7), MRI-FIRST (8) and 4M (9)) demonstrated

the superiority of a targeted approach compared to systematic biopsies. However, even this approach has some critical drawbacks: the technology is expensive, requiring adjunctive operational costs, a long highly specialized learning curve is required for adequate assessment of the images and correct targeting, agreement between uro-radiologists of different centres is highly variable and some areas still lack MRI access (10). In this complex landscape, High Resolution Micro Ultrasound (Micro-US) has emerged as an enhanced imaging technic designed to outpace conventional transrectal ultrasound (TRUS). As with the old generation of ultra-sonographers, it uses an endo-rectal probe to produce real-time images of the prostate but with an increased 3-fold image resolution, due to higher frequencies of the probe. Since its debut on the market described in 2014 by Pavlovich et al. (11), micro-ultrasound showed constant improvements in both sensitivity and specificity for PCa detection. Herein, we present a narrative review of the literature regarding the advantages of this new technique and its possible role in replacing conventional ultrasound for early detection and as alternative tool in mpMRI and focal therapy implementations. Advances in Urological Diagnosis and Imaging - 2020; 3,2

S. Scarcella, L. Dell’Atti, G. Milanese, G. Giannarini, A. Galosi

METHODS Literature search was conducted via PubMed, Web of Science, Embase and Cochrane Library databases up to April 1, 2020 using these following key words: “micro-ultrasound” and “prostate cancer”. This was done in order to ensure a comprehensive inclusion of all articles related to the use of High-Resolution Trans-rectal Micro-Ultrasound in PCa detection, targeting for sampling and focal therapy. Case reports, editorials, articles published in abstract form, review articles and articles not written in English were excluded. References from included studies were manually retrieved to identify additional studies of interest.

RESULTS A total of 8 articles were selected for this review, with main characteristics of the studies are summarized in Table 1.

HIGH-RESOLUTION MICRO-ULTRASOUND TECHNOLOGY High-resolution micro-ultrasound is an innovative imaging technique developed to increase the diagnostic accuracy of transrectal ultrasound-guided prostate biopsy, whilst preserving the convenience and affordability of traditional ultrasound systems. The technical improvements of this new system rely on a higher working frequency of 29 MHz, compared to the 9-12 MHz of conventional urologic ultrasounds. As well, the construction of the transducer includes 512 crystal components compared to 128. These technological improvements increased the overall resolution of the ultrasonography images to 70 microns, which is the diameter of a prostatic duct, whereas the conventional ultrasound systems have a lower resolution up

to 200 microns. In practical terms, most prostate cancers are described as hypoechoic lesions at low resolutions. However, with the higher tissue-structure details visible with the micro ultrasound technology, it is possible to perform a real time analysis of both the ductal prostatic anatomy and the cellular density. The ability to characterize these components allows the ultrasonographic definition of new tissue patterns of PCa with a higher sensitivity for malignancy. The first model of the ExactVu 29 MHz system (Exact Imaging, Toronto Canada) was tested in a pilot study in 2014 by Pavlovich et al. (11) assessing the micro-us ability of identifying suspected cancerous area. They compared Micro-US and standard US, analysing dynamic cine loops taken from 25 men with known prostate cancer.The direct comparison of ultrasonographic images to the final pathological report, obtained after radical prostatectomy, showed a significantly better identification of cancer foci compared to traditional ultrasonographic systems (79.9% vs 51.2%, p<0.008). In addition, a subsequent randomized multicenter trial quantified a 19% improvement rate of micro-us capability in the detection rate of clinically significant prostate cancer (12). In 2017, the second generation was released with supplementary upgrades in imaging quality, real time tracking and compatibility with MRI image fusion.

STANDARDIZATION OF IMAGE REPORTING: THE PRI-MUS PROTOCOL (PROSTATE RISK IDENTIFICATION USING MICRO-ULTRASOUND) The technical improvements of the ExactVu 29 MHz system enables a new level of imaging resolution in prostate gland ultrasonography, enhancing both the identification and the ability to real time target suspected areas during prostate biopsy. Similarly to PIRADS for mpMRI, in 2016 Ghai S, et al. (13)

Table 1. Characteristics of the studies included in our review.

Authors

Year Study design N. patients Outcomes

Pavlovich et al. (11)

2014

Prospective

Improved sensitivity of Micro-US (65.2% vs 37.7%) and increased visualisation of high grade lesions (84% vs 60%) compared to traditional TRUS.

Ghai et al. (13)

2016

Prospective

400

PRIMUS protocol demonstrated a sensitivity of 80% with a specificity of 37%. The protocol was more accurate for detecting high grade disease with a GS greater than 7 with a peak AUC of 74% (mean 66%).

Eure et al. (27)

2018

Retrospective

123

Micro-US detected 89% of clinically significant cancer, compared to 56% for mpMRI.

Lunghezzani et al. (22)

2018

Prospective

104

Micro-US sensitivity for csPCa was 94%. Negative predictive value was 90%, while the positive predictive value was 40% and the specificity was 28%.

Rohrbach et al. (12)

2018

Retrospective

163

Improved PRIMUS protocol resulted in an AUC value of 0.81 for csPCA when read by an expert, compared to the previous 0.74 of the first version of the PRIMUS protocol.

Abouassalay et al. (23)

2019

Prospective

Switching biopsy guidance to real-time micro-ultrasound increased detection rate on prostate biopsy from 44.8% to 56.7% with a relative increase of 26.7%.

Luger et al. (35)

2019

Prospective

372

PRIMUS protocol resulted in an AUC of 0.76 for predicting GG prostate cancer higher than score 1 in the peripheral zone. First application to the anterior zone showed an AUC of 0.80.

Stanton et al. (20)

2019

Prospective

Advances in Urological Diagnosis and Imaging - 2020; 3,2

Micro-US has the potential to replace the current clinical methods for targeted prostate biopsies and improve intraoperative monitoring in patients undergoing cryoablation.

High-resolution transrectal micro-ultrasound in prostate cancer detection Table 2. Prostate cancer risk according to PRIMUS (Prostate Risk Identification Using Micro-Ultrasound) criteria (13).

