Imaging and Technology in Urology 3031260570, 9783031260575

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Imaging and Technology in Urology Sotonye Tolofari Dora Moon Benjamin Starmer Steve Payne Editors Second Edition

123

Imaging and Technology in Urology

Sotonye Tolofari • Dora Moon Benjamin Starmer  •  Steve Payne Editors

Imaging and Technology in Urology Second Edition

Editors Sotonye Tolofari Northern Care Alliance Salford Care Organisation Manchester, UK Benjamin Starmer Liverpool University Hospitals Liverpool, UK

Dora Moon Lancashire Teaching Hospitals NHS Foundation Trust Preston, UK Steve Payne Manchester University NHS Foundation Trust Manchester, UK

Springer-Verlag London 2012 ISBN 978-3-031-26057-5    ISBN 978-3-031-26058-2 (eBook) https://doi.org/10.1007/978-3-031-26058-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2012, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

Part I Imaging Radiology 1

 Principles of X-ray Production and Radiation Protection ������������������    3 Paul M. Taylor

2

 How to Perform a Clinical Radiograph and Use a C-arm ������������������    9 Paul M. Taylor

3

Contrast Agents����������������������������������������������������������������������������������������   13 Anas Hattab

4

 Dual Energy X-Ray Absorptiometry (DXA) ����������������������������������������   19 Nicholas Faure Walker and Richard Whitehouse

5

 The Physics of Ultrasound and Doppler������������������������������������������������   25 Paul M. Taylor

6

 How to Ultrasound a Suspected Renal Mass����������������������������������������   31 Allen Ikwuagwu

7

 How to Ultrasound a Painful Testicle and Mass������������������������������������   39 Allen Ikwuagwu

8

 How to Do a Trans-Perineal Ultrasound Guided Biopsy of the Prostate ����������������������������������������������������������������������������������������������������   47 Omar El-Taji, Samih Taktak, and John McCabe

9

 How to Manage an Infected Obstructed Kidney����������������������������������   55 Louise E. Olson

10 Principles  of Computed Tomography (CT) ������������������������������������������   59 Richard Hawkins 11 How  to Do a CT Urogram (CT)��������������������������������������������������������������   65 Varun Misra and Ryan Pathak

v

vi

Contents

12 How  to Do a Renal and Adrenal CT������������������������������������������������������   71 Varun Misra and Ryan Pathak 13 How  to Do a CT in a Patient with Presumed Upper Tract Trauma����   77 Anas Hattab and Jonathan Smith 14 Principles  of Magnetic Resonance Imaging (MRI)������������������������������   83 Richard Hawkins 15 Safety  in MR Scanning����������������������������������������������������������������������������   89 Suzanne Phenna 16 Urological  Applications of MRI Scanning ��������������������������������������������   95 Varun Misra and Ryan Pathak 17 Vascular  Embolisation Techniques in Urology��������������������������������������  103 Symeon Lechareas Part II Imaging Nuclear Medicine 18 Radionuclides  and Their Uses in Urology����������������������������������������������  113 Matthew Memmott and Richard Lawson 19 Counting  and Imaging in Nuclear Medicine ����������������������������������������  117 Christopher Mathews-Aspinall and Richard Lawson 20 Principles  of Positron Emission Tomography (PET) Scanning ����������  121 Phei Shan Chuah and Seshadri Nagabhushan 21 PET-CT  Imaging in Prostate Cancer ����������������������������������������������������  127 Seshadri Nagabhushan and Phei Shan Chuah 22 Understanding  the Renogram: How It’s Done and How to Interpret It������������������������������������������������������������������������������������������������  133 Rakesh Sajjan and Mary Prescott 23 The  Diuresis Renogram: How It’s Done and How to Interpret It������  139 Rakesh Sajjan and Mary Prescott 24 Understanding  the DMSA Scan: How It’s Done and How to Interpret It������������������������������������������������������������������������������������������������  143 Rakesh Sajjan and Mary Prescott 25 How  to Do a Radioisotope Glomerular Filtration Rate Study������������  147 Sarah Sargant and Richard Lawson 26 Understanding  the Radionuclide Bone Scan: How It’s Done and How To Interpret It������������������������������������������������������������������������������������������������  153 Rakesh Sajjan and Mary Prescott 27 Renography  of the Transplanted Kidney: How It’s Done and How to Interpret It������������������������������������������������������������������������������������������������  159 Rakesh Sajjan and Mary Prescott

Contents

vii

28 Dynamic  Sentinel Lymph Node Biopsy in Penile Cancer��������������������  165 Ben Ayres and Nick Watkin Part III Technology Diagnostic Technology 29 Urinalysis��������������������������������������������������������������������������������������������������  171 David G. Ross 30 Principles  of Urine Microscopy and Microbiological Culture������������  177 Ffion E. Carlin and Cecilia M. Jukka 31 Urinary Flow Cytometry������������������������������������������������������������������������  183 Harry Rudman and Dora Moon 32 Urine Cytology ����������������������������������������������������������������������������������������  187 Nadira Narine and Durgesh N. Rana 33 Histopathological  Processing, Staining and Immuno-Histochemistry 193 Tegan Miller 34 Tumour Markers��������������������������������������������������������������������������������������  197 Alex Hoyle 35 Measurement  of Glomerular Filtration Rate (GFR)����������������������������  205 Stephen Brown 36 Assessment  of Urinary Tract Stones������������������������������������������������������  209 Robert C. Calvert 37 Principles  of Pressure Measurement������������������������������������������������������  215 Ian Pearce 38 Principles  of Measurement of Urinary Flow ����������������������������������������  219 Timothy Napier-Hemy and Richard Napier-Hemy 39 How  to Carry Out a Video Cystometrogram (VCMG) in an Adult����  223 Magda Kujawa 40 Sphincter Electromyography (EMG)����������������������������������������������������  229 Emma L. Foster, Katherine E. Burnett, and Christopher D. Betts Part IV Technology Operative 41 Operating Theatre Safety������������������������������������������������������������������������  237 Steve Payne 42 Principles of Decontamination����������������������������������������������������������������  241 Sotonye K. Tolofari 43 Patient  Safety in the Operating Theatre Environment������������������������  247 Steve Payne

viii

Contents

44 Venous Thromboembolic Prevention ����������������������������������������������������  253 Christian Longley 45 Anticoagulants and Their Reversal��������������������������������������������������������  261 Gidon Ellis 46 Haemostatic Agents, Tissue Sealants and Adhesives����������������������������  267 Omer Abdalla and Suresh Venugopal 47 Transfusion in Urology����������������������������������������������������������������������������  271 Craig Carroll, Jayne Peters, and Harriet Lucero 48 Cell  Salvage in Urological Surgery��������������������������������������������������������  277 Craig Carroll, Jayne Peters, and Harriet Lucero 49 Principles  of Urological Endoscopes������������������������������������������������������  283 Hari L. Ratan 50 Rigid Endoscope Design��������������������������������������������������������������������������  287 James Broome 51 Light  Sources, Light Leads and Camera Systems��������������������������������  291 Hari L. Ratan 52 Peripherals  for Endoscopic Use��������������������������������������������������������������  295 Steve Payne 53 Peripherals  for Laparoscopic Use����������������������������������������������������������  301 Dora Moon 54 Peripherals  for Mechanical Stone Manipulation����������������������������������  305 Ciaran Lynch 55 Sutures and Clips ������������������������������������������������������������������������������������  311 Bachar Zelhof 56 Contact Lithotripters������������������������������������������������������������������������������  319 Tom Brophy and Steve Payne 57 Monopolar Diathermy ����������������������������������������������������������������������������  325 Luke Forster 58 Bipolar Diathermy ����������������������������������������������������������������������������������  329 Luke Forster 59 Alternatives to Electrosurgery����������������������������������������������������������������  333 Bachar Zelhof 60 Operative Tissue Destruction������������������������������������������������������������������  337 Matthew Liew 61 Endoscopic  Use of Laser Energy������������������������������������������������������������  341 Tev Aho and Omar Al Kadhi

Contents

ix

62 Double  J Stents and Nephrostomy ��������������������������������������������������������  349 Tom Brophy and Steve Payne 63 Urinary  Catheters, Design and Usage����������������������������������������������������  355 Benjamin Starmer 64 Urological Prosthetics������������������������������������������������������������������������������  361 Ian Eardley 65 Mesh in Urological Surgery��������������������������������������������������������������������  367 Niyukta Thakare and Chris Harding 66 Irrigation  Fluids and Their Hazards������������������������������������������������������  373 Matthew Liew 67 Insufflants and Their Hazards����������������������������������������������������������������  377 Yuhao Zhang and Stephen Bromage 68 Laparoscopic Ports����������������������������������������������������������������������������������  383 Euan Green 69 Principles  of Robotic Surgery ����������������������������������������������������������������  387 Robin Weston 70 Setting  Up Robotic Surgery��������������������������������������������������������������������  393 Robin Weston 71 Principles  of Tissue Transfer for Urologists������������������������������������������  397 Patrick Gordon, Wai Gin Lee, and David Ralph Part V Technology Interventional 72 Neuromodulation  by Sacral Nerve Stimulation������������������������������������  405 Katherine E. Burnett, Christopher D. Betts, and Emma L. Foster 73 Principles  of Extracorporeal Shockwave Lithotripsy (ESWL) ����������  409 Robert C. Calvert 74 How  to Carry Out Shockwave Lithotripsy (SWL) ������������������������������  415 Robert C. Calvert 75 Novel Technologies for BPH��������������������������������������������������������������������  419 Craig Jones 76 Ablative Therapies ����������������������������������������������������������������������������������  427 Nikhil Mayor and Taimur T. Shah 77 Principles of Radiotherapy����������������������������������������������������������������������  433 Martin Swinton and Andrew Hudson 78 Brachytherapy  for Prostate Cancer ������������������������������������������������������  439 Mariam Obeid and Maria Serra

x

Contents

79 Augmented Intravesical Drug Administration��������������������������������������  447 Benjamin Starmer and Henry Lazarowicz Part VI Technology of Renal Failure 80 Principles  of Renal Replacement Therapy (RRT)��������������������������������  455 Mumtaz Patel 81 Principles  of Peritoneal Dialysis ������������������������������������������������������������  459 Dimitrios Poulikakos and David Lewis 82 Haemodialysis������������������������������������������������������������������������������������������  465 Mumtaz Patel 83 Principles of Renal Transplantation������������������������������������������������������  469 David Van Dellen and Jennifer Kingston Part VII Assessment of Technology 84 Key  Concepts in the Design of Randomised Controlled Trials������������  477 Kieran J. O’Flynn 85 Reporting  and Interpreting Data from RCTs ��������������������������������������  483 Kieran J. O’Flynn 86 Health Technology Assessment (HTA) ��������������������������������������������������  489 Luke Vale, Diarmuid Coughlan, and Michael Drinnan Appendices��������������������������������������������������������������������������������������������������������  493

List of Contributors

Omer  Abdalla  Liverpool Liverpool, UK

University

Hospitals

NHS

Foundation Trust,

Tev Aho  Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK Ben Ayres  St George’s University Hospitals NHS Trust, London, UK Christopher  D.  Betts  Salford Care Organisation, Northern Care Alliance, Salford, UK Stephen Bromage  Stockport NHS Foundation Trust, Stockport, UK James Broome  Salford Care Organisation, Northern Care Alliance, Manchester, UK Tom Brophy  Manchester Royal Infirmary, Manchester, UK Stephen Brown  Stockport NHS Foundation Trust, Stockport, UK Katherine  E.  Burnett  Salford Care Organisation, Northern Care Alliance, Salford, UK Robert  C.  Calvert  Liverpool University Hospital NHS Foundation Trust, Liverpool, UK Ffion  E.  Carlin  Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK Craig Carroll  Salford Care Organisation, Northern Care Alliance, Salford, UK Phei  Shan  Chuah  Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK Diarmuid Coughlan  Newcastle University, Newcastle upon Tyne, UK David  Van Dellen  Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK

xi

xii

List of Contributors

Michael  Drinnan  Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Ian Eardley  Leeds Teaching Hospitals NHS Trust, Leeds, UK Gidon Ellis  Royal Free London NHS Foundation Trust, London, UK Omar El-Taji  St Helens and Knowsley Teaching Hospitals NHS Trust, Prescot, UK Luke Forster  Frimley NHS Foundation Trust, Frimley Park Hospital, Frimley, UK Emma L. Foster  Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK Patrick Gordon  Leeds Teaching Hospitals NHS Trust, Leeds, UK Euan Green  Salford Care Organisation, Northern Care Alliance, Manchester, UK Anas Hattab  Manchester University NHS Foundation Trust, Manchester, UK Richard Hawkins  Mid-Cheshire Hospitals NHS Foundation Trust, Crewe, UK Alex Hoyle  Salford Care Organisation, Northern Care Alliance, Salford, UK Andrew Hudson  Christie Hospital NHS Foundation Trust, Manchester, UK Allen  Ikwuagwu  Royal Blackburn Hospital, Haslingden Road, Blackburn, Lancashire, UK Craig Jones  Salford Care Organisation, Northern Care Alliance, Manchester, UK Cecilia M. Jukka  Liverpool University Hospitals Foundation Trust, Liverpool, UK Omar  Al Kadhi  Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK Jennifer Kingston  Manchester University NHS Foundation Trust, Manchester, UK Magda  Kujawa  Stepping Hill Hopsital, Stockport NHS Foundation Trust, Stockport, UK Richard  Lawson  Nuclear Medicine Centre, Manchester University NHS Foundation Trust, Manchester, UK Henry Lazarowicz  Liverpool University Hospitals, Liverpool, UK Symeon Lechareas  Liverpool University Hospitals, Liverpool, UK Wai  Gin  Lee  University College London Hospitals NHS Foundation Trust, London, UK David Lewis  Salford Care Organisation, Northern Care Alliance Foundation Trust, Salford, UK Matthew Liew  Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK

List of Contributors

xiii

Christian Longley  Liverpool University Hospitals, Liverpool, UK Harriet Lucero  Salford Care Organisation, Northern Care Alliance, Salford, UK Ciaran Lynch  Liverpool University Hospitals, Liverpool, UK Christopher Mathews-Aspinall  Nuclear Medicine Centre, Manchester University Hospitals, Manchester, UK Nikhil Mayor  Imperial College London (ICL), Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK John McCabe  St Helens and Knowsley Teaching Hospitals, Prescot, UK Matthew  Memmott  Manchester Manchester, UK

University

NHS

Foundation

Trust,

Tegan Miller  Manchester Royal Infirmary, Manchester, UK Varun  Misra  Salford Care Organisation, Northern Care Alliance NHS Trust, Salford, UK Dora Moon  Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK Timothy  Napier-Hemy  Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK Richard Napier-Hemy  Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK Nadira Narine  Manchester University NHS Foundation Trust, Manchester, UK Mariam Obeid  The Christie NHS Foundation Trust, Manchester, UK Kieran  J.  O’Flynn  Salford Care Organisation, Northern Care Alliance, Manchester, UK Louise E. Olson  Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK Mumtaz  Patel  Manchester University Hospitals NHS Foundation Trust, Manchester, UK Ryan  Pathak  Salford Care Organisation, Northern Care Alliance NHS Trust, Salford, UK Steve Payne  Manchester Royal Infirmary, Manchester, UK Ian Pearce  Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK Jayne Peters  Manchester Foundation Trust, Manchester, UK Suzanne Phenna  Northern Care Alliance NHS Foundation Trust, Salford, UK

xiv

List of Contributors

Dimitrios  Poulikakos  Salford Care Organisation, Northern Care Alliance Foundation Trust, Salford, UK Mary Prescott  Manchester University NHS Foundation Trust, Manchester, UK David Ralph  University College Hospital, London, UK Durgesh N. Rana  Manchester University NHS Foundation Trust, Manchester, UK Hari L. Ratan  Nottingham University Hospitals NHS Trust, Nottingham, UK David G. Ross  Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UK Harry Rudman  Lancashire Teaching Hospitals Trust, Preston, UK Rakesh Sajjan  Manchester University NHS Foundation Trust, Manchester, UK Sarah Sargant  Manchester University NHS Foundation Trust, Manchester, UK Maria Serra  The Christie NHS Foundation Trust, Manchester, UK Seshadri  Nagabhushan  Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK Taimur T. Shah  Imperial College Healthcare NHS Trust, London, UK Jonathan Smith  St James’s University Hospital, Leeds, UK Benjamin Starmer  Liverpool University Hospitals, Liverpool, UK Martin Swinton  Christie Hospital NHS Foundation Trust, Manchester, UK Samih Taktak  St Helens and Knowsley Teaching Hospitals, Prescot, UK Paul M. Taylor  Manchester University NHS Foundation Trust, Manchester, UK Niyukta  Thakare  Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Chris Harding  Freeman Hospital, High Heaton, Newcastle upon Tyne, UK Sotonye  K.  Tolofari  Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UK Luke Vale  Newcastle University, Newcastle upon Tyne, UK Suresh  Venugopal  Liverpool University Hospitals, NHS Foundation Trust, Liverpool, UK Nicholas  Faure  Walker  Kings College Hospital NHS Foundation Trust, London, UK Nick Watkin  St George’s University Hospitals NHS Trust, London, UK

List of Contributors

Robin  Weston  Liverpool Liverpool, UK

xv

University

Hospitals

NHS

Foundation

Trust,

Richard Whitehouse  Manchester Royal Infirmary, Manchester, UK Bachar Zelhof  Manchester University, NHS Foundation Trust, Manchester Royal Infirmary, Manchester, UK Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK Yuhao Zhang  Stockport NHS Foundation Trust, Stockport, UK

Part I

Imaging Radiology

Chapter 1

Principles of X-ray Production and Radiation Protection Paul M. Taylor

Plain radiography, intra-venous urography, computed tomography (CT), and fluoroscopy all use ionizing radiation to produce the images used to investigate and treat patients with a wide variety of urological conditions. However, such image acquisition comes at the cost of radiation exposure with its associated risks. It is important to understand the principles behind X-ray production and radiation protection to make best use of these imaging modalities, while at the same time minimising the radiation burden to the patient.

Principles of X-Ray Production X-rays are part of the spectrum of electromagnetic radiation (Fig. 1.1), They are of higher frequency (3 × 1019 to 1016 Hertz) and shorter wavelength (10−8 to 10−12 m) than visible light. The higher frequency and associated higher energy values, typically in the range of 60–120 keV, allow them to penetrate tissue. The higher energy values also provide an explanation why they are potentially damaging to these tissues. X-rays are produced in a glass tube which contains an anode and a cathode in a vacuum (Fig. 1.2).

P. M. Taylor (*) Manchester University NHS Foundation Trust, Manchester, UK © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_1

3

4

P. M. Taylor

Decreasing wavelength Increasing frequency Increasing energy

Wavelength (metres) 106

103

Radio

10

10–3

Microwave

10–6

Infra-red

10–9

10–12

Visible X-Rays Light

10–15

Gamma Rays

Fig. 1.1  X-Rays place in the electromagnetic spectrum

X-Ray beam

Collimator

Glass Envelope

Lead housing

Tungsten Anode

Heated Cathode

Fig. 1.2  X-Ray generation and production of a beam for use in imaging

1  Principles of X-ray Production and Radiation Protection

5

The cathode is heated and this causes the release of free electrons. A very high voltage is applied between the anode and the cathode. The free electrons are then accelerated towards the anode where x-rays are produced by two mechanisms.

Bremsstrahlung or Breaking Radiation This is produced by the sudden deceleration of electrons as they pass close to an atomic nucleus. The resultant loss in kinetic energy results in the emission of X-rays. However, the loss of energy is variable, and so the electrons produce a spectrum of X-rays with different energy values. These are ineffective in producing an image.

Characteristic Radiation This is produced when an incoming electron has sufficient energy to overcome the binding energy of one of the electrons in the anode atom’s orbital shells. This orbital electron then “drops” into a lower energy shell, and the resulting energy loss is released as an X-ray with a particular fixed energy value. This radiation is of a specific wavelength and energy and can be used to produce an image.

X-ray Tube The production of X-rays by this process is relatively inefficient and the majority of the energy used is dissipated as heat. To ensure the heat is distributed evenly within the anode, the anode rotates during X-ray production. X-ray tubes producing a high output over an extended period of time, for example those used in CT systems, are additionally cooled by external cooling systems. The X-ray tube is encased in a protective lead housing to prevent X-rays ‘escaping’ The emission of X-rays from the tube is controlled by a collimator. This is usually adjustable in size and allows only X-rays involved in producing the image to exit. The exiting X-ray beam is directed to pass through the patient. Tissues of different radiographic density within the patient cause attenuation of X-rays at different rates. The radiographic density is related to the mean atomic number of the tissue. For example, the X-ray beam is attenuated to a much greater degree by bone, due to its high calcium content, than lung. This allows different tissue types to be differentiated in the final image. Conversely the majority of soft tissues, are of similar mean density and cannot be differentiated on conventional radiography.

P. M. Taylor

6

X-ray Detection To produce an image from the X-ray beam emerging from the patient and, a detection system is required. In conventional radiography X-ray film is contained within a cassette. A fluorescent screen made of phosphors lies in close contact with the film and acts as a detector system. When the X-ray beam strikes the screen within the cassette, light is emitted striking the film and producing a latent image. The film is then developed to produce a hard copy X-ray film. Modern radiography systems use either a reusable plate incorporating a photostimulable phosphor which is scanned after exposure to produce an image (Computed radiography-CR) or a matrix of individual detectors that produce a digital image directly without the use of an intermediate plate (Digital radiography­DR). The latter is comparable to a digital camera. Although X-ray attenuation is crucial to the formation of the image, it is also the source of radiation dose to the patient. In addition, X-rays passing through the patient are scattered in different directions and are a source of potential radiation dose to other people in close proximity, including health-care professionals.

Radiation Protection Ionising radiation can cause two distinguishable types of harm to the body, deterministic and stochastic effects.

Deterministic Effects These include skin erythema, cataracts and gonadal hypofunction. There is a threshold dose below which no damage occurs (Table 1.1). Above this level the severity of these effects depends on the total radiation dose. The dose is cumulative and the lifetime radiation dose should be considered rather than the dose from an individual examination.

Table 1.1  Thresholds for deterministic effects

Lens cataracts Skin erythema Testes-Temporary sterility Testes-Permanent sterility

>2.0 Sv >2.0 Sv >0.15 Sv >3.5 Sv

1  Principles of X-ray Production and Radiation Protection

7

Stochastic Effects Most significantly these include carcinogenesis and mutagenesis. These have no threshold dose, even a single exposure can cause damage. The frequency of stochastic effects increases with increasing dose, but their severity does not. Some tissues (e.g. breast) are more sensitive to radiation induced carcinogenesis than others (e.g. kidney). Radiation dosimetry is complex but in routine practice is best measured in milli-­ Sieverts (mSv). The theoretical lifetime risk of developing a fatal cancer caused by radiation exposure has been estimated at approximately 1 in 20,000 per mSv. It should be noted that although individuals receive a ‘normal’ dose of radiation from the environment and cosmic radiation, diagnostic radiology procedures are responsible for the greatest single manmade radiation dose to the population. The yearly background radiation dose in the UK is approximately 2 mSv per person. Regulations exist, which vary between countries, to prevent these unwanted effects. In the UK, the regulations include:

Ionising Radiations Regulations 2017 These primarily relate to the protection of people in their place of work and is enforced by the Health Security Authority. Radiation dose limits for employees are determined, and if exceeded, this must be investigated and reported.

Ionising Radiation (Medical Exposure) Regulations 2017 These concern protection of patients and identify responsibilities for employers, referrers, operators and practitioners. The referrer must supply sufficient information for the practitioner to make an informed judgment that the exposure is justified. An overarching principle of radiation protection is “ALARA’ keeping radiation exposure “as low as reasonably achievable” to both staff and patients. In practice this involves measures such as minimizing the number of X-ray exposures, using non ionising imaging techniques if appropriate, ensuring adequate collimation of the X-ray beam, keeping fluoroscopy time to a minimum, ensuring non-essential staff are not in the room when X-ray exposures are made, ensuring staff move away from the patient during exposure to minimize dose from scattered radiation and wearing appropriate safety garments (e.g. lead aprons thyroid shields etc.).

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Chest X-ray KUB X-ray Intravenous urogram Three phase CT urogram

0.02 mSv 0.6 mSv 3 mSv 15 mSv

Diagnostic reference levels (DRLs) exist which act as a guide to appropriate patient doses for particular examinations (Table  1.2). These are set nationally, although organisations often set their own lower levels. Exceeding a DRL for a single examination is not usually an issue, but if DRLs are regularly exceeded, this should be investigated.

