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Management of Thyroid Nodules and Differentiated
Thyroid Cancer A Practical Guide 1st Edition Sanziana A. Roman
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, specifcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microflms 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 specifc 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 affliations.
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This Book is dedicated to All who happened to have had Thyroid Cancer, hoping it might be of some Help and Support.
Preface
The second edition of this international reference book was published in 2018. Major and transformative advances have taken place in the research and management of thyroid cancer over the last 5 years. New studies and trials have been designed, many based on the explosion of knowledge about the molecular landscape of Thyroid Cancer and there has been on-going signifcant international collaboration towards uniform evidence-based guidelines and their implementation. The fervent hope is that every patient would have access to a current guideline-based effective, cost-effective, effcient, patient-focused, timely management wherever the patient is being treated. This book, in a tiny way, attempts to embody this view.
We are most grateful for the kindness and hard work of leading world authorities and of the excellent team at Springer, which made this third edition possible, despite the unforeseen pandemic and its unfortunate devastating global impact.
We sincerely hope it will be of some help to our patients and our professional colleagues.
Ujjal Mallick Clive Harmer
1 Advances in Thyroid Cancer Management Beyond the Pandemic . . . .
Ujjal K. Mallick and Clive Harmer
Part I Multidisciplinary Approach to Management of Thyroid Cancer
1
2 Review of NICE Thyroid Cancer Guidelines—UK 2022 . . . . . . 11 Nick Reed
3 African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings . . . .
Johannes J. Fagan, Mark Zafereo, Kathryn Marcus, Marika D. Russell, and Gregory Randolph
Part II The Diagnosis of Thyroid Cancer
19
4 Ultrasonography in Diagnosis and Management of Thyroid Cancer: Current International Recommendations 31 Dong Gyu Na, Ji-hoon Kim, and Eun Ju Ha
5 The Molecular Pathology of Thyroid Cancer 59 Mufaddal T. Moonim
Part III Initial Thyroid Surgery
6 Management of Papillary Thyroid Microcarcinoma: A Japanese Experience 77 Yasuhiro Ito, Akira Miyauchi, and Makoto Fujishima
7 Advances in Thyroid Surgery 87 Erin Buczek, Teresa Kroeker, Cristian Slough, Damilola R. Fakunle, Amr H. Abdelhamid Ahmed, and Gregory W. Randolph
8 Remote Access and Robotic Thyroidectomy: Current Status 101 Klaas Van Den Heede, Matilda Annebäck, and Neil Tolley
9
Contentious Issues in the Management of the Neck in WellDifferentiated Thyroid Cancers 111
Ashok R. Shaha and R. Michael Tuttle
Part IV Post Surgical Management of Differentiated Thyroid Cancer 10 Radioiodine Dosimetric Approaches: Current Concepts and Future Directions
Jan Taprogge, Glenn Flux, Kate Garcez, Matthew Beasley, and Jonathan Wadsley
11 External Beam Radiation in Differentiated Thyroid Cancer in the Era of IMRT and Modern Radiation Planning Techniques
Jelena Lukovic, James D. Brierley, and Aruz Mesci 12 Management of Post-operative Hypocalcemia
Claudio Marcocci 13 On ART, and ART (Ablative Radioiodine Therapy)!
Furio Pacini and Ujjal K. Mallick
Part V Follow Up and Longterm Management of Differentiated Thyroid Cancer 14 Radioiodine Refractory Thyroid Cancer 165
Fabian Pitoia, Anabella Smulever, and Fernando Jerkovich
E. Gréant, A. R. Shaha, and I. J. Nixon
Leslie Cheng and Kate Newbold
Joanna Klubo-Gwiezdzinska, Yevgenia Kushchayeva, Sudheer Kumar Gara, and Electron Kebebew
Leslie Cheng and Kate Newbold
20 Primary Mesenchymal Tumors of the Thyroid
Jiangnan Hu, Rodas Kassu, and Electron Kebebew
Part IX Future Developments and Directions for Research in Thyroid Cancer
21 Current Trends in Treatment and New Generation of Trials in Thyroid Cancer
Priyanka C. Iyer, Samer A. Srour, Marie Claude Hofmann, and Maria E. Cabanillas
22 Thyroid Cancer Clinical Trials
Allan Hackshaw
23 Thyroid Cancer Survivorship: Contemporary Themes
Katherine Kendell and Nicola Jane Armstrong
24 Differentiated Thyroid Cancer: A Health Economic Review
Matilda Annebäck, Klaas Van Den Heede, and Neil Tolley
Part X Covid-Sars-2 Pandemic: The Impact on Management of Thyroid Cancer—Key Lessons Learnt for the Future
25 Thyroid Cancer Surgery During the Pandemic—UK Perspective
Sumrit Bola and Vinidh Paleri
26 Impact on Non Surgical Management and Trials of Thyroid Cancer
Kathleen A. Farnell and Jon Wadsley
Contributors
Amr H. Abdelhamid Ahmed Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infrmary, Harvard Medical School, Boston, MA, USA
Matilda Annebäck Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Department of Surgery, Uppsala University Hospital, Uppsala, Sweden
Nicola Jane Armstrong Thyroid Multidisciplinaty Team, Newcastle upon tyne Hospitals NHS trust, Newcastle upon Tyne, UK
Matthew Beasley Department of Clinical Oncology, Bristol Cancer Institute, Bristol, UK
Sumrit Bola Deapartment of Head and Neck Surgery, The Royal Marsden NHS Foundation Trust, London, UK
James D. Brierley Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
Erin Buczek Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS, USA
Maria E. Cabanillas Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Leslie Cheng Thyroid Unit, The Royal Marsden NHS Foundation Trust, London, UK
Johannes J. Fagan Division of Otorhinolaryngology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Damilola R. Fakunle University of Cincinnati College of Medicine, Cincinnati, OH, USA
Kathleen A. Farnell Butterfy Thyroid Cancer Trust, Tyne and Wear, UK
Glenn Flux Department of Physics Institute of Cancer Research, Institute of Cancer Research, London, UK
Makoto Fujishima Department of Surgery, Kuma Hospital, Kobe, Japan
Sudheer Kumar Gara Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Kate Garcez Department of Clinical Oncology, Christie Hospital, Manchester, UK