Grade

Characteristics Of Micro-ultrasound Image

Relative Risk of Prostate Cancer

Small regular ducts, “Swiss Cheese”

0.28

Hyperechoic with or without ductal patches

0.49

Bright echoes in hyperechoic tissue

1.2

Heterogeneous cauliflower/smudgy/mottled appearance Bright echoes (“Starry Sky” appearance)

1.5

Irregular peripheral zone border Mixed echo lesions, Irregular shadowing

2.0

proposed a structured protocol, retrospectively validated, to standardise, interpret and classify different ultrasonographic patterns of cancer foci appearance in an imaging based scoring system. The key findings of the protocol are the capacity of differentiating PCa risk according to images characteristics and the linear relationship between PRIMUS risk score and the severity of disease, defined by pathology findings. This specific feature aims to increase the benefits of realtime prostate sampling during TRUS biopsy reducing the risk of re-sampling and false negative outcomes. Each increase in risk score category demonstrated 10.1% increase (95% CI 9.3-10.8) in the probability of csPCa. The risk score also increased with a Gleason Score (GS) sum of 0.15% (95% CI 0.09-0.21) and 0.58% (95% CI 0.430.73) for cancer length. Sensitivity and specificity were 80% and 37% respectively, and the mean receiver operating characteristic curve (ROC) area under the curve (AUC) was 60%. The protocol was more accurate for detecting high grade disease (Gleason Score sum greater than 7) with a peak AUC of 74% (mean 66%) (13). Moreover, Rohrbach et al. (12) analysed 1956 cores from 163 patients submitted to prostate biopsy procedure and proposed an implementation of the standard PRI-MUS protocol achieving an AUC value of 0.81 that confirmed the potential of Micro-US in detection of csPCa. The Figure 1 shows PRI-MUS categories of risk. Table 2 and the complete PRI-MUS protocol with image examples of each sonographic features of both malignant and benign variants. A reported limit of the PRI-MUS technique is its applicability and exclusive validation for the peripheral zone of the prostate, while research shows that up to 10-20% of PCa do not affect the peripheral zone component. To improve the applicability of the technique Luger F, et al. in 2019 published a prospective validation of the protocol reporting its accuracy to predict clinically significant cancer throughout the entire gland. They evaluated 399 prostate biopsies from 372 patients suspected for PCa with Micro-US. The application of the PRIMUS protocol resulted in an AUC of 0.76 for predicting GG>1 cancer in the peripheral zone with an accuracy that varied between 0.68-0.83 depending on prostate region, with highest accuracy in the prostate apex and lowest accuracy at the base (14).

APPLICATIONS OF MICRO-US PCA SCENARIOS

IN DIFFERENT

Early Detection In men suspected with PCa the conventional diagnostic pathway relies on 10-12 core TRUS guided prostate biopsy (TRUS-Bx). In recent years it has been challenged by the wide adoption of mpMRI prior to prostate sampling, as shown by different systematic reviews and randomised controlled trials (RCTs) (15). This led to the proposal of a different targeting procedure based on the concept of sampling only MRI suspicious areas (MRI-targeted biopsy) with the aim of improving accuracy in detecting clinically significant Prostate Cancer (csPCa), while reducing the number of biopsies performed and the detection of indolent disease, which may generate over treatment (16). However, whether MRI-informed targeted biopsy combined with systematic biopsy is a superior strategy than targeted biopsy alone for detecting PCa in men with a positive MRI remains debatable (17). Even though, international guidelines are supported by level 1 evidence, in daily urological practice the issue of which patients could benefit more by avoiding systematic biopsies, reducing the diagnosis of indolent PCa still remains a matter of debate (18). Conversely, some aggressive form of PCa such as the cribriform pattern are less detectable on mpMRI and could be missed with the MRI-TBx only approach. Furthermore, the use of multi-parametric mpMRI is not flawless missing up to 12-23% of GS ≥ 7 PCa (19). Beyond that, it requires a significant increase in operative costs, necessitating radiologists with expertise in reading/assessing PI-RADS score and it is still affected by a suboptimal rate of 60% agreement for peripheral prostatic lesions between different centres (20). Ghai, et al. 2018 suggested the use of MicroUS as a new imaging modality for PCa that may support and enhance early detection protocols. It is urologist-performed, does not require skilled radiological assessments and could help in a better identification of men that should be further submitted to prostate biopsy reducing false negative rates of standard procedures and unnecessary biopsies for patients without csPCa (21). Moreover, to address the Pca targeting approach conundrum, Lughezzani, et al. 2018, highlighted how Micro-US could achieve the same sensitivity of mpMRI for csPCa while allowing real-time targeting of suspected areas. The authors presented their initial experience with Micro-US and PRIMUS risk identification protocol tool diagnosing a cohort of patients with csPCa and imaging abnormalities detected at mpMRI scan. Micro-US sensitivity for csPCa detection was 94%, the negative predictive value (NPP) was 90% while the positive predictive value (PPV) was 40% and the specificity was 28%. High-resolution MicroUS showed comparable sensitivity to mpMRI in the identification of csPCa with the improvement of real time targeting of suspicious areas. With the aid of PRIMUS protocol Micro-US was able to gain optimal sensitivity and high negative predictive value (NPV) rates for csPCa. Specificity and positive predictive value (PPV) rates resulted suboptimal probably due to lack of experience with the new technique, as all practitioners were at the beginning of

Advances in Urological Diagnosis and Imaging - 2020; 3,2

S. Scarcella, L. Dellâ&#x20AC;&#x2122;Atti, G. Milanese, G. Giannarini, A. Galosi

their learning curve. Shifting to Micro-US Figure 1. for real time biopsy targeting determined a 27% relative increase on cancer diagnosis Assigning with a 45% to 57% median increment in PCa detection rate. Moreover, the application of the PRIMUS protocol resulted in a sharp reduction of un-sampled lesions with a 21% median increase of the Grade Group score of detected cancers (22). In advance, Abouuassaly, et al. 2019 presented their early experience using Micro-US for both systematic sampling and real time targeting of suspicious regions during prostate biopsy in 67 consecutive patients. The added value of Micro-US real time targeting established a cancer detection rate increase of prostate biopsy ranging from 44.8% to 56.7%, with a relative increase of 26.7% (23).