Further Reading The Ionising Radiations Regulations 2017. UK Statutory Instruments (2017) No. 1075. https:// www.legislation.gov.uk/uksi/2017/1075/contents/made The Ionising Radiation (Medical Exposure) Regulations 2017. UK Statutory Instruments (2017) No. 1322. https://www.legislation.gov.uk/uksi/2017/1322/made

Chapter 2

How to Perform a Clinical Radiograph and Use a C-arm Paul M. Taylor

Despite the widespread increased availability of CT and MRI, the plain radiograph (e.g., the KUB abdominal film) remains a key diagnostic tool for the urologist. In addition, the mobile image intensifier or C-arm allows real-time imaging to guide a variety of urological procedures. Although a radiographer is commonly employed to perform clinical radiographs and operate the C-arm, it is important that the urologist understands the principles behind their function to make best use of these modalities and ensure safe use.

How to Perform a Clinical Radiograph Before undertaking any radiographic examination, appropriate checks must be undertaken to ensure that the correct patient and anatomical region is being radiographed. For pre-menopausal women, if the abdomen or pelvis are to be irradiated, it is also important to assess if there is any possibility of pregnancy. Performing a clinical radiograph involves placing the appropriate body part of the patient between an X-Ray tube and a detector. The components of the X-Ray tube and detector were described in the Chap. 1. The patient should be placed as close as possible to the detector. The detector may be an X-Ray film, CR plate or a DR system. The X-Ray beam originates from a point source in the X-Ray tube anode and diverges to fill the area of the detector. By placing the patient close to the detector, the degree of magnification which occurs due to the divergence of the beam is minimized. Proximity to the detector also helps to maintain image quality by reducing the amount of scattered radiation

P. M. Taylor (*) Manchester University NHS Foundation Trust, Manchester, UK © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_2

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reaching the detector. The distance from the X-Ray tube to the detector varies depending on the examination but is typically 100 cm for an abdominal and 180 cm for a chest radiograph. The X-Ray beam is collimated as it leaves the X-Ray tube using an adjustable collimator to ensure only the structures to be imaged are irradiated. This reduces radiation dose to the patient and which degrades the image. Collimation of the x ray beam is facilitated by a light beam which overlies to the X-Ray beam and can be viewed by the operator. Relevant markers (e.g. side, time of examination, position of patient) are placed on the detector at a suitable site so as not to obscure any important image detail. Prior to exposure, three variables need to be determined—tube current measured in milliampere (mA), exposure time measured in seconds, and the peak tube voltage measured in kilovolts (kVp). The tube current measures the electrical current that flows through the cathode to the anode and thus the number of electrons produced. The exposure time determines the time for which X-Rays are produced. Tube current and exposure time determine the total amount of X-Rays produced and are often considered together as mAs (milliampere second). A larger mAs will be required for a larger patient. An inappropriate mAs will result in either an overexposed or underexposed film. The tube voltage determines the potential difference between the cathode and anode and affects the “power” of the X-Ray beam. Increasing the kVp increases the penetrating power of the X-Rays. A higher kVp potentially reduces the radiation dose to the patient but produces an image with less contrast which appears more grey and less black and white. Before the final exposure takes place, it is important to ensure that all people present are adequately protected from extraneous irradiation. This may involve standing behind a protective screen, leaving the examination room or wearing protective lead clothing. For radiographs of the chest or abdomen the patient is asked to hold their breath to avoid the image being blurred by respiratory motion. Conventional hard copy films are less common now, and typically the final CR or DR image will be stored on a Picture Archiving and Communication System (PACS) and viewed on a dedicated workstation or networked computer. Recent images are usually stored on a local server and older images on an off-site server resulting in a “filmless” environment.

How to Use a C-arm Image intensification systems are used to provide images during fluoroscopy (screening). Compared to radiography they use a much smaller dose of radiation to produce an image and allow constant updating of the image to produce a real time moving image.

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When X-Rays strike the front face of an image intensifier they cause light photons to be emitted from the detector input screen. The photons then strike a photocathode and are converted into electrons. The electrons are accelerated by a high voltage towards an output screen which converts the electrons back to light and an image is produced. By this process one X-Ray photon at the input screen is converted into several hundred thousand light photons at the output screen, enabling a good quality image to be produced almost instantaneously. Image intensification systems can be installed in fixed or mobile systems. The latter is often referred to as a C-arm system. These are widely used in operating theatres. There are specific considerations that apply to mobile fluoroscopic equipment. In a C-arm, the X-Ray tube and the intensifier are tethered and able to rotate whilst maintaining a fixed focal point, meaning projections at many different angles can be obtained without moving the patient. To allow the system to be mobile the X-ray tubes and intensifiers used in C-arms are smaller and lighter than those in fixed systems. This in turn results in a reduction in image quality. The device is controlled either by a handheld control or by foot pedals that allow screening (real- time images) or image capture (single image for permanent copy). Most C-arms require a key to operate them to prevent their use by unauthorized or untrained staff. Screening may be continuous fluoroscopy, during which the X-Ray beam is delivered constantly or pulsed fluoroscopy when the X-ray beam is delivered in short bursts (e.g., four frames per second), Pulsed fluoroscopy offers significantly reduced radiation dose but produces a “jerky” image rather than the smooth image provided by continuous fluoroscopy. The C-arm is commonly used in the operating theatre, often with many people present. Moreover, staff may be present for several procedures during a session and may be involved in similar weekly sessions. Although the radiation dose received for each procedure may be small it is possible for staff to receive a significant cumulative dose over several years. It is therefore crucial to keep radiation dose as low as possible. Ways to decrease dose to staff and patients include: 1. Keep screening time to a minimum. Only screen when necessary and never screen when not looking at the image. 2. Ensure the surgeon’s, and assistant’s, fingers are not in the primary beam. 3. Where possible use pulsed fluoroscopy rather than continuous fluoroscopy, with as low frame rate as practicable. 4. Use collimation to image only the exact region of interest. 5. Use high kVp if possible. This will increase the penetrative ability of the X-Ray beam, resulting in less absorption within the patient, but at the expense of image contrast 6. Position the detector as close to the patient as possible. This will also increase the quality of the image 7. Ensure all non-essential staff leave the operating theatre during screening. 8. Ensure remaining staff move as far away from the patient as possible to reduce the dose from scattered radiation. The inverse square law applies—doubling the distance reduces the radiation dose fourfold.

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9. Wear adequate protective garments, including thyroid shields. 10. If appropriate consult with the local radiation protection advisor to consider whether individual dose monitoring may be advisable.

Further Reading Joh JH. Endovascular intervention with a mobile C-Arm in the operating room. Vasc Specialist Int. 2019;35(2):70–6. Whitley SA, Dodgeon J, Meadows A, Cullingworth J, Holmes K, Jackson M, Hoadley G, Kulshrestha R.  Clark’s procedures in diagnostic imaging: a system-based approach. CRC Press; 2020.

Chapter 3

Contrast Agents Anas Hattab

Contrast agents are a heterogeneous group of pharmaceuticals used during radiological procedures to enhance tissue definition, enabling clearer delineation of normal anatomy and better characterisation of abnormalities. There are three main groups of contrast agents available: iodinated agents, gadolinium based agents and micro-bubble particles.

Iodinated Agents These are used as radiographic contrast agents. They are formed from organic acid salts of iodine. The relatively high molecular weight of iodine I127 makes it radio opaque. The initial use of sodium iodide as a contrast agent was limited by its toxicity; in the 1990s non-ionic contrast media were introduced being both better tolerated and safer. Non-ionic, low or iso-osmolar iodinated media are 5–10 times safer than the older, high osmolar ionic compounds. When injected intravenously (IV) iodinated agents are rapidly eliminated by renal excretion. They pass into the extra-vascular space and through the placenta but do not penetrate the blood brain barrier. Iodinated agents can be injected intra-­ arterially, directly into body cavities (e.g. bladder, ureter, biliary tree etc.), IV or orally. The timing of the images obtained during the contrast study is crucial in imaging specific body structures during scanning. The selection of a specific contrast will be determined by availability, local cost and application. Contrast agents are manufactured in varying concentrations: A. Hattab (*) Manchester Royal Infirmary, Oxford Road, Manchester, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_3

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• high concentration agents (high radio-opacity and viscosity)—used for IV enhancement during CT • low concentration agents (lower radio-opacity and viscosity)—used for direct examinations such as urethrography and direct pyelography. Iodinated agents are relatively safe with low overall rates of adverse reactions (0.15%). Common and rare reactions are outlined in Table  3.1. Life threatening reactions are rare with non-ionic contrast media, with the incidence between 0.004–0.04%. The risk of a severe reaction is greater after any previous contrast reaction, regardless of its severity. Any reaction should be recorded in the patient’s records, in the radiology report and on the radiology information system (RIS). The patient should be made aware of the risk of further allergy to contrast administration the MHRA should be informed.

Contraindications Renal impairment. Iodinated agents carry a risk of acute kidney injury (CI-AKI). The risk is increased in a patient with any of the following: • • • • • • • •

chronic kidney disease (eGFR  65 years of age are at particular risk. Radiographers will administer GCBA under a Patient Group Directive (PGD) specifying the need for an eGFR in all higher risk patients. The decision to give contrast to patients with an eGFR of 300 μm or glue followed by complete devascularisation of the kidney with

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proximal coils or vascular plugs in the renal artery, if necessary. Post-embolisation syndrome may occur if a large volume of tissue has been devascularised. This is characterized by severe pain, fever and virus type symptoms. Symptoms can last up to 72  h and mimic infection or abscess formation. A strict protocol of analgesia should be followed after the procedure as kidney ischemia may induce severe pain. Varicocele embolisation (Figs.  17.1 and 17.2) can be performed through the common femoral or internal jugular vein. Indications include chronic testicular pain and subfertility. It is a safe and minimally invasive procedure with short recovery Fig. 17.1  Selective left gonadal venogram prior to embolization which shows retrograde filling of the pampiniform plexus

108 Fig. 17.2 Post embolization venogram of the left gonadal vein which shows complete occlusion of the vessel. Embolization performed with platinum coils

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time. Selective internal spermatic venography is performed to confirm the presence of reflux and to assess for collaterals which are a common cause of recurrence. The catheter tip is advanced to just above the level of the inguinal ligament and a series of coils deployed from this point up to the level of L3. Bear, fibered or detachable coils are commonly used.

Post-surgical Pelvic Bleeding There is an increasing role in the management of arterial haemorrhage following pelvic surgery. Given the well-developed collateral and anastomotic supplies in the pelvis, bilateral internal iliac imaging is usually required unless an obvious focal bleeding point is seen on CT. If haemorrhage is limited to a single vessel, coils or gelfoam are the treatment of choice. Selective particle embolisation is used for more diffuse pathology such as bleeding bladder tumours. Rarely, selective bilateral internal iliac artery embolisation may be required. There is an increased risk of non-­ target necrosis in older patients, arteriopaths and those who have undergone radiotherapy due to collateral disruption. Prostatic artery embolization (PAE) is a minimally invasive treatment for benign prostatic hyperplasia (BPH) with the advantages of short hospital stay and repeatability. Indications for prostate artery embolization include those for other surgical options of bladder outflow obstruction. The procedure is performed through the right common femoral artery. Arterial rotation CT angiography (cone-beam CT) is performed to identify the anatomy. Bilateral embolization of the prostate arteries is targeted. The prostate artery must be super-selectively catheterised with a microcatheter and embolised with microspheres with a size of 300–500 μm.

Further Reading Sheth RA, Sabir S, Krishnamurthy S, et al. Endovascular embolization by transcatheter delivery of particles: past, present, and future. J Funct Biomater. 2017;8(2):12. Taslakian B, Ingber R, Aaltonen E, Horn J, Hickey R. Interventional radiology suite: a primer for trainees. J Clin Med. 2019;8(9):1347. Published 2019 Aug 30.

Part II

Imaging Nuclear Medicine

Chapter 18

Radionuclides and Their Uses in Urology Matthew Memmott and Richard Lawson

This chapter describes the ideal properties of radiopharmaceuticals and radionuclides that are required for nuclear medicine imaging with a gamma camera or a PET scanner. It shows the radiation dose to the patient from some nuclear medicine studies used in urology and explains the principles of radiation protection of the patient. Nuclear medicine utilises radioactive tracers to assess organ function. These tracers are called radiopharmaceuticals and many different radiopharmaceuticals are used depending on the organ or system to be studied. After administration to the patient, usually by intravenous injection, the amount of radiopharmaceutical appearing in different parts of the body is monitored by detecting the radioactivity. This can be done with non-imaging tests involving only blood samples (eg GFR, see Chap. 25), by taking images with a gamma camera (see Chap. 19), or imaging with a positron emission tomography (PET) scanner (see Chap. 20). Nuclear medicine images have poor spatial resolution but they demonstrate physiology rather than anatomy and so are complementary to other imaging modalities.