E. Gréant Department of Head and Neck Surgery, NHS Lothian, Edinburgh, UK
Eun Ju Ha Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea
Allan Hackshaw Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK
Clive Harmer Thyroid Unit, Royal Marsden Hospital, London, UK Medical Society of London, London, UK
Ian D. Hay Division of Endocrinology and Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
Marie Claude Hofmann Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jiangnan Hu Department of Surgery, Stanford University, Stanford, CA, USA
Yasuhiro Ito Department of Surgery, Kuma Hospital, Kobe, Japan
Priyanka C. Iyer Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Fernando Jerkovich Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina
Rodas Kassu Department of Surgery, Stanford University, Stanford, CA, USA
Electron Kebebew Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
Department of Surgery, Stanford University, Stanford, CA, USA Stanford Cancer Institute, Stanford University, Stanford, CA, USA
Katherine Kendell Department of Clinical Psychology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Ji-hoon Kim Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Joanna Klubo-Gwiezdzinska Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Teresa Kroeker The Texas Thyroid and Parathyroid Center, Austin, TX, USA
Yevgenia Kushchayeva Division of Endocrinology, University of South Florida, Tampa, FL, USA
Jelena Lukovic Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
Ujjal K. Mallick Northern Centre for Cancer Care, Freeman Hospital Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Claudio Marcocci Department of Clinical and Experimental Medicine, Endocrine Unit 2, University Hospital of Pisa, University of Pisa, Pisa, Italy
Kathryn Marcus Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infrmary, Harvard Medical School, Boston, MA, USA
Aruz Mesci Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
Akira Miyauchi Department of Surgery, Kuma Hospital, Kobe, Japan
Mufaddal T. Moonim Department of Pathology, Charing Cross Hospital, Imperial College Healthcare Trust, London, UK
Dong Gyu Na Department of Radiology, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon, Republic of Korea
Kate Newbold Thyroid Unit, The Royal Marsden NHS Foundation Trust, London, UK
I. J. Nixon Department of Head and Neck Surgery, NHS Lothian, Edinburgh, UK
Furio Pacini Endocrinology and Metabolism, University of Siena, Siena, Italy
Vinidh Paleri Department of Head and Neck Surgery, The Royal Marsden Hospital, London, UK
Fabian Pitoia Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina
Gregory W. Randolph Otolaryngology-Head and Neck Surgery, Division of Thyroid and Parathyroid Endocrine Surgery, Department of OtolaryngologyHead and Neck Surgery, Massachusetts Eye and Ear Infrmary, Harvard Medical School, Boston, MA, USA
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Nick Reed Department of Clinical Oncology, NHS Glasgow and Clyde, Glasgow, Scotland, UK
Marika D. Russell Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infrmary, Harvard Medical School, Boston, MA, USA
Ashok R. Shaha Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Weill-Cornell Medical College, New York, NY, USA
Cristian Slough Department of Otolaryngology-Head and Neck Surgery, Hawke’s Bay Fallen Soldiers’ Memorial Hospital, Hawke’s Bay District Health Board, Hastings, New Zealand
Anabella Smulever Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina
Samer A. Srour Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jan Taprogge Department of Physics Institute of Cancer Research, Institute of Cancer Research, London, UK
Neil Tolley Department of Endocrine and Thyroid Surgery, Hammersmith Hospital, London, UK
Department of Otorhinolaryngology and Head and Neck Surgery, St Mary’s Hospital, London, UK
Department of Surgery and Cancer, Imperial College, London, UK
R. Michael Tuttle Endocrinology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Klaas Van Den Heede Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium
Jonathan Wadsley Department of Clinical Oncology, Weston Park Hospital, Sheffeld, UK
Mark Zafereo Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, USA
Advances in Thyroid Cancer Management Beyond the Pandemic
Ujjal K. Mallick and Clive Harmer
Abbreviations
ATA American Thyroid Association
ATC Anaplastic thyroid cancer
BRAF B-Raf proto-oncogene
CPTC Childhood papillary thyroid carcinoma
CSM Cause-specifc mortality
DTC Differentiated thyroid cancer
DTC Differentiated thyroid carcinoma
ERK Extracellular signal-regulated kinase
FDA US Food and Drug Administration
FNA Fine needle aspiration
FTC Follicular thyroid cancer
U. K. Mallick (*)
Consultant Clinical Oncologist (Hon), Northern Centre for Cancer Care, Freeman Hospital Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK e-mail: u.mallick@btinterenet.com
U. K. Mallick, C. Harmer (eds.), Practical Management of Thyroid Cancer, https://doi.org/10.1007/978-3-031-38605-3_1
A physician is obligated to consider more than a diseased organ, more even than the whole person, the physician must view the person in his or her own world
—Harvey Cushing
Key Points
Changing incidence, “Less is More”— Minimalistic management options for low-risk DTC, adapting, adopting, and implementing current guidelines, intersocietal consensus (e.g. Martinique Principles) and global health approach for uniform equitable treatment, Next Generation Sequencing (NGS), Single cell Sequencing (Sc-Seq), molecular landscape of Thyroid Cancer (TC) with high frequency of druggable mutations and kinase fusions , basket trials and tumour agnostic drug approvals, dual kinase inhibition in BRAF V 600 E mutated ATC with signifcant impact, quality of life, survivorship issues, patient’s view, lessons of the pandemic, and possible emerging role of AI in the future.
According to GLOBOCAN cancer incidence and mortality fgures, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020 [1].