a Risk Score (via PRI-MUS) to each Prostate Region

Active Surveillance The aim of active surveillance (AS) protocols for PCa is to carefully and actively monitor untreated patients affected by low-risk prostate cancer without compromising curative treatment, when cancer progression is detected. The majority of protocols rely on standard ultrasound guided trans-rectal systematic biopsies, which have to be repeated every 6 to 24 months (24). This procedure has been considered the reference standard of care to monitor prostate cancer. Different authors have reported its inefficiency with 40-50% of patients diagnosed with indolent prostate cancer receiving a benignant pathology report at confirmatory biopsies (25). These inconsistencies highlight the inaccuracy of standard systematic biopsies that could lead to an underestimation of patients developing aggressive disease with the paradox of maintaining a conservative approach rather than a proper curative treatment. Therefore, mpMRI has been proposed as an alternative, or prior to biopsy, in different AS protocols in order to reduce the underestimation of disease progression. The combination of mpMRI and repeated biopsies reduced false negative and under-grading rates as consequence of non-sampled lesions. However, its considerable increment in costs and workflow complexity could rise the risk of deferred diagnosis in areas where mpMRI is not easily accessible (26). In a recent study Eure, et al. 2018 compared Micro-US imaging with mpMRI and standard US for visualizing prostate cancer in an active surveillance cohort of 123 patients. MpMRI and Micro-US both demonstrated superior sensitivity to cancer with GS sum 7 or higher compared to conventional ultrasound (p=0.02 McNemarâ&#x20AC;&#x2122;s test). Micro-US detected 89% of csPCa compared to 56% for mpMRI. These out-

Advances in Urological Diagnosis and Imaging - 2020; 3,2

standing results may have been affected by some of the limits of this study (single centre, selected small cohort of patients, single operator). With all these caveats this study clearly denotes the potential of Micro-US and PRI-MUS protocol as a promising tool to complement mpMRI and PI-RADS score in detecting and targeting PCa even in AS protocols (27).

High-resolution transrectal micro-ultrasound in prostate cancer detection

1) Peripheral zone â&#x17E;Ą 2) Border â&#x17E;Ą 3) Characterize Tissue (in PZ)

Focal Therapy The aim of focal therapies in the treatment of localized PCa is to selectively eradicate clinically significant cancers without compromising oncological safety while avoiding the sideeffects of radical, whole-gland treatments. The European Association of Urology (EAU) defined the use of focal ther-

apy for localized PCa an investigational modality due to the multifocal nature of PCa, reported in 60-80% of published series, and the lack of long-term oncological outcomes (6). The success of these minimally invasive treatments relies mostly on the adequate selection of proper candidates, but despite radiological development and routine integration in early detection protocols, mpMRI is still unable to Advances in Urological Diagnosis and Imaging - 2020; 3,2

S. Scarcella, L. Dellâ&#x20AC;&#x2122;Atti, G. Milanese, G. Giannarini, A. Galosi

identify and accurately locate all types of csPCa (28). Furthermore, mpMRI alone does not allow real time targeting and monitoring during the procedure. Despite the type of energy used to ablate prostatic tissue, lesion targeting and treatment monitoring presently must rely on standard transrectal B-mode ultrasound or TRUS-MRI fusion imaging guidance (29). Stanton, et al. 2019 suggested the innovative use of MicroUS in conjunction with standard ultrasonography to intraoperatively evaluate prostate cancer lesions in 4 patients submitted to cryotherapy for localized PCa. All subjects were diagnosed by confirmatory TRUS biopsy pathology and had prior mpMRI scan. All men were went through Micro-US before, during and after the procedure, comparing the results to the standard of care TRUS. Authors pointed out the advantages of Micro-US as an in-office technique that provided high spatial resolution with the additional intraoperative assessment of suspected areas of prostate gland and capsule, without the drawbacks of mpMRI. Despite the scarce number of patients included, these probings suggest the potential role of Micro-US in replacing current standard methods for intraoperative monitoring during focal therapies treatment for csPCa (30).

DISCUSSION Over the past years several innovations in the diagnostic pathway of PCa have been introduced, mpMRI being one of the most prominent. However, even when implementing mpMRI, early detection may still remain challenging and troublesome. The lack of a gold standard imaging test with sufficient sensitivity imposes the necessity to associate radiological scans, clinical, laboratory and pathological findings for correct screening and diagnosis PCa (31). Therefore, the widespread use of prostate mpMRI increased the urological workflow complexity with higher operative costs, heterogeneous reproducibility results and difficulty to access the latest technology in some areas (32). Despite level 1 evidence and inclusion in international guidelines, the use of mpMRI has not completely eliminated the biopsy-related risk of over-detection of clinically indolent PCa and under-detection of csPCa (33). In this context, high-resolution micro-ultrasound is a new imaging modality that has shown the increase of overall diagnostic accuracy of current standard diagnostic pathway for PCa. The technology has been developed to support higher working frequencies of 29MHz and with 512 crystals improved transducers, compared to the standard B-mode ultrasonography. All these technological advances allow a scanning resolution up to 70 microns, the dimension of a prostatic duct, with a better spatial representation of the whole prostatic gland, its capsule and the surrounding anatomical structures such as the seminal vesicles. Moreover, a specific diagnostic tool was developed to increase both reproducibility and clinical application of micro-US, whilst keeping the procedure affordable, simple, and reproducible, with a short learning curve and in an out-patient setting with real time scanning modality. As PIRADS model for mpMRI, the PRIMUS protocol was developed to support urologists in improving detection