Radiopharmaceuticals The radiopharmaceutical has two parts; a pharmaceutical and a radionuclide label. An ideal radiopharmaceutical should have the properties shown in Box 18.1.

M. Memmott · R. Lawson (*) Manchester University NHS Foundation Trust, Manchester, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_18

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Box 18.1 The characteristics of an ideal radiopharmaceutical • The label should remain bound to the pharmaceutical in-vivo • The pharmaceutical should concentrate only in the organ under investigation • Background remaining in rest of the body should be low • It should not be toxic to the patient and not interfere with the physiological process under investigation • Ideally the radionuclide should emit only gamma rays (no alpha or beta emissions because these are too easily absorbed by the body) • For imaging with a gamma camera, the gamma rays emitted should have a suitable energy; more than 100 keV so that they can escape from the patient and less than about 300 keV so that they can be stopped by the gamma camera detector. • For imaging with a PET scanner the radionuclide should emit positrons with a low energy so that they only travel a short distance in the patient before combining with an electron to give a pair of 511 keV gamma rays (see Chap. 20) • The radionuclide should have a suitable half-life (the time it takes for half the radioactivity to decay away). In most applications a half-life of a few hours gives enough time to prepare the radiopharmaceutical and complete the test. • It should be cheap and readily available

Radionuclides A radionuclide is a radioactive form of an atom (Appendix 3). Table 18.1 shows the properties of some radionuclides that can be used in nuclear medicine. For the majority of gamma camera imaging studies the preferred radionuclide is technetium-99 m (99mTc). Tc is the chemical element, ‘99’ is its mass number and the ‘m’ means that it is a metastable (excited) state. 99mTc has the properties shown in Box 18.2.

Box 18.2 The properties of technetium-99 m • It decays by emission of gamma rays only (no alpha or beta emission) • The gamma ray energy is 140  keV (which is ideal for gamma camera imaging) • It has a half-life of 6 hours (which is very convenient) • It is readily available from a generator which can provide a daily supply of 99m Tc from the decay of a longer lived parent (99Mo)

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18  Radionuclides and Their Uses in Urology Table 18.1  Properties of some radionuclides Radionuclide Technetium-99 m Fluorine-18 Gallium-68 Carbon-11

Emission 140 keV gamma ray Positron →two 511 keV gammas Positron →two 511 keV gammas Positron →two 511 keV gammas

Half-life 6 hr 110 min 68 min 20 min

Production method Generator Cyclotron Generator Cyclotron

Nuclear medicine departments will obtain the radiopharmaceuticals that they need for their investigations from a nearby radiopharmacy. In the radiopharmacy 99m Tc is extracted from a 99Mo generator by a process called elution. The eluate is added to a sterile vial containing the freeze-dried pharmaceutical which must then be used within a few hours. Most radiopharmacies will have access to a 99Mo generator, so 99mTc radiopharmaceuticals are widely available. For PET studies Gallium-68 (68Ga) can be extracted from a generator in a similar way to 99mTc, but it is much more expensive and not widely available. Carbon-11 (11C) can only be produced in a cyclotron and it has a very short half-life so it is only available in a few centres that have an on-site cyclotron. Fluorine-18 (18F) is also produced in a cyclotron, but it has a longer half-life so it can be purchased from a nearby supplier. Because these radionuclides are very easily detected, it is possible to administer very small quantities of pharmaceutical (micrograms or less) so that they do not disturb the normal functions of the organ or system under investigation. This is known as the tracer principle.

Radionuclide Dosimetry The radiation dose to the patient can be kept low by using suitable radionuclides, since most of the gamma rays escape from the patient (because of the suitable energy), and the radioactivity doesn’t linger unnecessarily long (because of the short half-life). The radiation dose obviously depends directly on the amount of radionuclide administered. This is measured in units of MBq (MegaBequerels)—1 MBq is a million atoms disintegrating every second. The radiation doses from some nuclear medicine procedures used in urology are shown in Table 18.2. For comparison, the radiation dose in the UK from natural background averages 2.2 mSv per year. It can be seen that the radiation dose from most gamma camera studies is less than one year’s natural background whilst PET studies, which are largely used for malignant conditions, give a higher dose.

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Table 18.2  The radiation dose received from some nuclear medicine studies carried out on urological patients Procedure PET scan for tumour imaging PET scan for prostate cancer PET scan for prostate cancer PET scan for prostate cancer PET scan for prostate cancer PET bone scan Gamma camera bone scan Renogram Renogram DMSA scan GFR determination

Radio-­pharmaceutical 18 F FDG 18 F choline 18 F PSMA 68 Ga PSMA 11 C choline 18 F sodium fluoride 99m Tc MDP 99m Tc DTPA 99m Tc MAG3 99m Tc DMSA 99m Tc DTPA

Typical administered activity 400 MBq 370 MBq 280 MBq 200 MBq 370 MBq 250 MBq 600 MBq 200 MBq 100 MBq 80 MBq 10 MBq

Radiation dose to the patient 7.6 mSv 7.4 mSv 5.5 mSv 4.6 mSv 1.6 mSv 4.3 mSv 3.0 mSv 1.0 mSv 0.7 mSv 0.7 mSv 0.05 mSv

Radiation Protection in Nuclear Medicine Any risk must be justified by a benefit to the patient and so, just as with X-ray studies, all nuclear medicine studies in the UK come under the Ionising Radiation (Medical Exposure) IR(ME)R Regulations. This means that the clinical referrer must provide the necessary clinical information for the practitioner to justify carrying out the procedure. In nuclear medicine the practitioner is always a consultant who holds a licence from the Administration of Radioactive Substances Advisory Committee (ARSAC) authorising them to carry out a specific procedure. Employers must also hold a licence, listing the practitioners and procedures authorised for each specific site or installation under their management. Research studies require a separate ARSAC certificate for each project. Although patients will themselves remain radioactive for a few hours after these studies they do not constitute a significant hazard and will not need any special nursing precautions. Although much of the radiopharmaceutical is excreted in the urine, normal hygiene precautions (such as plastic apron and gloves) are sufficient to avoid accidental ingestion of radioactivity by nursing staff. However, it would be sensible not to do a cystoscopy on the same day as a bone scan or a renogram if this can be avoided.

Further Reading Sharp PF, Gemmell HG, Murray AD, editors. Practical nuclear medicine. 3rd ed. Springer; 2005.

Chapter 19

Counting and Imaging in Nuclear Medicine Christopher Mathews-Aspinall and Richard Lawson

Nuclear medicine studies require the detection of gamma-emitting radiopharmaceuticals within the patient’s body. This chapter describes equipment for counting the activity in blood samples and imaging with a gamma camera. The PET scanner, which is used for imaging positron emitting radionuclides, is described in Chap. 20.

Sample Counting and External Counting The simplest sort of nuclear medicine test just produces blood samples which need to be assayed for radioactivity (eg GFR, see Chap. 25). This can easily be done by putting a sample into a well-type counter where it is surrounded by a scintillation crystal (Fig. 19.1). This crystal emits a flash of light when it is hit by a gamma ray and the light is detected by a photomultiplier tube, which converts the light into an electronic pulse and the number of pulses are then counted. Because this type of counter is very efficient at detecting gamma rays, it is possible to measure extremely small quantities of radioactivity in this way. This is why very small administered activities can be used in GFR studies, resulting in a very small radiation dose to the patient. Studies like the renogram (see Chap. 22) require monitoring of the amount of radiopharmaceutical in the kidneys with time. In the past this was done by placing scintillation counters against the patient’s back, over each kidney. Because the counter is further away from the radiation source, this type of ‘external’ counting is not as efficient as the well counter and so it requires higher administered radionuclide doses. The main problem with external counting is that it is not possible to accurately separate activity in the kidney from nearby non-renal background activity. C. Mathews-Aspinall · R. Lawson (*) Nuclear Medicine Centre, Manchester University Hospitals, Manchester, UK e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_19

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Radioactive Sample Lead Shielding

Electrical Pulse

Photomultiplier

Scintillation Crystal

Fig. 19.1 Schematic diagram of a sample counter. The sample is surrounded by a scintillator crystal, where incident gamma rays create light which is detected by a photomultiplier tube

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Gamma Ray Scintillation Light

The Gamma Camera and Collimation The gamma camera is a device that not only detects gamma rays (Appendix 1) emerging from the patient, but can also determine their position. It can, therefore, produce an image of the distribution of radiopharmaceutical within the patient. The gamma camera contains a single large scintillation crystal (typically 500  mm x 350 mm) and an array of many photomultiplier tubes. When a gamma ray hits the crystal, scintillation light is emitted and collected by all the photomultipliers. Signals from the photomultipliers are then fed into a computer which calculates the interaction position from the distribution of light collected. Gamma rays are, however, emitted from the patient in all directions and so, in order to produce an image it is necessary to fit a collimator in front of the scintillation crystal. A collimator is, essentially, a lead plate with tens of thousands of parallel holes in it, each about 2 mm in diameter. The holes restrict the accepted gamma rays to just those that are travelling close to perpendicular to the face of the collimator. The spatial resolution of the gamma camera, a measure of its ability to see fine detail, is determined by the size of the holes in the collimator, which allows a small range of gamma ray directions to be accepted in practice. This means that resolution gets worse with distance, so that the image becomes more blurred the further away the object is from the gamma camera. Collimator hole size also affects the sensitivity of the gamma camera. Small holes give good resolution but poor sensitivity, whilst large holes give poor resolution but better sensitivity. Thus gamma cameras are provided with a range of different collimators for different purposes (Fig.  19.2). At a distance of 10  cm the resolution might be about 7 mm when using a low energy high resolution (LEHR) collimator, which has small holes, or 9  mm with a low energy general purpose (LEGP) collimator (medium holes) or 13 mm with a low energy high sensitivity (LEHS) collimator (larger holes). The sensitivity of the LEGP collimator would be about twice that of the LEHR and the LEHS four times the LEHR. So choice of collimator is always a balance of resolution against sensitivity. Although the collimator is an essential part of forming the image it engenders inefficiency; it blocks about 99.99% of emitted gamma rays because they aren’t

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Fig. 19.2  A gamma camera with two detectors, one above the patient couch and the other below it. A selection of collimators are stored on the carts in the background

travelling in the right direction. Consequently, gamma camera imaging studies require larger administered activities, and longer imaging times, in order to obtain sufficient counts for analysis. Even with higher doses and longer counting periods nuclear medicine images will have only a small number of counts in each image pixel. This means that the images tend to be ‘noisy’. For a static study like a DMSA kidney scan (see Chap. 24) the gamma camera will use a LEHR collimator in order to obtain best possible resolution but will have to acquire each image for about 5 minutes in order to obtain sufficient counts to see real activity above the noise. Modern gamma cameras often have two detectors so that two views can be obtained simultaneously to reduce the scanning time. This can be particularly helpful for studies such as bone scans (see Chap. 26). The gamma camera can also be used for dynamic studies, like the renogram (see Chap. 22), where a series of images are acquired showing how the distribution of activity changes with time.

SPECT and SPECT-CT Gamma Cameras can produce 3D images of the activity distribution in the body using a technique called Single Photon Emission Computed Tomography (SPECT). This involves taking images at many angles all the way around the patient and

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reconstructing cross sectional slices using a computer. Typical scan times are around 20 minutes. An issue with SPECT alone is that some gamma rays, emitted from inside the patient, may be absorbed or scattered by tissue before they reach the gamma camera. This process is referred to as attenuation. Attenuation results in a reduction of measured counts in deeper tissues, affecting the appearance of SPECT slices and affecting quantification. Modern gamma cameras can be combined with a CT scanner. This allows a CT scan to be acquired with the patient in the same position as they were for the SPECT, meaning the SPECT and CT images can be fused together. Since CT images represent varying attenuation of different tissues, an attenuation map can be created. Attenuation correction can then be applied to the SPECT to improve image quality and quantification. Furthermore, SPECT-CT studies have the advantage of combining the functional information provided in SPECT, with anatomical localisation from the CT. This is particularly helpful to localise metastases in bone scans (see Chap. 26), where the SPECT alone may show a region of suspicious uptake that cannot be localised to specific anatomy until fused with CT.