In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Against this background, the estimated incidence of new cases of thyroid cancer, the commonest endocrine cancer, in the United States in 2023 is likely to be 43,720 of which 12,540 are males and 31,180 are females. The total number of cases of death from thyroid cancer in 2023 is likely to be 2120 of which 970 are males, and 1150 are females [2].
The commonest type of thyroid cancer, Differentiated Thyroid Cancer (DTC) ranks highest (98%) amongst the other cancers with high survival rates prostate (97%), testis (95%), and for melanoma (94%).
After decades of increase due to overdiagnosis of LRDTC, thyroid cancer incidence rates have
U. K. Mallick and C. Harmer
declined since 2014 by about 2% per year because of changes in clinical practice guidelines restricting over-detection by unnecessary ultrasound and needle biopsies, recommendations against thyroid cancer screening by the USPSTF, and possibly in a small way some coding changes for follicular variant of papillary thyroid carcinoma during 2015–2017 . However, disease-specifc mortality had not increased [2–4].
In the past, vast majority of LRDTC were treated by Total Thyroidectomy (TT) and Radioiodine Ablation (RAIAB). One of the reasons was to ablate the remaining normal thyroid remnant—Radioiodine Remnant Ablation (RRA) to make Thyroglobulin (TG) and subsequent Radioiodine Scan (RS) more sensitive in detecting residual and recurrent disease early. However, since the availability of serial-sensitive TG and high-resolution ultrasound (US) of the neck (the commonest site of recurrence in LRDTC), this was not essential and detecting residual and progressive disease usually within 3–6 years or so became possible. Other reasons for postoperative RAI is Adjuvant RAI (ARAI) for presumed microscopic disease in intermediate risk and some low-risk cases and therapeutic RAI (TRAI) in high-risk cases with known metastatic disease to improve disease-specifc survival and recurrence rates [5, 6].
The overall outcome of LRDTC is excellent. Because of this in recent years, the therapeutic philosophy has taken a minimalistic and “Primum Non Nocere” (First do no Harm) and “Less is More” approach. The paradigm of almost routine TT +RAIAB is shifting.
Two large multicentre randomised controlled trials (RCT) provided level 1 evidence that after 3 years of follow-up in selected cases of LRDTC total thyroidectomy only by a specialist surgeon is non-inferior to TT + RAI 1.1GBq in terms of event rates or recurrence rates ([7], Allan Hackshaw-Personal Communication). However, specialist multidisciplinary team management, proper case selection, and preoperative risk stratifcation, surgery by a high-volume surgeon with careful intraoperative assessment, and postoperative risk stratifcation are critical. The criteria for postoperative decision to use RAI based on US
and thyroglobulin level need further clarifcation at this time as the detailed fndings of another trial is awaited (Allan Hackshaw-personal communication). Also perhaps slightly longer period of follow-up would be helpful.
Now for selected LRDTC—Active Surveillance (AS) without immediate surgery, Thyroid Lobectomy (TL) not TT, Thermal RFA , TT without RAIAB, and TT+RAIAB are all possible options depending on proper risk stratifcation using the ATA risk category.
These are based on few level 1 evidence from RCT and more on well-designed prospective non-randomised studies, retrospective studies, analysis of registry data, etc. Because of this paucity of level 1 evidence at present, the controversy continues although time and cost-intensive RCTs continue to be designed and published [8–17].
Because of this doctor-patient shared decisionmaking for an individualised treatment plan is of paramount importance, making sure that the right risk stratifed thyroid cancer in the right patient (with full understanding) is treated by the right specialist multidisciplinary team with the right evidence-based guidance in right time, every time, everywhere to echo the dictum of the National Academy of Medicine. Also because of this controversy, the team needs to carefully assess which option suits the patient best given the patient’s age, sex, general health, job, family and societal commitments, psychological makeup to cope with protracted treatment, follow-up and its fnancial pressures in certain health care settings, etc. Dr. Cushing’s adage is so appropriate in the setting of LRDTC!
This personalised and nuanced minimalistic approach for the treatment of LRDTC remains one of the central issues in the Thyroid Cancer Management.
Leading world authorities will give their latest views on this very important topic in this edition to help the readers with their practical day-to-day clinical activities, detailing the advantages and disadvantages of each approach.
However, according to some authorities there has been slightly increased incidence of advanced thyroid cancers in recent years as well, possibly
related to obesity and environmental factors. This is also supposed to be associated with slightly increased incidence-based mortality [18–22].
DTC is stratifed for recurrence by ATA classifcation and overall outcome by the AJCC TNM 8th edition.
Recent advances in surgical approaches, Intraoperative Neural Monitoring (IONM), radioiodine treatment, theranostics, radioiodine dosimetry, advances in radiotherapy, and other forms of local treatment as required will be discussed by world leaders.
In recent years, major efforts have been taken to develop international and intersocietal consensus such as the Martinique Principles for a uniform approach to radioiodine therapy and its concepts.
While LRDTC is highly curable, advanced DTC has a poor prognosis specially if it is radioiodine refractory. In addition, Medullary Thyroid Cancer (MTC), Poorly Differentiated Thyroid Cancer (PDTC), and ATC have worse prognosis and until recently ATC was untreatable and incurable. Major international guidelines and scholarly articles have been produced to facilitate and improve outcome.
Thyroid cancer is a tumour type with one of the highest proportion of actionable mutations after gastrointestinal stromal tumour (76%) and thyroid cancer (60%). TCGA analysis also showed that thyroid cancers harbour the highest frequency of oncogenic driver kinase fusions of all solid tumours [23, 24].