Advances in Urological Diagnosis and Imaging - 2020; 3,2

rates of csPCa and reduce false negative ones (34). This is of paramount importance considering prostate cancer screening in everyday urological practice. The majority of patients need to be screened through laboratory PSA alteration, abnormal DRE or alterations of highly specific serum/urinary test such as PCA3, Pro-PSA or PHI.The use of mpMRI undoubtedly increased the overall prostate cancer screening accuracy but, even when detected at imaging, targeting small non-palpable lesions, without a dedicated real-time imaging modality, remains an un-resolved concern. Micro-US is capable to enhance the visualization of intraprostatic structures allowing a more accurate detection of PCa foci compared to standard US B-mode. Its routine application in support with mpMRI could reduce false negative rates and unnecessary biopsies that still affects screening protocols for PCa (23). Alongside with screening protocols, another debated issue within the urological community is the efficacy of AS protocols. We should balance between the oncological safety of not treating patients diagnosed with indolent PCa, while determining the right timing and screening modality to further diagnose cancer progression, without compromising the option of a curative treatment. According to EAU guidelines the combination of mpMRI and repeated systematic biopsies is mandatory to reduced false negative and under-grading rates, despite disadvantages of operative cost increments and workflow complications (6). Micro-US technology and the PRIMUS protocol could represent a promising tool also in AS population, implementing mpMRI and PI-RADS score in detecting and targeting csPCa with and overall sensitivity of 60-90% according to a recently published research. Moreover, in the controversy regarding the most accurate image targeting modality, systematic TRUS-Bx vs MRI-TBx alone, shifting to micro-US guidance demonstrated a 27% relative increase rate on cancer diagnosis, on account of a more precise real time targeting modality (22). The application of the PRIMUS protocol reduced by 21 % the rate of un-sampled lesions and increased significantly the median Grade Group score of detected cancers (35). Micro-US could improve not only the diagnostic pathway of prostate cancer but also focal therapy treatment monitoring, according to some innovative authors. The European Association of Urology stated that focal therapy for localized PCa is an investigational approach to be proposed only in clinical trials. This is due to the absence of validated criteria for patients selection, lack of long term oncological outcomes and the fact that mpMRI alone does not allow a real time targeting and monitoring of cancer foci ablation during the procedure (36). Despite these drawbacks, that still need to be properly addressed, a single study reported the leading-edge use of Micro-US to real time monitor the ablation of cancer lesions in patients submitted to cryotherapy for localized PCa.This original research suggested the potential role of Micro-US not only for improving the accuracy of PCa screening and diagnostic protocols, (37) but also in active treatment of PCa encouraging future research settings for the application of this technology (30). Our review has several limitations. Firstly, Micro-US is a recently developed technology and all presented data are exploratory. Secondly, there is still a lack of quality assess-

High-resolution transrectal micro-ultrasound in prostate cancer detection

ment criteria for this technology. The majority of these studies are small, retrospective and single-center, and there is substantial heterogeneity in terms of inclusion criteria. This prompted us to perform a narrative review instead of a Systematic Review with Meta-Analysis. We need largescale studies to validate the clinical application of Micro-US as a tool for improving diagnosis and treatment of csPCa.

CONCLUSIONS Micro-ultrasound is an emerging technology with preliminary data that are beginning to build evidence regarding its clinical applications in PCa detection, targeting for sampling, AS protocols and focal treatment. While simplifying both patient experience and cancer detection Micro-US could sustain the existing urological practice defined by its accessibility with no contraindications. Moreover, micro-US and PRI-MUS grading system seem to have a shorter learning curve compared to mpMRI. Further research is warranted.

REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics 2018. CA Cancer J. Clin. 2018; 68,7-30. 2. AIOM - Italian Association of Medical Oncology. Annual report 2019. 3. Fitzmaurice C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability- adjusted life- years for 32 cancer groups, 1990 to 2015. JAMA Oncol. 2017; 3,524.

a novel micro-ultrasound scanner. Ultrasound in Med & Biol. 2018; 44(7):1341-1354. 13. Ghai S, Eure G, Fradet V, et al. Assessing cancer risk on novel 29 MHz microultrasound images of the prostate: creation of the microultrasound protocol for prostate risk identification. J Urol. 2016; 196(2):e562-e569. 14. Luger F, Gusenleitner A, Kaar J, et al. Does 29Mhz MicroUltrasound Provide Uniform Diagnostic Accuracy Within and Beyond the Peripheral Zone? Annal Urol & Nephrol. 2019; 1(4). AUN.MS.ID.000519. 15. Moore CM, Robertson NL, Arsanious N, et al. Image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. Eur. Urol. 2013; 63:125-40. 16. Porpiglia F, Manfredi M, Mele F, et al. Diagnostic pathway with multiparametric magnetic resonance imaging versus standard pathway: results from a randomized prospective study in biopsy-naive patients with suspected prostate cancer. Eur Urol. 2017; 72:282-8. 17. Giannarini G, Padhani AR. Which biopsy strategy should be recommended in men with a positive prostate MRI: targeted sampling alone or combined with systematic biopsy? Advances in Urological Diagnosis and Imaging 2020. In press. 18. Dell’Oglio P, Stabile A, Soligo M, et al. There Is No Way to Avoid Systematic Prostate Biopsies in Addition to Multiparametric Magnetic Resonance Imaging Targeted Biopsies. Eur Urol Oncol. 2019; 3(1):112-118. 19. Le JD, Tan N, Shkoliar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole- mount histopathology. Eur. Urol. 2015; 67:569-576. 19. Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur. Radiol. 2012; 22:746-57. 20. Rosenkrantz AB, Ginocchio LA, Cornfeld D, et al. Interobserver reproducibility of the PI-RADS version 2 lexicon: A multicenter study of six experienced prostate radiologists. Radiology 2016; 280:793-804.

4. Serefoglu EC, et al. How reliable is 12-core prostate biopsy procedure in the detection of prostate cancer? Can. Urol. Assoc. J. 2013; 7, E293-E298.

21. Ghai S, Van der Kwast T. Suspicious findings on micro-ultrasound imaging and early detection of prostate cancer Urology. Case Reports. 2018; 98e100.