Data Analysis Gamma cameras usually have dedicated nuclear medicine computer processing systems associated with them. These are particularly useful for analysing data from dynamic studies like the renogram (see Chap. 22). The operator can draw regions of interest around each kidney on the computer images and generate curves showing how the activity changes with time. This overcomes the problems of external counting where the kidney location could not be seen and also makes it possible to exclude non-renal background. Raw gamma camera images usually need some processing before they are interpreted. Therefore the nuclear medicine computer is used to analyse the data and display a summary of the results. Then a screen capture of the results can be sent to the hospital Picture Archiving and Communication System (PACS).

Further Reading Sharp PF, Gemmell HG, Murray AD, editors. Practical Nuclear Medicine. 3rd ed. Springer; 2005. Cherry SR, Sorenson JA, Phelps ME. Physics in nuclear medicine. 4th ed. Saunders Elsevier; 2012.

Chapter 20

Principles of Positron Emission Tomography (PET) Scanning Phei Shan Chuah and Seshadri Nagabhushan

Positron Emission Tomography (PET) is a form of Nuclear Medicine imaging which uses positron-emitting radionuclides (e.g. carbon, fluorine, gallium). Positrons react with electrons in tissues of interest to produce two diametrically opposed gamma photons which are picked up by a ring of detectors in the gantry. The clinical uses of PET scanning mainly include prostate cancer, but it also plays a role in metastatic seminoma and urothelial cancer.

Introduction Positron Emission Tomography (PET) is a form of Nuclear Medicine imaging which uses positron-emitting radionuclides rather than the gamma-emitting radionuclides used in conventional planar and single photon emission computed tomography (SPECT).

PET Radionuclides There are several radionuclides which are suitable for PET. Many have half-lives of minutes rather than hours and require production using a cyclotron. For such radionuclides, rapid radiochemistry must be followed by imaging using a PET scanner on the same site as the cyclotron. However, centres remote from cyclotrons can be P. S. Chuah · S. Nagabhushan (*) Department of Nuclear Medicine, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_20

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Table 20.1  Physical properties of positron-emitting radionuclides Positron-emitting radionuclide Carbon-11 Nitrogen-13 Oxygen-15 Fluorine-18 Gallium-68 Rubidium-82

Half-life 20 mins 10 mins 2 mins 110 mins 68 mins 76 s

Positron energy (MeV) 0.96 1.19 1.74 0.63 1.83 3.15

Production method Cyclotron Cyclotron Cyclotron Cyclotron Generator (Ge-68) Generator (Sr-82)

supplied with isotopes which have longer half-lives, such as Fluorine-18 (half-­ life  =  110  mins), or can be eluted from a generator, such as Gallium-68 (half-­ life = 68 mins, eluted from a Germanium-68 generator). The same rationale in selecting an appropriate radionuclide for conventional nuclear medicine imaging applies to PET radionuclides. One of the advantages of PET is that the positron-emitting isotopes such as Carbon, Nitrogen, Oxygen and Fluorine can be directly substituted into molecules that occur naturally in the body (e.g. Fluorine can replace Hydrogen). This produces PET radiotracers that are exact positron-emitting analogues of the molecule that is being imaged, and such a radiotracer can be reliably assumed to behave in exactly the same way. PET radiotracers can be used to study a wide range of physiological and pathological processes. The most commonly used radiotracer in clinical practice is 18 F-labelled fluoro-deoxyglucose (18F-FDG). This is an analogue of glucose, which is trapped within cells following phosphorylation by hexokinase. It is widely used in oncology imaging as more glucose is required by anaerobic glycolysis within tumours than aerobic glycolysis in normal tissue, so pronounced FDG uptake is seen in many tumour types, leading to images with good contrast between malignant and benign structures (Table 20.1).

The Physics of PET Scanning When a PET radiotracer is injected into the patient, it is absorbed by the body and accumulates within the tissues of interest. As the radiotracer decays, it emits a positron, which travels a short distance before annihilating with an electron in the surrounding tissue to produce two back-to-back 511  keV gamma photons. These gamma rays are then detected by a ring of detectors surrounding the patient in the PET scanner. This is called ‘in coincidence’ (Fig. 20.1). The positron is assumed to have met the electron somewhere along the ‘line of response’ defined by the coincident gamma rays. Millions of these lines of response are recorded in a typical PET scan and then reconstructed to map out the 3D distribution of the positron-emitting radionuclide within the body. This process is called ‘annihilation coincidence detection’ which serves as the basis of PET imaging. Annihilation coincidence detection significantly increases the sensitivity of PET compared to conventional SPECT. The spatial resolution of PET is around 5–8 mm compared to SPECT which is around 8–12 mm.

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511 keV gamma

Radioisotope Positron

Electron

Coincidence Unit

511 keV gamma

Fig. 20.1  Annihilation and coincidence detection

PET Scanners in Clinical Practice Stand-alone PET scanners have largely been superseded by modern hybrid PET-CT scanners. The combination of PET and CT scanners in one unit, allows accurate alignment of functional information from PET and structural information from CT. Registered PET-CT imaging can precisely identify areas of physiological and pathological uptake, and thus increase the diagnostic accuracy. CT images are also used to correct for physical limitations in PET imaging such as attenuation and scatter. A modern PET-CT scanner is shown in Fig. 20.2. The bore of a PET-CT scanner like this is approximately a metre long which is longer than a CT scanner but shorter than an MR scanner. The use of PET-CT in urology is rapidly expanding due to technical advances of modern PET-CT scanners and development of new positron-emitting radiopharmaceuticals such as 18F-NaF, 18F-choline, 18F-Fluciclovine, 68Ga-PSMA and 18F-PSMA, in addition to 18F-FDG. One of the challenges of PET-CT in urological disorders is the biodistribution and physiological urinary excretion of most PET tracers which can reduce the sensitivity to detect pathology within or around the urinary tract. Despite this challenge, PET-CT is proven to be useful for staging of locoregional and distant metastasis (Fig. 20.3), detection of recurrence, evaluation of treatment response and as a prognostic indicator in urological malignancy. In addition, PET-CT is increasingly becoming an indispensable tool in theranostics. Theranostics are agents that enable both diagnostic imaging and therapy by utilising the same specific molecular target. PET-CT is used to identify molecular-­ targeted receptors, guide molecular-targeted radionuclide therapy and assess response to treatment. One example is the use of 18F-PSMA PET-CT or 68Ga-PSMA PET-CT as pre-therapy and post-therapy imaging for 177Lu-PSMA radionuclide therapy in patients with metastatic castration resistant prostate cancer.

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Fig. 20.2  A modern PET-CT scanner

Fig. 20.3 Maximum intensity projection (MIP) image of 18F-PSMA PET-CT in a patient with prostate cancer and rising serum PSA level, demonstrating multiple PSMA-avid left iliac chain nodal metastases (red arrow)

P. S. Chuah and S. Nagabhushan

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PET-CT Interpretation and Reporting In clinical practice, visual assessment of PET-CT images is usually the mainstay of image interpretation. Quantitative measurement of PET is often utilised to provide a more objective and accurate evaluation of treatment response and prognostication while minimising inter-observer variability. Various quantitative measures have been derived from 18F-FDG PET studies. Standardised uptake value (SUV) is a semiquantitative measure of tracer uptake in a region of interest which is normalised to the injected activity and patient’s body weight. In 18F-FDG PET-CT, activity in a lesion is often expressed in the terms of SUVmax or the value of the most intense pixel in the region of interest. It is used to aid the differentiation of benign from malignant processes and assessment of tumour changes in serial scans. However, care must be taken when interpreting SUVs and similar measurement from PET scans. Such measurements are much less accurate for small lesions, particularly those 7) often display high FDG uptake. Its utility in the evaluation of prostate cancers in comparison to conventional imaging techniques has been superseded by the newer prostate-­specific radiotracers. 18

 F-Sodium Fluoride (18F-NaF) 18

F-NaF is a PET radiotracer used in the evaluation of osteoblastic bone metastasis. It has a similar mechanism of action with its gamma emitting radiotracer counterpart, 99mTc-labeled phosphonates (see Chap. 26). It works by chemisorption of fluorine directly into the surface of bone matrix and converting hydroxyapatite to fluorapatite. 18F-NaF PET-CT is advantageous over 99mTc-labeled bone scintigraphy with its shorter scanning time, better image quality, higher spatial resolution and tumour to background ratio. It more sensitive when compared to SPECT tracers for the evaluation of bone metastasis. 18

 C-Choline and 18F-Choline 11

Choline is an essential component for the synthesis of the phospholipid cell membrane. It is internalised into the cell and undergoes phosphorylation into phospholipid by the enzyme choline kinase. The overexpression of choline kinase enzyme

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in prostate cancer serves as the basis for choline-labelled PET imaging. Choline tracer can be labelled with isotopes such as Carbon-11 (11C-Choline) or Fluorine-18 (18F-Fluroethylcholine and 18F-Fluromethylcholine). Normal biodistribution is in the salivary glands, liver, spleen, pancreas and variable bowel activity. Normal prostate usually exhibits faint activity, but can be seen more avidly in prostatitis and benign prostatic hyperplasia. Choline PET imaging plays a role in the detection of biochemical relapse (BCR). The sensitivity and specificity of choline PET-CT for all sites of recurrence in patients with BCR are 86–89 and 89–93% respectively. The positivity detection rate correlates with the PSA level and PSA doubling time when PSA level is at least >1–2 ng/ml.

 Ga-PSMA and 18F-PSMA 68

Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein which is expressed on the membrane of prostatic epithelial cells. Overexpression of PSMA in prostate cancer by 100–1000 times more than normal tissue makes PSMA a desirable tracer. Its expression is associated with higher Gleason score and androgen independence. It can be labelled with Fluorine-18 (18F-PSMA) or Gallium-68 (68Ga-PSMA). Although 68Ga-PSMA offers on-site radiopharmaceutical production, 18F-PSMA shows lower urinary excretion which makes it more favourable in the assessment lesions close to the urinary tract. Normal physiological activity is seen in lacrimal and salivary glands, liver, spleen, kidneys, and intestine. An important pitfall of PSMA PET imaging is the physiological ganglionic uptake which may be misinterpreted as nodal metastasis. The clinical application of PSMA PET imaging includes primary staging of high risk prostate cancer. 68Ga-PSMA PET is more sensitive in detection of nodal and distant metastasis compared to conventional imaging (CT and bone scan). PSMA PET imaging is also useful in the identification of metastasis in patients with BCR when serum PSA level is very low (>0.2 ng/l). The detection rate increases with serum PSA level. Identification of lymph node metastasis 2

Ga-PSMA (%) 45 59 75 95 68

F-PSMA (%) 62 75 91 94 18

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 F-Fluciclovine 18

F-Fluciclovine is a radiolabelled synthetic amino acid that is taken up into cells by transporters (LAT-1 and ASCT2) which are present in high numbers in prostate cancer cells. The short uptake period for 18F-fluciclovine allows scans to be done 3–5 min after administration, compared with alternative PET tracers, which need about 1 h for optimal uptake. 18F-Fluciclovine PET-CT can detect recurrence at low serum PSA levels (3 RBCs/hpf; specificity    65–80%. A trace of haematuria should be considered negative, while ≥1+ is considered significant. Non-haemolysed and haemolysed are of equal significance. Who to Investigate—NICE Guidelines [NG12]—Indication for referral on a suspected cancer pathway: 1. Aged 45 years or older and have: • Unexplained visible haematuria without UTI, or, • Visible haematuria that persists or recurs after successful treatment of UTI. 2. Aged 60 years or over with unexplained non-visible haematuria, and either: • dysuria, or, • a raised WCC on a blood test. Significance—5–13% of patients with non-visible haematuria (NVH) will have urological cancer. In patients with NVH, the IDENTIFY Study, found no bladder cancer in patients aged under 35 years, and, no Upper Tract Urothelial Cancer in patients aged under 60 years (Tables 29.1 and 29.2). Table 29.1  Urinary Tract Cancer Detection in patients with non-visible haematuria referred on a suspected cancer pathway [1]

Table 29.2 Diagnoses of patients investigated for microscopic haematuria [2]

Urological Cancer Diagnosis Bladder cancer Upper tract urothelial cancer Renal cancer

Diagnosis No cause identified UTI Nephrological causes (IgA nephropathy, etc.) Bladder cancer Stones Prostate cancer Kidney cancer Upper tract urothelial cancer

% of patients 13.1% 0.36% 0.5%

% of patients 68.2 13 9.4 4.8 4 0.3 0.2 0.1

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Protein How?—Based on protein error of indicators principle. Tetrabromophenol blue changes colour in response to the presence of protein in urine. Sticks are very sensitive, and a trace corresponds to 0.15–0.3 g/L, + to 0.3 g/L, ++ to >1 g/L, +++ to 2.5–5 g/L, and ++++ to >10 g/L proteinuria. Normal urinary protein should be less than 15 mg/dL or  70/PCR > 100 mg/mmol or the urinary ACR > 30/ PCR > 50 mg/mmol with microscopic haematuria.