But major advances in the methodologies over the last few years such as NGS have provided detailed knowledge of the molecular underpinnings of thyroid cancer allowing specifc gene-directed systemic treatments with better outcomes. In addition, advances in the feld of Sc-Seq have enabled transcriptomic and other information at a single-cell resolution rather than bulk sequencing providing averaged data. This provides valuable information regarding ITH, TIME, Circulating Tumour Cells (CTC), etc. helping our understanding of the tumour dynamics and biology and planning of precision targeted therapy with better outcomes.
Some of the actionable or druggable targets in thyroid cancer are BRAF V600E and KRAS, NRAS, and HRAS mutations. In addition, kinase fusions involving NTRK, RET, ALK, and other fusions are oncogenic drivers and have been identifed as actionable targets in thyroid cancer. They are being treated with selective MKIs with progression-free survival beneft though overtime acquired resistance does develop after initial response when new treatments are required.
In recent years, new forms of trials with master protocols or basket trials have shown that some drugs are effective in treating a range of tumours with a specifc gene alteration or biomarker regardless of their histology or anatomical site of origin and are called tumour agnostic drugs. Such drugs have been approved by FDA and also are being used in thyroid cancer with better outcomes and acceptable side effects. For example, following the phase II Basket Trial, the ROAR study, FDA, and regulatory bodies in other countries have authorised the dual treatment by dabrafenib (BRAFV600E MAPK inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC. This has been a major advancement in ATC with durable responses which previously was untreatable and incurable with an Objective Response Rate of about 55% including three complete responses; the 12-month Overall Survival (OS) was just over 50% with reasonable tolerance and manageable toxicity.
In recent years, many non-selective multikinase inhibitors (MKI), including sorafenib, lenvatinib, and cabozantinib, have been used for the therapy of aggressive radioiodine (RAI)-resistant DTC and cabozantinib and vandetanib for MTC.
Selpercatinib and pralsetinib selectively inhibit mutant RET in MTC, but they can also block the RET fusion proteins-mediated signalling found in PTC and are being used. Selective inhibitors, entrectinib and larotrectinib, have been approved for use in patients with progressive RAI-resistant TC harbouring NTRK fusion proteins.
Some of these new gene-specifc treatments are also being used in the neoadjuvant setting for advanced diseases. Some also have been used for
U. K. Mallick and C. Harmer
redifferentiation of radioiodine-resistant DTC for retreatment with RAI again.
In addition to druggable gene alterations, tumour mutational burden, microsatellite instability status, and PD-L 1 status are being evaluated for the appropriateness of use of immunotherapy for some of these tumours [25–33].
Progress in liquid biopsy such as (CTC) and circulating free tumour DNA (ct-DNA) are emerging as additional bio-markers. It can help early detection, monitoring, and early treatment of recurrent disease by a blood test to improve outcomes without the need for multiple tissue biopsies particularly from metastases in inaccessible areas. Serial assessment can provide information about tumour heterogeneity, clonal evolutional trajectory of progressive tumours, and detection of resistant clones. But further developments are necessary before routine clinical use is possible though is being used in trial settings in some tumours.
Many tumours will become resistant after initial period of response to non-selective and selective kinase inhibitors. Instead of further multiple tissue biopsies, liquid biopsy with CTC or ctDNA by a simple blood test can detect the resistant cell clone and help design subsequent treatment [34–37].
World experts discuss these in detail in this edition informing us about the current state of the art and the future directions of research.
The world faced the unforeseen pandemic in 2020 and millions of lives were unfortunately lost. But an unprecedented spirit of international collaboration was unlocked and professionals, scientists, and people crossing all boundaries devoted themselves to making major innovative, transformative scientifc advances in a global effort to combat the pandemic. Diagnostic tests, innovative viral m-RNA-based vaccines, new drugs and therapeutics, new reliable large trial designs, etc. were all developed with unimaginable speed to tackle the pandemic frst.
Major positive systemic changes and adaptations in health care delivery also affected all types of cancer management including thyroid cancer
management. Safe and timely diagnosis and treatment were planned if necessary with the help of digital technology such as telemedicine, remote technical and quality assurance mitigating workforce and equipment shortages, while many were busy treating covid-19 patients on the frontline not only taking appropriate care but also taking considerable personal risk.
Highly successful trials such as the Recovery Trial during the pandemic also showed that reliable trials with newer design and newer methods of conducting can be done effciently and in a time-effcient manner. Remote randomisation, treatment, monitoring, (decentralising the processes), integrating research data with patientreported outcomes and routine data and other developments in trials is discussed by world expert statisticians and clinicians and professionals.
Written by world authorities from several countries like the previous editions, this third edition hopes to embrace and embody this philosophy of international and intersocietal collaboration and disseminate the recent advances in the feld of thyroid cancer with a truly global health perspective.
There is variation in thyroid cancer treatment between country to country and not infrequently between different parts of the same country. This is due to multiple factors surrounding the implementation of guidelines. Although the situation is improving, currently guidelines cannot give strong recommendations in every clinical scenario due to paucity of randomised trials and therefore can be interpreted differently by different clinicians; limited availability of health care resources and limited access to specialist care provided by multidisciplinary teams with high-volume professionals are also likely caused in some areas. This is being addressed by best possible adaptation of international guidelines to the specifc country’s health care infrastructure as detailed in the guidelines section. Also international and intersocietal collaboration and consensus statements are facilitating implementation of uniform guidance as far as practicable for equitable delivery of evidencedbased care reducing such variations within a global health perspective [13, 38, 39].
Although most LRDTC are curable, thyroid cancer patients are well known to have poor quality of
life comparable to some of the major cancers, high anxiety level, and fnancial burden of protracted treatment and follow-up. Global dissemination of information and guidelines, optimal communication with patients, survivorship and psychosocial support, patient education, and co-operation between specialists are therefore essential [40–42].
Artifcial Intelligence (AI) or the ability of computer machines to apply almost human-like reasoning to solving problems usually involves two techniques. Machine learning, in which computers learn by observing data provided by humans, and Deep Learning, which uses Artifcial Neural Networks (ANN) similar to the functional structure of the brain to analyse data. The latter has a nontransparent black-box pattern of working which is not fully “Explainable” and is a cause for concern in direct patient care according to some [43].