5. Tokas T, Grabski B, Paul U, et al. A 12-year follow-up of ANNA/CTRUS image-targeted biopsies in patients suspicious for prostate cancer. World J Urol. 2018; 36:699-704.

22. Lughezzani G, Saita A, Lazzeri M, et al. Comparison of the Diagnostic Accuracy of Micro-ultrasound and Magnetic Resonance Imaging/Ultrasound Fusion Targeted Biopsies for the Diagnosis of Clinically Significant Prostate Cancer. Eur Urol Oncol. 2018; 2(3):329-332.

6. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol. 2017; 71:618-29. 7. Kasivisvanathan V, Rannikko AS, Borghi M, et al. PRECISION Study Group Collaborators. MRI-targeted or standard biopsy for prostatecancer diagnosis. N Engl J Med. 2018; 378:1767-77. 8. Rouvière O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a pro-spective, multicentre, paired diagnostic study. Lancet Oncol. 2019; 20:100-9. 9. Van der Leest M, Cornel E, Israël B, et al. Head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study. Eur. Urol. 2019; 75:570-8. 10. Futterer JJ, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? A systematic review of the literature. Eur. Urol. 2015; 68,1045-1053. 11. Pavlovich CP, Cornish TC, Mullins JK, et al:High-resolution transrectal ultrasound: pilot study of a novel technique for imaging clinically localized prostate cancer. Urol Oncol. 2014; 32:34.e27. 12. Daniel Rohrbach, Brian Wodlinger, Jerrold Wen, et al. HighFrequency quantitative ultrasound for imaging prostate cancer using

23. Abouassaly R, Klein EA, El-Shefai A, et al. Impact of using 29MHz high-resolution micro-ultrasound in real-time targeting of transrectal prostate biopsies: initial experience. World J Urol. 2019; 38(5):12011206. 24. Hamdy FC, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 2016; 375(15):1415-1424. 25. Thomsen FB, et al. Active surveillance for clinically localized prostate cancer: a systematic review. J Surg Oncol. 2014; 109(8):830-5. 26. Schoots IG, et al. Magnetic resonance imagingtargeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound- guided biopsy:a systematic review and meta- analysis. Eur. Urol. 2015; 68,438-450. 27. Eure G, et al. Comparison of conventional transrectal ultrasound, magnetic resonance imaging, and micro-ultrasound for visualizing prostate cancer in an active surveillance population: A feasibility study. Can Urol Assoc J. 2019; 13(3):E70-E77. 28. Woo S, Suh C H, Kim SY, et al. Diagnostic performance of prostate imaging reporting and data system version 2 for detection of prostate cancer: a systematic review and diagnostic meta-analysis. Eur. Urol. 2017; 72,177-188.

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S. Scarcella, L. Dell’Atti, G. Milanese, G. Giannarini, A. Galosi

29. Tourinho-Barbosa RR, et al. Focal Therapy for Localized Prostate Cancer with Either High Intensity Focused Ultrasound or Cryoablation: A Single Institution Experience. J Urol. 2020; 203: 320. 30. Stanton W, Crawford ED, Arangua P, et al. Evaluation of the 29 MHz Micro-Ultrasound Imaging for Prostate Cancer Diagnosis and Treatment. Annal Urol & Nephrol. 2019; AUN.MS.ID.000515. 31. Ilic D, et al. Prostate cancer screening with prostatespecific antigen (PSA) test: a systematic review and meta- analysis. BMJ. 2018; 362,k3519. 32. Stabile A, et al. Factors Influencing Variability in the Performance of Multiparametric Magnetic Resonance Imaging in Detecting Clinically Significant Prostate Cancer: A Systematic Literature Review. Eur Urol Oncol. 2020; 3(2):145-167. 33. Panebianco V, et al. An update of pitfalls in prostate mpMRI: a

practical approach through the lens of PI-RADS v. 2 guidelines. Insights Imaging. 2017; 9,87-101. 34. Klotz CM. Can high resolution micro-ultrasound replace MRI in the diagnosis of prostate cancer? Eur Urol Focus. 2019; 6(2):419423. 35. Luger F, Gusenleitner A, Kaar J, et al. A prospective validation of the diagnostic accuracy of pri-mus for prostate cancer risk identification. J Urol. 2019; 201:E1078. 36. European Association of Urology. EAU guidelines on prostate cancer. EAU https://uroweb.org/guideline/prostatecancer/. 2020. 37. Zhang M, Wang R, Wu Y, et al. Micro-Ultrasound Imaging for Accuracy of Diagnosis in Clinically Significant Prostate Cancer: A Meta-Analysis. Front. Oncol. 2019; 9:1368.

CORRESPONDENCE Simone Scarcella, MD Department of Urology, Polytechnic University of Marche Region University Hospital “Ospedali Riuniti” 71 Conca Street - 60126 Ancona - Italy E-mail: simoscarc@gmail.com Tel.+39 3924677442

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C ASE

REPORT

Incidental diagnosis of primary lung cancer with choline PET/CT in a patient affected by prostate cancer: Changing of treatment strategies Cristina Mariucci 1, Fabiola Patani 1, Francesco Fenu 1, Andrea Benedetto Galosi 2, Giovanna Mantello 1 2

Department of Radiation Oncology, University Hospital “Ospedali Riuniti”, Ancona, Italy; Department of Urology, University Hospital “Ospedali Riuniti”, Ancona, Italy.