Leucocytes How?—Leucocyte esterase is produced by neutrophils which catalyses the hydrolysis of either derivatised pyrrole amino acid ester to liberate 3-hydroxy-5-phenol pyrrole or indoxyl carbonic acid ester to indoxyl. Pyrrole or indoxyl then reacts with a diazonium salt to produce a purple product. Significance—The list of potential causes of persistent pyuria is long; however, the presence of urinary leucocytes is often used as an indicator of UTI along with dipstick nitrites. Its performance in this setting is shown in Table 29.3. Table 29.3  Utility of leucocyte esterase and nitrite urinalysis in the detection of UTI [3] Dipstick result LE positive Nitrite positive LE or nitrite positive LE and nitrite positive

Pooled sensitivity % 72 54 81 43

Pooled specificity % 82 98 77 96

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Nitrites How?—Nitrite in the urine reacts with ρ-arsanilic acid to form a diazonium compound which couples with 1,2,3,4-tetrahydrobenzo(h)-quinolin-3-ol to produce a pink colour. Significance—Nitrites when present in urine are the result of bacteria reducing urinary nitrates. Around 60% of Gram-negative bacteria are capable of this, which, together with the requirement of at least 105 bacteria per milliliter for a positive test, limits the sensitivity of this test in the clinical detection of UTI (Table 29.3).

pH How?—Double indicator principle, methyl red and bromothymol blue, which provides a broad range of colours to cover a urinary pH range of 5–8.5 (visually). Significance—Urinary pH typically reflects plasma pH. An exception is in renal tubular acidosis where there is an inability to acidify urine in response to an acid load. Urinary pH is potentially important in urolithiasis. Uric acid stone formation requires a pH  10 mmol/l, the renal threshold.

Potential Errors When Reading a Dipstick Potential sources of false positive and negative dipstick test results are shown in Table 29.4.

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Table 29.4  Sources of false positive and negative urine dipstick results Test Haemoglobin

Protein

False positive Myoglobin Bacterial peroxidases Hypochlorite Menstruation Dehydration Exercise –

Leucocytes

Formalin Vaginal discharge

Nitrites

–

Glucose

–

False negative Reducing agents: 1. Ascorbic acid 2. Captopril

Dilute or alkaline urines Bence-Jones proteins Glycosuria (>3 g/dL) Ascorbic acid Cephalexin Imipenem Meropenem Clavulanic acid Tetracycline Non-nitrate-reducing bacteria Low nitrate diets Dilute urine Urine in the bladder for 65 years, men or young children. A large proportion of urine samples tested by microbiology laboratories will show no evidence of infection on culture or are contaminated and therefore uninterpretable.

F. E. Carlin (*) · C. M. Jukka Liverpool University Hospitals Foundation Trust, Liverpool, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_30

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Methods of Urine Collection If urinary tract infection (UTI) is suspected, a urine sample should ideally be collected prior to initiation of any therapy and sent for microscopy and bacterial culture. This will be helpful to guide diagnosis and target appropriate antibiotic treatment. Traditionally, a universal container is used for specimen collection. Specimen container lids should be tightly secured to prevent leaks, labelled correctly, and transported promptly to the laboratory for processing. When delays are expected, containers with boric acid preservative (bacteriostatic) should be used or samples should be refrigerated prior to transport to prevent bacterial overgrowth and false positive culture results. Early morning urine samples are preferred for testing as the urine is more concentrated and it allows bacteria time to multiply overnight. However, in practice, most cultures are obtained when the patient sees the clinician. Specimen collection should be a clean catch midstream urine (MSU) and the patient should be instructed in the proper technique. This involves parting the labia or retracting the prepuce prior to collection; this helps to minimise contamination of the sample with the commensal bacterial flora of the genital area, reducing false positive results and the need for repeat sampling. When it is only possible to obtain a catheter specimen of urine (CSU), the specimen should be obtained aseptically from a sample port in the catheter tubing (not be obtained from the collection bag). Suprapubic aspirate of urine (SPA) is a collection method which can be used in neonates and infants under 24 months as it is difficult to obtain a “clean catch” in this group of patients. Though recommended, in practice this technique is rarely performed as it is invasive. For male infants, or un-­ catheterised incontinent adult males, an alternative method of urine specimen collection can be attempted using a reservoir such as a sheath type of convene. Pads for females and smaller infants are sometimes used, though these methods are associated with high rates of contamination.

Traditional Microscopy and Non-culture Methods Investigation of urine samples involves microscopy, used to identify the presence of white blood cells, red blood cells, casts, epithelial cells, bacteria, and other cellular components present in the urine. Traditionally this has been done using a microscope and is recommended for all symptomatic patient groups to assist in the interpretation of culture results and diagnosis of UTI. Modern urine microscopy is now largely done using automated analysers which can produce objective digital images of the examination results. Their use facilitates faster turnaround times and reduced laboratory staff workload compared to traditional methods, consequently reducing costs.

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Automated urinalysis endeavours to measure or describe the formed elements in the urine. Three techniques are currently available: 1. Fluorescein flow cytometry with diode laser and hydrodynamic focused conductometry (IQ Sprint®) 2. Flow cell digital imaging of un-centrifuged urine and automated recognition software (UF-1000i®) 3. Microscopic urine sediment analysis, digital imaging, and automatic particle recognition (Sedimax®) Flow cytometry works by measuring electric impedance (for volume), light scatter (for size) and use of fluorescent dyes (for nuclear and cytoplasmic staining). The particles are characterised using these measurements and the results are displayed as scattergrams. In particle recognition systems (e.g. Sedimax®), the urine specimen passes through the analyser and a camera captures up to 500 frames per specimen. Each image is classified by size, shape, contrast, and texture features. This has been found to be more reliable for identifying cellular components. Sensitivity of the automated analysers is high, but with consequently reduced specificity. Skilled biomedical laboratory assistants are still required to review certain particles (e.g. Trichomonas vaginalis, yeasts etc.). Regardless of the screening result, culture is still recommended for all specimens from children, pregnant women, immunocompromised patients, and those with persistent symptoms but recurrent negative results. For samples not in these categories, culture is only performed if the number of white blood cells (WBCs) on microscopy is >40 WBCs per microlitre (μl) of urine.

Pyuria and / or Bacteriuria Significant pyuria is present in 96% of symptomatic patients with bacteriuria of >105 colony forming units (cfu) per millilitre (ml) of urine on culture. Sterile pyuria (pyuria associated with no growth on routine culture media) may be seen after recent or concurrent treatment with antimicrobial agents or can be associated with calculi, bladder neoplasms, genital tract infection, infection due to a fastidious organism (i.e Chlamydia trachomatis, Mycoplasma genitalium, etc) or urogenital tuberculosis. If Chlamydia or Gonorrhoeal infection is suspected these must be tested separately and require a first catch urine sample in men; or a vaginal swab in women.

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Culture Methods Commonly used methods for quantification of bacteria in urine include the calibrated loop technique and multipoint technology. Examples of culture media used for inoculation of urine can be seen in Table 30.1. Culture of urine by multipoint method may be performed using micro-titre trays containing agar and read manually, or automated with data transferred to the laboratory information management system. This technology is the most efficient for a laboratory handling large number of specimens (Fig. 30.1).

Table 30.1  The advantages and disadvantages of commonly used culture media for inoculation of urine specimens Culture Media Blood agar

Advantages Discrimination of gram-positive bacteria; enables identification of proteus spp. by swarming

Cystine lactose electrolyte deficient(CLED)

Discrimination of gram-negative bacteria by lactose fermentation and colony appearance; inhibits swarming of proteus spp Enables colour identification of Poor growth of some gram-­ Escherichia. Coli (pink), enterococci positive bacteria (blue or green), klebsiella-Enterobacter-­ Serratia group (purple), and proteus-­ Morganella-­Providencia group (brown)

Chromogenic agar

Disadvantages No inhibition of swarming of proteus spp.; poor discrimination of different species of Enterobacteriaceae Poor growth of some gram-­ positive bacteria

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Fig. 30.1  Micro-titre trays

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Interpretation and Use of Culture Results Culture results should be correlated with clinical presentation, individual patient risk factors and presence or absence of pyuria or squamous epithelial cells (which indicate the degree of contamination). Culture of single pure (or predominant) organisms ≥105 colony forming units (cfu) /ml with urinary tract symptoms is diagnostic of UTI. Antibiotic treatment should be guided by the identified pathogen susceptibility pattern and local antibiotic guidelines indicating preferred choices of antibiotics for different patient groups. Patients with confirmed recurrent urinary tract infection or challenging resistance patterns may warrant discussion with a microbiologist and investigation for associated complications.

Further Reading United Kingdom standards for microbiology investigations (UKSMI)- GOV.UK, B41i18: investigation of urine. Public Health England; published July 2014. Updated January 2019. Broeren MA, et  al. Screening for urinary tract infection with the sysmex uf-1000i urine flow cytometer. J Clin Microbiol. 2011;49(3):1025–9. Hay AD, Birnie K, Busby J, et  al. The diagnosis of urinary tract infection in young children (DUTY): a diagnostic prospective observational study to derive and validate a clinical algorithm for the diagnosis of urinary tract infection in children presenting to primary care with an acute illness. Health Technol Assess. 2016;20(51):1–294.

Chapter 31

Urinary Flow Cytometry Harry Rudman and Dora Moon

Flow cytometry (FCM) is a process of cumulative cytometric assessment of a population of cells in solution. Cytometric characteristics of individual cells are assessed through measurement of differential light scatter and fluorescence emitted by illuminated cells. Urinary flow cytometry (UFC) has appeal as a diagnostic technique within the field of clinical microbiology due to rapid availability of results by comparison to traditional methods such as urine microscopy, culture and sensitivity.

Principles of Flow Cytometry FCM is an analytical method that provides rapid assessment of cellular characteristics through the measurement of light scattered by illuminated cells. Particles within a specimen are analysed individually, whilst in flow, producing a cumulative set of results for a given population. At the point of analysis, cells are exposed to a light source, typically an arc lamp or laser. Multiple characteristics of a cell can be assessed according to the subsequent light scatter. For example, the amount of light scattered back towards a light source, or reflected, is indicative of cell size. Conversely, light detected laterally or beyond the cell is indicative of cellular complexity, or the density of organelles within the cell. To provide additional information and aid discrimination, cells may be stained with fluorescent labels known as fluorochromes. Fluorochromes can attach directly to cellular structures or may be conjugated with intermediaries such as antibodies.

H. Rudman (*) · D. Moon Lancashire Teaching Hospitals Trust, Preston, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_31

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Components and Function of a Urinary Flow Cytometer Urine specimens for analysis by FCM may be centrifuged prior to analysis, although most contemporary systems accept native samples. Depending on the model of flow cytometer a volume of ~1-4 ml of urine is required. Processing and analysis of the specimen has several stages, as follows (Fig. 31.1): • Following aspiration, specimens are stained using fluorochromes that target cellular nucleic acids as well as the cellular membrane. • The specimen is passed through a liquid sheath, which generates flow of cells at a constant velocity, through a narrow window of incident light (hydrodynamic focusing). • An optics system focuses incident light on passing cells and collects the scattered light and fluorescence, passing this to photomultiplier tubes (PMTs). Scattered light and fluorescence are measured in forward and lateral direction. • An analogic signal is generated within each PMT for each cell. The pattern of light signal for each particle is analysed using a series of algorithms to profile the cellular “fingerprint” and categorise the cell type. Contemporary flow cytometers, such as the Sysmex UF-5000® (Sysmex Corporation, Kobe, Japan), are able to identify and quantify numerous types of cells including erythrocytes, leucocytes, bacteria, epithelial cells and casts. Modern systems incorporate two separate analysis channels, with one specifically for counting bacteria, operated at a different temperature and stained with tailored fluorochromes.