Explosion of medical data and revolution in data-driven medicine have necessitated embedding data analytics, Artifcial IntelligenceMachine Learning operations in many aspects of health care, and it is no surprise that its role is increasingly being assessed in the feld of thyroid cancer. AI-driven algorithms are being used for accurate, objective and fast radiology, and pathological diagnosis and in risk stratifcation of thyroid nodules (already four AI platforms have been approved by the FDA), assessment of cytopathology, involvement of lymph nodes and in genomics for prediction of gene mutation, storage and analysis of -omics data helping precision oncology, etc. It is also a great help in quality control, managing workfow, training, managing staff shortages, and remote guidance even in limited resource settings [43].
Like many new advances, its use is likely to evolve in the thyroid cancer feld but costeffective, user friendly, reliable, validated AI platforms are required. More importantly, clinicians need to be trained and reassured about the reliability of AI black box algorithms as used in direct patient care.
Many guidelines such as EU guidelines, US Food and Drug Administration (FDA) whitepaper, guidelines from the National Institute for Health and Care Excellence (NICE), etc. recommend AI should be robust, ethical, and lawful.
And many authorities feel it should augment the actions of humans through explainable transparent decision pathways rather than black box opaque decision-making which is the usual way ANNs work [43–50].
As before, this book is aimed at experts of all disciplines who are members of a specialist multidisciplinary team involved in the day-to-day management of thyroid cancer including trainees and students. In addition, in the new postpandemic world this might be a helpful resource book for information technologists involved in telemedicine and AI in health care, health policy makers, hospital managers, geneticists, researchers, scientists, and statisticians.
Like the previous editions, its focus is providing a practical, person-centred approach that also informs and empowers patients for shared decision-making during their treatment journey with a chapter written by an expert patient and patient adviser.
The publication of this third edition would not have been possible without the collaborative leadership, profound kindness, hard work, commitment, and enthusiasm of respected international experts in thyroid cancer from several countries and the world leading Springer editorial team led by Melissa Morton who ignored the many major problems facing the post-pandemic world and sacrifced their precious time to offer their expertise and valuable contributions.
We extend our thanks and heartfelt gratitude to all of them.
We thank our wives and family for their tolerance and kind support during the preparation of the book.
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12. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133. https://doi. org/10.1089/thy.2015.0020
13. Zafereo M, Yu J, Onakoya PA, Aswani J, Baidoo K, Bogale M, Cairncross L, Cordes S, Daniel A, Diom E, Maurice ME, Mohammed GM, Biadgelign MG, Koné FI, Itiere A, Koch W, Konney A, Kundiona I, Macharia C, Mashamba V, Moore MG, Mugabo RM, Noah P, Omutsani M, Orloff LA, Otiti J, Randolph GW, Sebelik M, Todsen T, Twier K, Johannes J. Fagan. African Head and Neck Society Clinical Practice guidelines for thyroid nodules and cancer in
developing countries and limited resource settings. Head Neck. 2020;42(8):1746–56. (3rd edition)
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15. Orloff LA, Noel JE, Stack BC Jr, et al. Radiofrequency ablation and related ultrasound-guided ablation technologies for treatment of benign and malignant thyroid disease: an international multidisciplinary consensus statement. Head Neck. 2022;44(3):633–60. https://doi.org/10.1002/hed.26960.
16. Chou R, Dana T, Haymart M, Leung AM, Tufano RP, Sosa JA, Ringel MD. Active surveillance versus thyroid surgery for differentiated thyroid cancer: a systematic review. Thyroid. 2022;32(4):351–67. https:// doi.org/10.1089/thy.2021.0539. Epub 2022 Mar 17
17. Jasim S, Patel KN, Randolph G, Adams S, Cesareo R, Condon E. American association of clinical endocrinology disease state clinical review: the clinical utility of minimally invasive interventional procedures in the management of benign and malignant thyroid lesions. Endocr Pract. 2022;28(4):433–48. https://doi. org/10.1016/j.eprac.2022.02.011
18. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA. 2017;317(13):1338–48. https://doi.org/10.1001/ jama.2017.2719
19. Yan KL, Li S, Tseng CH, Kim J, Nguyen DT, Dawood NB, Livhits MJ, Yeh MW, Leung AM. Rising incidence and incidence-based mortality of thyroid cancer in California, 2000–2017. J Clin Endocrinol Metab. 2020;105(6):dgaa121. https://doi.org/10.1210/ clinem/dgaa121
20. Wilhelm A, Conroy PC, Calthorpe L, Shui AM, Kitahara CM, Roman SA, Sosa JA. Disease-specifc survival trends for patients presenting with differentiated thyroid cancer and distant metastases in the United States, 1992–2018. Thyroid. 2023;33(1):63–73. https://doi.org/10.1089/thy.2022.0353. Published Online:13 Jan 2023
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22. Karzai S, Zhang Z, Sutton W, Prescott J, Segev DL, McAdams-DeMarco M, Biswal SS, Ramanathan M Jr, Mathur A. Ambient particulate matter air pollution is associated with increased risk of papillary thyroid cancer. Surgery. 2022;171(1):212–9. https://doi. org/10.1016/j.surg.2021.05.002. Epub 2021 Jun 29
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25. Lubitz CC, Sadow PM, Daniels GH, Wirth LJ. Progress in treating advanced thyroid cancers in the era of targeted therapy. Thyroid. 2021;31(10):1451–62. https:// doi.org/10.1089/thy.2020.0962. Epub 2021 Jun 22
26. Shonka DC Jr, Ho A, Chintakuntlawar AV, Geiger JL, Park JC, Seetharamu N. American Head and Neck Society Endocrine Surgery Section and International Thyroid Oncology Group consensus statement on mutational testing in thyroid cancer: defning advanced thyroid cancer and its targeted treatment. Head Neck. 2022;44(6):1277–300. https://doi. org/10.1002/hed.27025. Epub 2022 Mar 11
27. Fugazzola L, Elisei R, Fuhrer D, Jarzab B, Leboulleux S, Newbold K, et al. European Thyroid association guidelines for the treatment and follow-up of advanced radioiodine-refractory thyroid cancer. Eur Thyroid J. 2019;8:227–45. https://doi.org/10.1159/000502229
28. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Oncol. 2022;33:406–15.