Objective: Prostate cancer (PCa) is a heterogeneous disease with an overall long natural history and a biological behavior ranging from indolent to aggressive; in biochemical failure with progressive high levels of prostate specific antigen (PSA), imaging plays a critical role to differentiate local recurrence from distant spread of disease, developing a management of appropriate treatment strategies. Choline PET/CT (Cho-PET-CT) may be successfully applied to evaluate a variety of other malignancies; detection of a second tumor really change the management of the patient, especially for therapeutic strategies. On the basis of these considerations, our aim was to describe therapeutic choices and modalities after the detection from Cho-PET/CT of a second lung malignancy in a patient with also PCa local relapse. Material and methods: From our Radiation Oncology Institution, a case with PCa who experienced a local relapse and a second primary lung cancer detected by Cho-PET/CT (Choline PET/CT) was selected and described. Results: Between 2019 and 2020 a patient affected by PCa local relapse underwent to Cho-PET/CT, that found an increased uptake to a lung nodule; clinical and radiological findings were reported. On the basis of Cho-PET/CT, therapeutic strategy was defined within Uro-Oncologic multidisciplinary team (UO-MDT); patient underwent surgery for pulmonary malignancy and, later, pelvic stereotactic radiation therapy (SBRT) for PCa local relapse. He well tolerated radiation treatment with G0 toxicity (according to CTCAE v. 4.03 scale). After 12 months from lung lobectomy, follow-up CT scans were performed with no pathological findings. Conclusion: As highlighted in literature, our report showed the Cho-PET/CT ability to identify tumor lesions other than PCa with favorable results. Since treatment strategies have been influenced by Cho-PET/CT, our case confirmed the need to accurately ensure any possible “unusual” site of choline uptake in order to clinically manage these patients.

SUMMARY

KEY WORDS: Prostate Cancer; Radiotherapy; Choline-PET/CT; Lung Cancer; Oligometastatic.

INTRODUCTION Approximately one-third of patients affected by localized PCa will experience a biochemical recurrence with an increase in the serum PSA level within 10 years after primary therapy. In these patients 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG-PET/CT) lacks sensitivity; in contrast radiolabeled Choline (Cho) PET/CT is crucial to restage the disease detecting local recurrence and/or distant metastases; almost in 50% of patients this imaging diagnostic tool impacts on therapeutic choice. Choline is a natural blood constituent and a precursor of cell membrane phospholipids; tumor cells with high proliferative activity will have a rapid biosynthesis of cell membranes and the uptake rate of choline will be proportional to the rate of tumor duplication. Choline uptake is significantly higher in malignant

tumors than in benign lesion, expecially for tumors of head and neck, lung, bone and soft tissue (1). We report the clinical history of a PCa patient with a second malignancy detected by Cho-PET/CT, with a relevant impact on his overall therapeutic management.

CASE

REPORT

In 2006 a 76-year old man affected by prostatic adenocarcinoma was treated with radical prostatectomy and pelvic lymphadenectomy. Pathological stage of disease was pT2c pN0, 9 excised lymph nodes negative, perineural infiltration, Gleason Score 6 (3+3). From 2017 to 2019, PSA levels increased up to 2.37 ng/mL. In February 2019, a ChoPET/CT highlighted an increased uptake in the right superior lung lobe and in the ipsilateral mediastinum (maxSUV = 5.2). Advances in Urological Diagnosis and Imaging - 2020; 3,2

C. Mariucci, F. Patani, F. Fenu, A.B. Galosi, G. Mantello Figure 1. Lung nodule detected by Cho-PET/CT (A, B). Pararectal nodule on Cho-PET/CT described as local recurrence (C).

CONCLUSION As described in this report, early detection of a second malignancy from Cho-PET/CT allowed a radical treatment strategy with the improvement of overall survival. ChoPET/CT accuracy has been reported in literature (1, 2); Khan et al. showed superiority of 18F-FDG-PET/CT on Cho-PET/CT for detection of lung cancer less than 2 cm in diameter (3). In conclusion, in patients affected by biochemical recurrence who undergo Cho-PET/CT, as in our described case, it is necessary to exclude a possible further malignancy. In the context of our reported case, Cho-PET/CT detected a second lung malignancy and guided UO Multidisciplinary Team towards an immediate surgery for lung cancer due its worst prognosis and a delayed prostate recurrence SBRT.

REFERENCES 1. Sollini M, Pasqualetti F, Perri M, et al. DetGenito-ection of a second malignancy in prostate cancer patients by using [18F]Choline PET/CT: a case series. Cancer Imaging. 2016; 16:27. 2. Peng Z, Liu Q, Li M, et al. Comparison of (11)C-choline PET/CT and enhanced CT in the evaluation of patients with pulmonary abnormalities and locoregional lymph node involvement in lung cancer. Clin Lung Cancer. 2012; 13(4):312-20. 3. Khan N, Oriuchi N, Zhang H, et al. A comparative study of 11Ccholine PET and [18F]fluorodeoxyglucose PET in the evaluation of lung cancer. Nuclear Medicine Communications. 2003; 24,359-366.

At the same time further increased uptake was found behind the bladder (maxSUV = 8.9) (Figure 1), subsequently described by MRI as PCa local relapse (sizes of 1.8 cm). A 18-FDG-PET/CT confirmed lung nodule, max diameter 3.3 cm and maxSUV = 3.2, then biopsied with diagnosis of non small cell lung cancer. At right lobectomy with mediastinal lymphadenectomy, indicated by UO-MDT, resulted lung adenocarcinoma, R0 and G2, stage pT2a, pN0 on 16 removed lymph nodes. No adjuvant therapies have been suggested. A CT scans performed at 12 months from lung surgery showed no evidence of disease. After the progressive increase of PSA level to 4.54 ng/mL a Cho-PET/CT confirmed the increased uptake behind bladder, on the left site (maxSUV = 9.6, sizes 18 mm), and a pelvic SBRT with total dose of 3500 cGy in 5 fractions was delivered with an excellent tolerance. Androgen Deprivation Therapy (ADT) was also prescribed.

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CORRESPONDENCE Giovanna Mantello Department of Radiation Oncology, University Hospital â&#x20AC;&#x153;Ospedali Riunitiâ&#x20AC;? Ancona, Italy E-mail: giovanna.mantello@ospedaliriuniti.marche.it Phone number: 071-5965792

C ASE

REPORT

Pararectal lymph node metastases in prostate cancer patients: Report of two cases Fabiola Patani 1, Cristina Mariucci 1, Francesco Fenu 1, Andrea Benedetto Galosi 2, Giovanna Mantello 1 2

Department of Radiation Oncology, University Hospital “Ospedali Riuniti”, Ancona, Italy; Department of Urology, University Hospital “Ospedali Riuniti”, Ancona, Italy.