PMTs

Liquid Sheath

Side-scattered light Fluorescence Forward-scattered light

Laser

Fig. 31.1  Components of a urinary flow cytometer

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 pplications of Urinary Flow Cytometry Within A Clinical Microbiology Identification of uropathogens through the traditional, gold-standard method of urine microscopy and culture typically takes between 18 and 48  hours, meaning same-day results are unlikely. When you consider that the majority of urine specimens analysed are negative, there is an obvious role for screening of specimens as a time and cost-saving exercise. UFC has emerged as an effective screening tool used to rule out urine specimens that do not require culture and sensitivity. If the bacterial cell count, as measured by FCM, is not sufficiently high, samples do not proceed to culture. Individual laboratories are able to choose their own cut-off values for bacterial count, and may choose to incorporate the presence of leucocytes, or other cell types, in their decision making. This method has been demonstrated to have adequate sensitivity and specificity in detecting significant bacterial growth when examined alongside paired urine culture results. Authors report maintaining sensitivity of >95% whilst significantly reducing the number of samples requiring culture. Technological advances within the field of UFC mean systems have an increasing ability to characterise pathogens. The third generation Sysmex UF-5000® is able to flag specimens as gram positive or negative with results reportedly comparable to traditional gram staining. In the future, it may be possible for specific organisms to be identified by FCM alone.

Further Reading Alvarez-Barrientos A, Arroyo J, Canton R, Nombela C, Sanchez-Perez M. Applications of flow cytometry to clinical microbiology. Clin Microbiol Rev. 2000;13(2) Jolkkonen S, Paattiniemi E, Karpanoja P, Sarkkinen H. Screening of urine samples by flow cytometry reduces the need for culture. J Clin Microbiol. 2010;48(9)

Chapter 32

Urine Cytology Nadira Narine and Durgesh N. Rana

The stage and grade of urothelial carcinoma (UC) are of great importance at diagnosis as non muscle-invasive disease (stage I) shows better outcomes then muscleinvasive disease (stage II-IV). Histology is the gold standard for diagnosis as the recommendation for detrusor muscle invasion can only be determined with histological biopsies. Urine cytology plays an important part in the diagnosis and surveillance of high grade urothelial carcinoma, including carcinoma in situ.

Introduction The stage and grade of urothelial carcinoma (UC) are of great importance at diagnosis as non muscle-invasive disease (stage I) shows better outcomes then muscle-­ invasive disease (stage II-IV). Histology is the gold standard for diagnosis as the recommendation for detrusor muscle invasion can only be determined with histological biopsies. Cytology has a limited but specific role in the diagnosis of UC. It’s main goal is in the diagnosis of high-grade urothelial carcinoma (HGUC) including carcinoma-­ in-­situ (CIS). It is used mainly by clinicians if: • there are no visible papillary lesions at flexible cystoscopy in the presence of persistent visible haematuria • there are red patches at flexible cystoscopy which may represent inflammation or CIS

N. Narine (*) · D. N. Rana Cytology Department, Manchester University NHS Foundation Trust, Manchester, UK e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_32

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• lesions that are difficult to visualise e.g. calyceal diverticulae • patients in whom clinically / radiologically HGUC is suspected but are unable to have invasive investigations due to co-morbidities. Because of the anatomical continuity of the renal pelvis, ureter, bladder and urethra, cytology is well suited to guide clinicians to further investigations when cystoscopy is indeterminate or negative. A negative cytology has a high negative predictive value of underlying high-grade disease. Similarly, the sensitivity of urine cytology is high in HGUC.

Sampling Types Voided Urine Although theoretically more cellular, the first morning voided urine is prone to degeneration. A full voided sample (i.e. not mid-stream) is collected in a sterile container at any time of day. A volume between 25–30 mL is adequate. Samples should be transported to the laboratory as soon as possible after collection to avoid degeneration. Some centres recommend fixing in an equal volume of an alcohol based fixative.

Catheterised and Ilieal Conduit Urine Samples taken from a drain bag are not suitable for cytological assessment as they are very degenerate and contaminated by material from the bag. Instead the catheter or conduit should be directed into a sterile container for fresh collection.

Aspirated Urine, Washes and Brushes Urinary samples may be collected from any part of the urinary tract by aspiration, washing or brushing. As much as possible of the aspirated or washing sample should be retrieved. In instances of brushings from an obvious lesion, this brush should be fixed in an alcohol based fixative, to prevent degeneration.

Preparation Concentration of all types of urinary tract samples by centrifugation with subsequent preparation by at least one cytospin or a single megafunnel or Liquid Based Cytology (LBC) preparation for Papanicolaou (Pap) staining is sufficient for cytological reporting.

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Diagnostic Categories The Paris System (TPS) for Reporting Urinary Cytology is a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of HGUC as well as the risk of high grade malignancy (ROHM) for each diagnostic category. The main goal of urinary cytology is the detection of HGUC. The distinction of HGUC from benign changes and low-grade neoplasms (LGUNs) is central to the clinical utility of urine cytology. The second edition of the Paris System for Reporting Urinary Cytology (TPS) proposes five diagnostic categories: Unsatisfactory: adequacy of urine samples for the diagnosis of HGUC is dependent on collection type, cellularity, volume and cytomorphological findings with the latter being the most important characteristic as any atypia is reported as such irrespective of the other parameters. A urine sample is only deemed unsatisfactory if: • the sample is acellular or obscured by debris • any visible cytological features are benign and the sample volume is fewer than the recommended volume of 25–30 mL The ROHM in samples reported as unsatisfactory is 0–16%. Negative for high grade urothelial carcinoma (Fig. 32.1): this refers to those urinary samples which have cellular features that pose no significant risk for HGUC

Fig. 32.1  Voided urine sample showing scattered single benign urothelial cells together with neutrophils. This is negative for high grade urothelial carcinoma. SurePath Pap ×400

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and has a ROHM of 8–24%. It includes those samples which comprise cells with the following features in any combination: • • • • • • • • •

Benign urothelial cells Squamous epithelial cells Glandular / columnar cells Epithelial cells showing cytopathic effects of human papilloma or herpes simplex virus Renal tubular cells +/− renal casts Cells with degenerative changes Benign urothelial tissue fragments (BUTF) secondary to instrumentation or infections Cells showing iatrogenic changes secondary to BCG, chemotherapy or radiotherapy Low-grade urothelial neoplasia (LGUN)

Atypical Urothelial Cells: to reduce the number of indeterminate/atypical rate of reports in urinary cytology and provide clarity to clinicians, TPS has defined the Atypical Urothelial Cells (AUC) category as samples which contain non-basal urothelial cells with mild to moderate cytological atypia with a nuclear to cytoplasmic ratio ≥0.5. Cells must be well preserved to raise the concern of AUC and the ROHM is 25–53%. Suspicious for High Grade Urothelial Carcinoma: According to TPS, the diagnosis of Suspicious for High-Grade Urothelial Carcinoma (SHGUC) is used when there are well preserved urothelial cells with severe atypia which quantitatively fall short of a diagnosis of HGUC. The ROHM ranges from 59–94%. High Grade Urothelial Carcinoma (Fig. 32.2): the diagnostic criteria for the diagnosis of High-Grade Urothelial Carcinoma (HGUC) confers a ROHM of 76–100%. The primary goal of urinary cytology is in the diagnosis of HGUC and this is aided by the well-defined set of criteria established.

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Fig. 32.2  Voided urine sample showing many single malignant urothelial cells with hyperchromatic, enlarged nuclei. Red blood cells and necrosis are noted in the background. This is high grade urothelial carcinoma. SurePath Pap ×400

Summary Although limited, cytology has a specific and important role in the diagnosis of HGUC due to excellent sensitivity. It can sample the entire urinary tract and provide important information to clinicians on further management.

Further Reading National Institute for health and care excellence. Bladder cancer: diagnosis and management. NICE; 2015. https://www.nice.org.uk/guidance/ng2. Sundling KE, Antic T & Pambuccian SE.  In: Wojcik EM, Kurtycz DFI & Rosenthal DL, editors. The Paris system for reporting urinary cytology. 2nd ed. Switzerland: Springer Nature; 2022. p. 1–5.

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Rezaee N, Tabatabai ZL, Olson MT. Adequacy of voided urine specimens prepared by ThinPrep and evaluated using the Paris system for reporting urinary cytology. J Am Soc Cytopathol. 2017;6(4):155–61. https://doi.org/10.1016/j.jasc.2017.04.001. The Royal College of pathologists. Tissue pathways for diagnostic cytopathology, October 2019. https://www.rcpath.org/uploads/assets/b328ab3d-­f574-­40f1-­8717c32ccfc4f7d8/G086-­Tissue-­ pathways-­for-­diagnostic-­cytopathology.pdf. VandenBussche CJ, Chandra A, Heymann JJ, McCroskey Z, Owens CL, Schubert PT, Wang Y. In: Wojcik EM, Kurtycz DFI, Rosenthal DL, editors. The Paris system for reporting urinary cytology. second ed. Springer Nature: Switzerland; 2022. p. 21–62.

Chapter 33

Histopathological Processing, Staining and Immuno-Histochemistry Tegan Miller

Histological examination of biopsy material is imperative to diagnosis. It consists of three stages before the histological slide can be interpreted: tissue fixation, tissue processing and staining. Following this, the stained slide is analysed by a histopathologist, who makes a diagnosis depending on factors including morphological features, as well as the use of further stains such as immuno-histochemistry. There are many new developments within uropathology, including the use of molecular techniques in newly defined renal neoplasms, new immunohistochemical stains and, with respect to prostate cancer, the potential future use of Artificial Intelligence.

Introduction Histological examination of biopsy material is an important adjunct to diagnosis. It consists of three stages before the histological slide can be interpreted: tissue fixation, tissue processing and staining.

Tissue Fixation Formalin is the standard fixative used in many histopathology departments as it is compatible with most histological stains, preserving tissues for many months. Tissue fixation occurs when cross-linking of proteins takes place and this preserves cellular morphology. Formalin penetrates tissue at approximately 0.5 mm per hour T. Miller (*) Department of Histopathology, Manchester Royal Infirmary, Manchester, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_33

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so it is important to immerse tissues, particularly large specimens, in adequate volumes of fixative. Poor fixation of tissue can lead to difficulties in assessing morphology microscopically.

Processing of Tissue Samples Tissue may be received as small biopsy fragments, core biopsies, chips or larger resection specimens. Smaller samples are placed directly into plastic cassettes for processing. Larger resections are ‘cut up’ into cassette-size pieces approximately 30 × 25 mm, and up to 4 mm in thickness. Techniques using ‘mega’ cassettes, to enable entire slices of a whole organ to be seen on one slide, are also in standard use particularly for histological examination of radical prostatectomy specimens. Tissues placed in cassettes undergo automated processing involving a series of steps over several hours. 1. Dehydration. Water is removed from the tissue and replaced by graded alcohol. 2. Clearing. The alcohol is then replaced by a clearing agent to help tissue infiltration by the embedding medium (the most commonly used clearing agent is xylene). 3. Embedding. Xylene is replaced by paraffin wax in the embedding step to make the tissues hard enough to cut. 4. Cutting. When cooled, the embedded tissue is cut into very thin sections, normally 3–4 microns, with a microtome knife. 5. Mounting. These slices are then mounted onto glass slides ready for staining. Smaller samples such as bladder and prostate core biopsies may have multiple levels cut through one sample, and sections inbetween the levels saved for immuno-histochemical staining, if required.

Staining Haematoxylin and eosin (H&E) staining is the stain most commonly used in histopathology. Haematoxylin stains cell nuclei blue, while eosin stains cytoplasm, connective tissue and other extracellular substances, pink or red. H&E staining can be used to determine the size and shape of the nucleus in tumour cells and to show the percentage of tumour cells that are dividing. Recognition of nuclear features such as nucleoli is important particularly in the diagnosis of prostate carcinoma, and prostatic intra-epithelial neoplasia (PIN) in some cases. Immuno-histochemical staining can be used in several ways. It may be used to identify the tissue of origin of metastatic tumours or to identify specific tumour markers or tumour types. The basis of immuno-histochemistry is an antigen antibody reaction, revealed in the tissue by a chromogen complexed with, or activated

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by, antibody, which is visualised by the pathologist down the microscope. Antibodies have been specifically developed against particular tissue antigens. A panel of immuno-histochemical stains, to support a particular diagnosis, and rule out alternative diagnoses, is generally used.