29. Shaha AR. Anaplastic thyroid cancer: shifting paradigms—a ray of hope. Thyroid. 2023;33(4):402–3. https://doi.org/10.1089/thy.2023.29150.sha Published Online: 28 February 2023
30. Gild ML, Bullock M, Tsang V, Clifton-Bligh RJ, Robinson BG, Wirth LJ. Challenges and strategies to combat resistance mechanisms in thyroid cancer therapeutics. Thyroid. 2023;33(6):682–90. https:// doi.org/10.1089/thy.2022.0704
31. Chmielik E, Rusinek D, Oczko-Wojciechowska M, Jarzab M, Krajewska J, Czarniecka A, et al. Heterogeneity of thyroid cancer. Pathobiology. 2018;85(1–2):117–29. https://doi. org/10.1159/000486422
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Part I
Multidisciplinary Approach to Management of Thyroid Cancer
Review of NICE Thyroid Cancer Guidelines—UK 2022
Nick Reed
Introduction
The purpose of this document is to review the recent publication by the National Institute for Health and Care Excellence (NICE) regarding the management of differentiated thyroid cancer (DTC) in the NHS England. The following reference will provide the reader with a background to NICE processes [1]. It maybe helpful to start to explain what are guidelines and what is the rationale for producing guidelines and try to explain the difference between guidance, guidelines and protocols and these terms are sometimes used interchangeably.
Guidelines are usually evolutionary and often form a series of publications over a number of years refecting changes in clinical practice. The key point is that they are evidence based and make recommendations for delivery of care. They are useful reference documents for clinical decision-making and also audit and benchmarking. They also help to establish minimal standards of care. This is helpful for both large and small units and helps to ensure similar standards are applied in both. They provide good practice guidance and recommendations rather than mandating the level of care. It is hoped that the consequence is an improvement in overall standard of
N. Reed (*) Department of Clinical Oncology, NHS Glasgow and Clyde, Glasgow, Scotland, UK
care. This guideline presents a new review of the topic in differentiated thyroid cancer. Guidance tends to be a more informal process, as it implies guiding clinical care. Protocols more usually apply to the details of clinical trials.
It covers both those with thyroid nodules suspicious of malignancy and confrmed thyroid cancer. Thyroid cancer itself is relatively uncommon although its incidence has been rising but thyroid lumps, nodules and swellings are frequent and usually innocent. The target audience is generally medical staff, nurses, allied health professionals, medical physics and nuclear medicine staff, charities, heath care providers/commissioners and patients and their families. This is a broad remit and the challenge is to make it readable for all groups. This is of course not a textbook.
In this new NICE guideline we will indicate how this changes clinical practice, what has been added as a new recommendation for care and what has been replaced or updated [2]. It is broken up into a number of component sections including diagnostic techniques, surgery, the role of radio iodine, medical treatment, external beam radiotherapy and follow up. The diagnostic sections include imaging, biochemistry, cytology and histopathology. Molecular profling is still establishing its role as technology changes so rapidly.
The composition of the members of the NICE guideline refects the multidisciplinary management of thyroid cancer and includes ENT and
U. K. Mallick, C. Harmer (eds.), Practical Management of Thyroid Cancer, https://doi.org/10.1007/978-3-031-38605-3_2
thyroid/endocrine surgeons, pathologists, imaging specialists, endocrinologists, clinical oncologists, nuclear medicine specialists, general practitioners and nurses.
Other papers have described in detail the processes used to determine NICE guidelines but this short paper will focus on the changes and challenges and highlight some of the controversies. Modern medicine is rarely black and white and there are frequently grey areas where even experts may disagree but generally we are able to achieve a consensus and it is hoped that this document has fulflled that aspiration.
The document specifcally covers differentiated thyroid cancer, namely papillary, follicular and oncocytic (Hurthle cell) variants. It does not include medullary thyroid cancer (MTC) nor anaplastic thyroid cancer (ATC). It also excludes paediatric thyroid cancer and recurrent thyroid cancer.
The topics covered include the following:
1. Management of suspected thyroid cancer, diagnostic procedures
2. Patients planned for surgery
3. Confrmed diagnosis of DTC
4. Information about Radio-iodine
5. Biochemical monitoring and tumour markers
6. Follow up of DTC
The cancer journey starts with symptoms suggestive of an underlying thyroid cancer although recent practice has seen a rising incidence of incidentally detected tumours on imaging. This is followed by the diagnostic procedures to establish a diagnosis. These include Ultrasound and cytology with Rapid On Site Evaluation (ROSE). Tumour markers play a limited role, they have no place in diagnosis but are valuable in post therapy management. Other imaging will be discussed including CT scans, MRI and nuclear medicine scans. Some aspects of these topics are covered by other NICE guidelines [3]. Molecular pathology is an emerging topic in DTC.
The patient may present with symptoms, most commonly a lump in the neck or goitre but an
increasing number have thyroid nodules incidentally picked up on scans done for other purposes. In recent times with the increasing role of FDG PET scans for staging cancers, avid uptake is seen in the thyroid gland. Most patients with a lump are now referred to dedicated neck lump clinics run by ENT surgeons or specialist thyroid or endocrine surgeons. Rarely patients will present with metastatic disease in bones or lungs.