Objective: Prostate cancer represents the second tumour with the highest incidence of all cancers in men worldwide and early biochemical recurrence (detected by PSA levels) could be predictive for local pelvic recurrence as pelvic nodal relapse. Standard imaging (CT and MRI) is usually applied to investigate pelvic lymph node metastases in patients with advanced prostate cancer. 68Ga-PSMA-ligand positron emission tomography in combination with computerized tomography (68Ga-PSMA-PET/CT) represents a new diagnostic strategy for detection of lymph node metastases from prostate cancer; in fact prostate specific membrane antigen (PSMA) seems to be an effective tool for detection of prostate cancer metastases because of its high expression by nearly all prostate tumour cells. Pararectal area is a rare site of metastases from advanced prostate cancer and therapeutic modalities (hormonal therapy, stereotactic body radiotherapy – SBRT) were explored by few scientific studies. On the basis of these considerations, objective of this report was the introduction of two cases with pararectal lymph node metastases from prostate cancer; assessment and treatment were described for both studied patients. Material and methods: From a single Radiation Oncology Department, oligometastatic patients with pararectal lymph node metastases from prostate cancer were selected and analyzed. Results: Between 2019 and 2020, two patients were detected. Clinical and pathological characteristics, diagnostic modalities including 68Ga-PSMA-PET/CT, and selected therapeutic approaches (hormonal therapy and stereotactic body radiotherapy, SBRT) were described. Uro-oncologic Multidisciplinary Team (UO-MDT) prescribed hormonal therapy with regular checks of PSA levels to the first patient; SBRT was administered in the second case with G0 toxicity. Conclusion: Since prostate cancer rarely relapses in the pararectal region, it is necessary to exclude ano-rectal malignancies that usually metastasize to mesorectum. From our reported case, 68Ga-PSMA-PET/CT resulted a diagnostic tool useful to confirm pararectal lymph nodes as from prostate cancer, supporting the therapeutic choices.

SUMMARY

KEY WORDS: Prostate Cancer; Radiotherapy; PSMA-PET/CT; Oligometastatic; Mesorectal Metastasis.

INTRODUCTION

CASE REPORTS

There are few reports in literature concerning pararectal lymph node metastases from prostate cancer and their therapeutic choices since tumours originating from sites different from rectum rarely metastasize to the mesorectum (1). Mesorectal nodes, similarly to other nodal oligometastases from prostate cancer, detected with 68Ga-PSMA-PET/CT (2), can take advantage from local therapies, first of all SBRT +/- hormonal therapy. Our aim was to describe cases with pararectal lymph nodes from prostate cancer detected and treated in our Department.

First case regards a 64-year-old man, asymptomatic, in great general conditions (ECOG 0). In August 2019, with a routine biochemical control, PSA level of 2.48 ng/ml was detected; patient underwent prostatic biopsy in September 2019 with diagnosis of prostatic adenocarcinoma, Gleason score 7 (4+3). In December 2019 radical prostatectomy and pelvic lymphadenectomy roboticassisted were performed, confirming the diagnosis of prostatic adenocarcinoma with neoplastic vascular invasion (pathological stage pT3a pN1, R0). In January 2020, after a detection of PSA level of 0.19 ng/ml and then in February 2020 of 0.23 ng/ml, a pelvic MRI showed three pathologiAdvances in Urological Diagnosis and Imaging - 2020; 3,2

F. Patani, C. Mariucci, F. Fenu, A.B. Galosi, G. Mantello

cal lymph nodes (sizes of 24x10 mm, 12x8 mm and 8 mm, respectively) in the mesorectal area, strongly suspected for metastases. Endoscopy and transrectal ultrasound scanning, performed to investigate the possible anorectal origin, resulted negative. In May 2020, a Ga-PSMA-CT/PET highlighted an increased uptake in the three lymph nodes described by the previous abdominal CT, and allowed to refer these radiological findings to metastases from prostate cancer. Size and number of lymph nodes guided UO-MDT to prescribe hormonal therapy with periodic control of PSA levels. The second case is a 70-year-old man in great general conditions (0 according to ECOG scale). No relevant co-

morbidities and no urinary alterations were reported. In November 2018, radical prostatectomy and pelvic lymphadenectomy were performed. Basal PSA level was 6.7 ng/ml. Histological exam described a prostate acinar adenocarcinoma, Gleason score 9 (4+5), perineural infiltration, pathological stage pT2a pN0 M0. From January 2019 to May 2020, PSA levels progressively increased up to 0.293 ng/ml. In June 2020, a Ga-PSMACT/PET described an increased uptake in left para-rectal area, interpreted as a unic mesorectal nodal metastasis from prostate. SBRT 3500 cGy in 5 fractions was administered. In planning phase, Ga-PSMA- CT/PET was matched with planning CT to delineate Biological Target Volume

Figure 1. Patient 1: Pararectal nodes increased uptake on Ga-PSMA-PET/CT (A, B); Patient 2: Single pararectal node increased uptake on Ga-PSMA-PET/CT (C); GTV (pink), PTV (red) and rectum (shaded red) during planning phase of SBRT on coronal plane (D).

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Unusual pararectal nodes in prostate patients

(BTV = GTV) as the area with increased uptake. Five mmPTV was used to compensate residual set up and organ motion uncertainties; daily CBCT was performed before each fraction (Figure 1). No acute toxicity was recorded (Grade 0 according to CTCAE v. 4.03 scale).

CONCLUSION Ga-PSMA-PET/CT, as reported in literature and in the two described cases, represents a new diagnostic method for diagnosis of lymph node metastases (1) for prostate cancer relapse, also in not usual site, like mesorectal region. First presented case in this report was a patient with three large lymph node metastases in mesorectal area; since he experienced a biochemical recurrence in a short time from prostatectomy (two months), considering multiple (number of 3) nodes with large sizes, hormonal therapy was the therapeutic choice. Therapeutic approach for the second case described in our report with a slow increase of PSA levels and a single pararectal nodal metastasis was SBRT, supported by literature demonstrating local control rates up to 92% at 5years and 5-year OS of up to 88% (3).