I mmuno-Histochemical Stains Commonly Used in Urological Diagnosis Prostate carcinoma—unless poorly differentiated, these stains can be used to confirm cells of a prostatic origin either in primary or metastatic locations: • prostate specific antigen (PSA) • prostatic acid phosphatase (PAP) • NKX3.1 Benign prostate glands usually have a basal layer (which can be identified with immuno-histochemistry) and malignant prostate glands do not have a basal layer. The absence of this basal layer can be used to help in the assessment of atypical small acinar proliferations (ASAP) when trying to differentiate a benign process from adenocarcinoma. High molecular weight cytokeratins and p63 are commonly used markers of basal cells in this scenario. Alpha-methylacyl-CoA racemase (AMACR) is often positive in malignant prostate glands and can be used to support a morphological diagnosis of prostate cancer. Urothelial carcinomas generally stain with: • • • •

Cytokeratins (CK) 7 and 20 GATA-3 Uroplakin CK 34BE12

CK20 and p53 staining patterns can be useful in supporting a diagnosis of carcinoma in-situ (CIS). Renal cell carcinomas generally stain with: • PAX-8 • CD10 • RCC (renal cell carcinoma antibody) Other antibodies are of use in the differentiation of different types of primary renal malignancies. CAIX (carbonic anhydrase IX) is useful in the diagnosis of clear cell renal cell carcinoma (RCC). CK7 can be helpful, for example in the differentiation of oncocytoma from chromophobe RCC. CK7 is also positive in papillary RCC. TFE3 (transcription factor gene product) is a marker of translocation carcinomas.

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Testicular tumours: • Testicular germ cell tumours and intra-tubular germ cell neoplasia, depending on the subtype, stain for a variety of markers, including OCT3/4, CD30, CD117, PLAP, glypican-3, SALL4, HCG and AFP. • Inhibin, SF-1, melan A and calretanin can be useful markers of some sex cord stromal tumours.

New Developments in Pathology There has been much interest in recent years into the potential future use of Artificial Intelligence (AI) in histopathology, particularly in diagnosing and grading prostate cancer in biopsies. Many algorithms use Machine Learning techniques, such as Deep Learning, to enable the comparison of a scanned image with a large collection of images previously scanned, with the ability of algorithms to ‘learn’ and develop. Ongoing studies (at the time of publication) suggest that the highest performing of these algorithms can achieve, and possibly surpass, the diagnostic accuracy of a general pathologist. Further development is required in this area before clinical application. The classification of renal neoplasms is expanding, with several molecularly defined entities, which may require immuno-histochemistry (and potentially molecular techniques) for diagnosis, including tumours with abnormalities involving FH, SBHB, TFEB, TFE3 and ALK genes.

Further Reading Suvarna SK, Layton C, Bancroft JD. Bancroft’s theory and practice of histological techniques. 8th ed. Elsevier Health Sciences; 2018. Nagpal K, Foote D, Liu Y, Chen PHC, Wulczyn E, Tan F, et al. Development and validation of a deep learning algorithm for improving Gleason scoring of prostate cancer. Npj Digit Med. 2019;2(48) https://doi.org/10.1038/s41746-­019-­0112-­2. Bulten W, Kartasalo K, Chen PHC, Ström P, Pinckaers H, Nagpal K, et al. Artificial intelligence for diagnosis and Gleason grading of prostate cancer: the PANDA challenge. Nat Med. 2022;(13):154–63.

Chapter 34

Tumour Markers Alex Hoyle

The terms ‘tumour marker’ and ‘biomarker’ are often used synonymously when describing cancer related markers within uro-oncological literature. In the context of this chapter, a tumour marker is referred to as a biochemically detected indicator, capable of predicting cancer. A biomarker may be considered a biochemical or histopathological marker capable of predicting treatment response or cancer prognosis.

Bladder Cancer The National Institute for Clinical Excellence (NICE) recommends the use of tumour markers as adjuncts to cystoscopic bladder evaluation for suspected bladder cancer. Urine cytology is the most well recalled and accurate urinary tumour marker. It has high sensitivity (80–90%) and specificity (98–100%) for detecting high-grade urothelial lesions and carcinoma in situ due to high tumour cell shedding. This falls dramatically to (0–100%) and (6–100%) respectively in the detection of low-grade disease. Unreliability of cytology in low-grade disease, and false negative rates of 10–20% in high-grade disease cannot reliably avoid cystoscopic bladder evaluation. Cytology has fallen from routine clinical practice due to diagnostic dilemmas caused by false positive results. However, many clinicians still use cytology when assessing upper tract urothelial cancer and monitoring high-grade bladder cancer. Urine cytology is reported using the Paris system for reporting 2.0 (Table 34.1) following collection of an entire voided bladder volume. This is typically performed during the second void of the day, thus avoiding the effects of cellular degradation A. Hoyle (*) Salford Care Organisation, Northern Care Alliance, Salford, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tolofari et al. (eds.), Imaging and Technology in Urology, https://doi.org/10.1007/978-3-031-26058-2_34

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seen in stagnant urine voided following sleep. Avoidance should be considered in patients with recent UTIs to minimise false positive results, or immediately following endoscopy which may overly dilute urine. Novel biomarkers (Table 34.2) boast higher sensitivity than cytology for all bladder cancer. Unfortunately, these markers still cannot compete with the reliability of Table 34.1  The Paris system

Criteria 1 2 3 4 5 6 7

Outcome Nondiagnostic/unsatisfactory Negative for high-grade urothelial carcinoma Atypical urothelial cells Suspicious for high-grade urothelial carcinoma High-grade urothelial carcinoma Low-grade urothelial carcinoma Other primary and secondary malignancy and miscellaneous lesions

Table 34.2  Novel bladder cancer tumour markers Tumour marker Fluorescence in situ hybridisation (FISH) probe set

Brand name/ Manufacturer Urovysion

Nuclear Matrix protein (NMP—22)

Matritech

Bladder Tumour Antigen (BTA) STAT

Polymedco

Bladder Tumour Antigen (BTA) TRAK Fluorescent monoclonal antibodies against M344, LDQ10 and 19A211 Multiplex immunoassays

Polymedco

Reverse transcription quantitive polymerase chain reaction

CxBladder

ImmunoCyt/ uCyt+

CertNDx

Mechanism Urine test—Detects aneuploidy of chromosomes 3, 7 and 17, and loss of 9p21 loci in malignant urothelial cells Urine test—nonchromatin structure that maintain nuclear shape. Released from tumour cells after lysis Urine point of care test (qualitative)—monoclonal antibodies to detect complement factor H related protein and complement factor H Urine laboratory assay (quantative)—as BTA STAT

Sensitivity 42–83% pTa–pT1 92–100% ≥pT2 51–85%

Specificity 72% all

53–89%

54–93%

17–78%

51–95%

Urine test—3 fluorescent 53.8–94.1% monoclonal antibodies directed at urothelial antigens. M344 and CEA 19A211 found in 71–90% of pTa and pT1 TCC Urine test (DNA)—analyse 92% presence of FGFR3, quantified matrix metalloproteinase (MMP-3) and hypermethylation of TWIST1 and NID2 Urine Test—X5 mRNA markers 82% (CDC2, HOXA13, MDK, IGFBP5, CXCR5)

77–96%

61–80.7%

51%

85%

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cystoscopic bladder evaluation. Coupled to this, a lower specificity has limited their uptake within most urology units within the UK.

Prostate Cancer Prostate specific antigen (PSA) was characterised in 1979 for the monitoring of prostate cancer. Catalona et al., first reported the outcomes of PSA detectable prostate cancer in localised disease. PSA is a 34-kDA glycoprotein produced by columnar acinar and ductal prostatic epithelium with a half-life of 2–3 days. It is a member of the human kallikrein family (HK3), (Diagram 34.1). These are serine proteases that cleave protein peptide bonds, thus resulting in liquifying seminal coagulum to enable fertilisation. It is typically found in high concentration in sperm but low concentration in blood and urine. 75% of PSA is bound within blood (complexed) and metabolised in the liver. Complexed PSA is stable and bound to either α1-antichymotrypsin (ACT) or α2-macroglobulin (AMG). The remaining 25% is unbound or ‘free’ and is typically unstable. Examples of unstable PSA include Pro-PSA (transitional zone, cancer) and benign PSA (transitional zone, BPH). PSA is used to support detection, risk stratification, staging, surveillance, treatment monitoring and prognosis of prostate cancer. The most controversial role of PSA is within screening. There is no defined normal PSA level and thus defining an “abnormal” cut-off remains contentious. Age specific PSA reference ranges recognise the influence of age on PSA value. An abnormal PSA classified as >4.0 ng/mL balances the trade-offs between sensitivity and specificity. Using this value, a diagnostic specificity of 91% and sensitivity of 21% increasing to 51% in high-grade cases can be quoted. Despite this, the PCPT trial highlighted the limitations of using this PSA value alone in detecting significant prostate cancer (Table 34.3). Digital rectal examinations can further influence prostate cancer detection against PSA alone (Table 34.4). Novel tumour markers have improved sensitivity compared to PSA (Table 34.5) but are infrequently used following the introduction of multiparametric MRI imaging which provides additional staging information with a high negative predictive value. Detection of clinically significant disease no longer relies on PSA alone, but a multi-modal stratification. Diagram 34.1 Relationship of PSA to hK family

Prostate

Active complexed PSA

Pro-PSA

PrePro-PSA

Pro-hK2

HK2

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Table 34.3 Prostate Cancer Prevention Trial (PCPT), Risk of significant disease with low PSA

PSA Level 0.0–0.5 ng/ml 0.6–1.0 ng/ml 1.1–2.0 ng/ml 2.1–3.0 ng/ml 3.1–4.0 ng/ml

Table 34.4  Risk of prostate cancer based upon PSA and DRE [1]

Gleason 3 + 3 (%) 5.8 9.1 15 19.3 20.2

Gleason ≥ 3 + 4 (%) 0.8 1.0 2.0 4.6 6.7

Normal DRE (%) 10 17 23 25 50

Abnormal DRE (%) 15 30 40 50 >75

PSA 0.1–1 ng/ml 1.1–2.5 ng/ml 2.6–4.0 ng/ml 4–10 ng/ml >10 ng/ml

Table 34.5  Novel prostate cancer tumour markers

Tumour marker SelectMDx

Blood or urine test Urine

Engrailed-2

Urine

Microseminoprotein-B (MSMB)

Urine

RT-PCR

Blood

PCA3

Urine

Detect HOXC and DLX1 mRNA expression

E2 protein by ELISA Low levels of MSMB— regulated apoptosis Detects specific mRNA of tumour markers, ie PSA or HK2 Detects DD3 RNA and PSAmRNA in urine

Sensitivity Specificity Facts 76.9% 49.6% Significant prostate cancer detection figures. NPP 98% 66% 88.2% First pass urine post DRE 71% 71%

0–88%

N/A

84% (PSA 80% (PSA 4–10) 4–10)

Use alongside PSA and DRE Perform post DRE

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Testicular cancer Three tumour markers have roles in the diagnosis, monitoring, staging and prognosis of patients with suspected or confirmed germ cell tumours (GCT). Alpha fetoprotein (AFP), Beta Human Chorionic Gonadotrophin (βHCG) and Lactate Dehydrogenase (LDH) either in isolation or in combination are raised in 50% of all patients with testis tumours. These tumour markers have a high specificity but lower sensitivity. 30% of Seminoma GCTs and 50–60% of non-seminomatous GCTs present with raised tumour markers. Table 34.6 demonstrates the individual characteristics of each tumour marker. Patterns in marker positivity may support the prediction of final histological subtype. Pure choriocarcinoma and pure seminoma GCT do not produce AFP. Yolk sac tumours present with raised AFP in >90% of cases. βHCG is markedly raised in choriocarcinoma and the finding of excessive βHCG levels (>100,000 mIU/mL) support the role for additional staging to evaluate the presence of brain metastases. βHCG shares close molecular characteristics to thyroid stimulating hormone (TSH). An unexplained “thyroid storm” can therefore be a rare presentation of high metastatic burden βHCG secreting choriocarcinoma. An appreciation of tumour marker half-life can support the planning of post operative tumour marker re-sampling. Persistence in post operative tumour markers should highlight the risk of residual disease either systemically or within the contralateral testicle. Following histological confirmation, the pre-operative tumour marker profile supports disease staging (Table 34.7) and prognosis (Table 34.8) as per the IGCCCG guidelines. The assessment of post chemotherapy residual retroperitoneal lesions required knowledge of tumour marker dynamics to determine management. Persistence of which will commonly require salvage chemotherapy over surgical excision. Table 34.6  Testicular cancer tumour makers Tumour Marker AFP βHCG LDH

Size (Daltons) 70,000 38,000 1,34,000

Normal range