The next step is to discuss the management at the Multi-Disciplinary Team (MDT) meeting, also known as the Tumour Board.
Diagnostic Procedures
Ultrasound (US) and Fine Needle Aspiration Cytology (FNAC) are the mainstay of testing. There are different US techniques which are discussed. This generated much diffculty as there are many techniques but grey scale US was considered to be the best initial procedure. Grading systems are used to “score” the fndings which can be combined with the results of FNAC as discussed. Both lobes should be checked as well as the regional nodes.
FNAC is well established and easily carried out as a day case procedure. It maybe liquid based cytology, direct smear or both, and this is usually determined by local practice and experience. Within the UK the Royal College of Pathologists (RCPath) reporting system is used and given that this is a UK based guideline it is anticipated this will be used [4].
Rapid OnSite Evaluation (ROSE) has been shown to signifcantly reduce the number of nondiagnostic tests. This will require a change of practice where this is non standardly used. It is again expected that this will be cost effective but local audits are its introduction are recommended.
When to carry out Core biopsy? This is proposed when the FNAC is inadequate or indeterminate, however after one inadequate sample it is proposed to repeat the FNAC and if still indeterminate, proceed to a core needle biopsy (CNB). When a Thy3a is seen, repeat sampling with
N. Reed
FNAC or CNB is recommended which is a change from previous practice. Active surveillance may also be considered. For Thy3f lesions, recommendation to proceed to a diagnostic lobectomy is more usually advised. For Thy4 or Thy5 immediate referral to surgery is usual with the debate only being whether to offer lobectomy or total. This refects current practice.
Blood sampling and tumour markers: There is no value from the use of Thyroglobulin (Tg) screening, it is only of value after total thyroidectomy and even then there may be limitations which are discussed later in document. Thyroid peroxidase antibody testing (TPO) may have a role in supporting FNAC interpretation especially if thyroiditis is suspected. It is only recommended where there is indeterminate pathology. Calcitonin is only measured if there is a strong Family History or strong suspicion of MTC. There is no justifcation for doing this routinely in suspected thyroid cancers, it should be targeted at patients with known risk factors such as family history. Many of these will already be attending endocrine genetics clinics.
When is CT or MRI required? What is the place of staging CT? The committee felt that staging scans were no longer routinely recommended for T1 and T2 tumours unless some clinical suspicion of more advanced disease or concern for metastasis. For more advanced tumours (T3 and T4) CT scanning is needed to stage and help plan surgery. It is anticipated this will have little impact on current practice in the UK.
Impact of contrast scans on subsequent RAI scheduling? Following use of contrast scans there needs to be delay before RAI can be used. This must be borne in mind when scheduling RAI. Most authorities recommend waiting at least 8 weeks otherwise treatment with RAI may be compromised.
Is there any continuing role of radio-isotope scans? This is now considered unnecessary as a routine and arguably may offer potential harm from unnecessary radiation exposure. Scanning may be of more value in looking for recurrent disease which is outwith the remit of the guideline.
Molecular profling may have an important supplementary role especially in borderline cases and will be discussed later. It will also feature strongly in recommendations for research.
Surgical Management
Who should operate? The committee did not address this issue but it should be a team experienced in managing thyroid cancer and will usually be from ENT/Head and Neck Oncology, thyroid and endocrine surgical background.
Which procedure? Hemi vs total thyroidectomy? The surgical management of thyroid cancer has changed enormously in the past 15–20 years. Traditionally a total thyroidectomy was offered as standard except in small lesions. However with many incidentally identifed small tumours there has been a re-assessment of what surgical procedure is required, and this has extended to include some larger tumours with lower risk factors. The decision will also be affected by the likely indication of whether to give (or withhold) RAI. Given the lower relapse rate after Total thyroidectomy, this is still considered standard for higher risk cases, eg large tumours or bilateral disease, signifcant capsular and/or vascular invasion.
For lower risk cases a diagnostic hemithyroidectomy maybe offered which allows the option of active surveillance or completion after review of pathology and other factors. An Italian trial did show a signifcant proportion of patients on active surveillance choosing delayed intervention with subsequent completion.
HOT study. This trial is investigating whether total thyroidectomy is still required in low risk cases. It opened only relatively recently but will help to address if a lobectomy is a safe alternative in low risk cases. This question will be highlighted in future research. This trial compares a total thyroidectomy vs hemi-thyroidectomy [5].
When there is uncertainty, a diagnostic lobectomy should be offered and then discussed at the MDT.
Management of Nodal disease. The committee used existing clinical experience as there was no evidence to support other recommendations. It is recommended that the nodes are dealt with at time of primary surgery rather than as delayed or two step procedure. When nodal disease seems confned to lateral neck, a compartment orientated lateral neck dissection is standardly recommended, and similarly if central nodes then a compartment orientated central neck dissection is offered. There may be considerations of ipsilateral central dissection if considered appropriate.
Prophylactic neck surgery is more controversial. Whilst it may reduce risk of relapse, this may be counterbalanced by higher risk of hypoparathyroidism and to a lesser extent recurrent laryngeal nerve damage. On balance the committee favoured NOT performing prophylactic neck dissections.
Impact of pregnancy. Thyroid cancer found in pregnancy or in the year after pregnancy is not uncommon. The issues are most challenging in early pregnancy. Given that most thyroid cancer is relatively slow growing, it is generally recommended to delay any surgery until second or third trimesters. Imaging should try and avoid ionising radiation so US tends to be favoured, however if there is evidence of rapid growth discussion should occur at the MDT and individual decisions made about timing of surgery.
Pathology: The WHO Blue book revision 2022 has made some signifcant changes to pathology classifcation but came too late for the NICE guideline publication [6].