Evaluation of the delay in starting hormonal therapy needs to be considered. To conclude, helped from Ga-PSMA-PET/CT, exclusion of ano-rectal tumours, that frequently metastasize to the mesorectal area, seems to be necessary for consequent therapeutic management; moreover, shared discussion of treatment strategies into multidisciplinary team is mandatory for this setting of patients.

REFERENCES 1. Mourra N, Parc Y, McNamara D, et al. Lymph Node Metastases of Prostatic Adenocarcinoma in the Mesorectum in Patients With Adenocarcinoma or Villous Tumor of the Rectum With Collision Phenomenon in a Single Lymph Node: Report of Five Cases. Dis Colon Rectum. 2005; 48:384-389. 2. Hijazi S, Meller B, Leitsmann C, et al. See the Unseen: Mesorectal Lymph Node Metastases in Prostate Cancer. The Prostate. 2016; 76:776-780. 3. Chow K, McCoy P, Stuchbery R, et al. Developments in oligometastatic hormone‑sensitive prostate cancer. World Journal of Urology. 2018; 37(12):2549-2555.

CORRESPONDENCE Fabiola Patani Department of Radiation Oncology, University Hospital “Ospedali Riuniti” Ancona, Italy E-mail: fabiola.patani@yahoo.it Phone number: 071-5965792

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Istruzioni Autori AUDI.qxp_Stesura Seveso 29/11/18 10:15 Pagina 1

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REFERENCES

Advances in Urological Diagnosis and Imaging is a free open access journal. The Journal has the purpose of promote, spread and favorite the scientific knowledge and research in diagnosis and imaging in Urology, Andrology and Nephrology. Advances in Urological Diagnosis and Imaging publishes every 4 months original articles, reviews, case reports, position papers, guidelines, editorials, abstracts and congress proceedings.

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RESPONSIBILITIES Manuscripts are accepted with the understanding that they have not been published or submitted for publication in any other journal. Authors must submit the results of clinical and experimental studies conducted according to the Helsinki Declaration on clinical research and to the Ethical Code on animal research set forth by WHO (WHO Chronicle 1985; 39:51). The Authors must obtain permission to reproduce figures, tables and text from previously published material. Written permission must be obtained from the original copyright holder (generally the Publisher). Manuscripts must be written in English language in accordance with the “Uniform Requirements for Manuscripts submitted to biomedical journals” defined by The International Committee of Medical Journal Editors (http://www.ICMJE.org). Manuscripts in Italian language can be published only after translation (expenses will be charged to the Authors). Manuscripts should be typed double spaced with wide margins. They must be subdivided into the following sections: Title page - It must contain: a) title; b) a short (no more than 40 characters) running head title; c) first, middle and last name of each Author without abbreviations; d) University or Hospital, and Department of each Author; e) last name, address and e-mail of all the Authors; f) corresponding Author; g) phone and/or fax number to facilitate communication; h) acknowledgement of financial support; i) list of abbreviations.

SUMMARY

The Authors must submit a long English summary (300 words, 2000 characters). Subheadings are needed as follows: Objective(s), Material and method(s), Result(s), Conclusion(s). After the Summary, three to ten key words must appear, taken from the standard Index Medicus terminology.

TEXT

For original articles concerning experimental or clinical studies, the following standard scheme must be followed: Summary - Key Words Introduction - Material and Methods - Results - Discussion - Conclusions - References - Tables - Legends - Figures. Case Report should be divided into: Summary - Introduction (optional) Case report(s) - Conclusions - References (Discussion and Supplementary Figures, Tables and References can be submitted for publication in Supplementary Materials).

SIZE

OF MANUSCRIPTS

Literature reviews, Editorials and Original articles concerning experimental or clinical studies should not exceed 3500 words with 3-5 figures or tables, and no more than 30 references. Case reports, Notes on surgical technique, and Letters to the Editors should not exceed 1000 words (Summary included) with only one table or figure, and no more than three references. No more than five Authors are permitted.

TABLES

Tables must be aimed to make comprehension of the written text easier. They must be numbered in Arabic digits and referred to in the text by progressive numbers. Every table must be accompanied by a brief title. The meaning of any abbreviations must be explained at the bottom of the table itself.

FIGURES

Figures are also graphics, algorithms, photographs, drawings. Figures must be numbered and quoted in the text by number. The meaning of all symbols, abbreviations or letters must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in one or more separate pages. Please follow these instructions when preparing files: • Do not include any illustrations as part of your text file. • Do not prepare any figures in Word as they are not workable. • Line illustrations must be submitted at 600 DPI. • Halftones and color photos should be submitted at a minimum of 300 DPI.

MANUSCRIPT

REVIEW Only manuscript written according to the above mentioned rules will be considered. All submitted manuscripts are evaluated by the Editorial Board and/or by two referees designated by the Editors. The Authors are informed in a time as short as possible on whether the paper has been accepted, rejected or if a revision is deemed necessary. The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise, without altering its contents. Submission of a manuscript implies acceptation of all above rules.

MANUSCRIPT

PRESENTATION Authors must submit their manuscripts (MAC and WINDOWS Microsoft Word are accepted) to the Assistant Editor (dellatti@hotmail.com).

PROOFS

Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to the Corresponding Author. Proofs should be returned within seven days from receipt.

Ed sept_Cop+Ed+fisse 2006 24/09/20 17:28 Pagina IV 12:27 Pagina 1 21/09/20

ATLANTE di ECOGRAFIA UROLOGICA, ANDROLOGICA e NEFROLOGICA PASQUALE MARTINO

PRESENTANO

124 autori 592 pagine + di 1500 immagini ecografiche 61 video Hardcover Cofanetto

Costo di copertina € 180,00

Sconto del 50%

Per gli iscritti alle Scuole di Specializzazione in Urologia, Andrologia, Nefrologia (Inserendo il Codice: SPEC20-21).

Prezzo finale: € 90,00* L’opera è acquisabile inviando un’e-mail a: atlantediecografia@gmail.com * IVA e Spese di spedizione comprese