Post-Operative Management
Following surgery the case should be taken back to the MDT for further discussion of management. The frst discussion is to decide whether further surgery is required or active surveillance or even discharge if a low risk tumour. Low risk patients will not need anything other than surveillance although for how long and how to monitor is debatable. Low risk will be determined by age,
N. Reed
pathology grade and subtype, and the degree of capsular and vascular invasion.
For higher risk patients, completion will be recommended and the patient sent back to surgical team. Following this it is back to the MDT for further discussion as to the need to offer adjuvant RAI vs surveillance.
Need for RAI
The MDT or tumour board will discuss the role of adjuvant RAI. This should be in concordance with National guidelines. We have seen a marked change in guidance from high usage of radioiodine usage to far greater selectivity and discussion about high versus low activities. Traditionally many patients were given a standard of high dose usually in range of 80–100 mCi (3700–4000 MBq) but recent trials such as HiLo and ESTIMABL have shown higher activity is only needed for higher risk cases and low activity (1100 MBq) is safe option in lower risk patients [7–10].
Now the focus is on whether RAI can be withheld in low risk cases again from the ESTIMABL2 and ION trials. Results are still awaited but represent a signifcant change in approach avoiding the use of RAI in truly low risk cases. When indicated low dose (1100 MBq) is now the standard of care in these lower risk cases [11, 12].
This essentially leaves three risk groups. Those where RAI is strongly indicated, secondly those where the risk of relapse is low so that RAI can be avoided. Finally there is the “uncertain group” where its role is unclear and the specialist will discuss with the individual the pros and cons of administering RAI. Within the group where RAI is clearly indicated the discussion will involve whether to give high or low activities. Nowadays the majority will fall into the intermediate risk group were 1.1GBq is recommended whereas the high risk group receive upto 3.7 GBq.
Within the UK, patients are referred for RAI, depending on local practice to clinical oncolo-
gists, endocrinologists or nuclear medicine physicians. All practitioners must have an ARSAC certifcate and work within the multi-disciplinary team. Once again the impact on current management is minimally affected as most practitioners have already adopted the guidance.
Preparation for RAI
A number of steps are required prior to booking treatment. These include checking appropriateness for a radionuclide. These include discussing Fertility issues and contraception. Pregnancy is an absolute contra-indication. Pregnancy should be avoided for at least 6 months post RAI and contraception used. Males must abstain from fathering children for at least 6 months. Patients need to be counselled about radiation protection issues, in hospital and post discharge. This is not within the scope of this document.
Thyrogen stimulation vs Thyroid Hormone withdrawal (THW). Historically in preparation for RAI, patients were switched from levothyroxine to liothyronine and then hormone treatment was withdrawn to achieve a stimulated TSH. This is now achieved with use of recombinant TSH (thyrogen). It avoids hormone withdrawal and all the misery associated with this. It is used in nearly all situations nowadays and its use has become standard practice. Quality of life is maintained and patients can return to normal lifestyle and work more quickly.
Radionuclide Therapy
What activity is recommended? This is discussed above. Low activity 1100 MBq is used for most cases which are low or intermediate risk. The higher activity of 3700 Mq is reserved for higher risk cases. There is no strong evidence to support even higher activities which were used in the past. The majority of patients require a single administration. Generally a maximum of 4–6
activities may be given. Beyond this this there is little evidence to suggest any further beneft and risk of myelodysplasia and leukaemias start to rise to concerning levels. There are now effective alternative medical therapies for iodine refractory disease.
Diet. It is recommended to use a low iodine diet for 1–2 weeks pre treatment, generally avoiding seafood, excess dairy and a few other foods. Most departments have their own sheets that are handed out.
Timing. The use of adjuvant RAI is usually advised within 3 months of surgery. It is usually recommended to withhold a repeat dose format least 4–6 months to allow recovery from myelosuppression.
Post discharge care. Each department will produce its own leafet or handout for post treatment care. Generally the main cautions involve minimising risk of radiation exposure to young persons or pregnant women. These comply with the national guidelines.
External Beam Radiotherapy (EBRT)
Adjuvant neck/nodal irradiation is rarely used. Similarly it is very infrequent to use sequential RAI and EBRT. There will be occasional cases where radio-iodine maybe contra-indicated and EBRT considered as an option. Usually EBRT is reserved for locally recurrent or persistent disease which is outwith the scope of this document. Similarly EBRT maybe used for treatment of symptomatic bone metastases or spinal cord compression. Rare follicular thyroid cancer cases will actually present with bone metastases and EBRT may be used for initial symptom control whilst awaiting planned elective surgery and RAI. In the case of patients presenting with solitary or oligometastatic bone disease, high dose palliative is usually recommended as these patients can live for many years or even be cured. Symptomatic management for acute bleeding may very rarely be indicated. These are all really uncommon situations.
Thyroid Hormone Replacement
What hormone replacement is required? Initially it is not just replacement but suppressive doses of levothyroxine that are required to keep the TSH level in range 0.5–1 IU/L, at least for the frst 2 years. For low/intermediate risk patients the doses may then be modifed to allow the TSH to rise to range 1 to 3. This is to reduce risks of atrial fbrillation and osteoporosis. For high risk patients or those with metastases, continued suppression is advised. Levothyroxine is the preferred hormonal replacement, usual starting doses are 2 mg/kg but the doses are titrated against the TSH levels. Patients should be monitored for symptoms and biochemical evidence of over or under-replacement. This is required lifelong but usually only annually after 10 years. Liothyronine or even combinations are occasionally used. It should not be recommended as a standard but maybe useful in individual patients.
Dynamic Risk Stratifcation (DRS)
Low/intermediate risk vs High risk/metastatic. Recent experience has shown that follow up strategies may be decided by determining if patients fall into lower or high risk groups. The measurement of thyroglobulin at 9–12 months may help to predict the likely risk of relapse. This can be supported by neck ultrasound. Previously stimulated Tg was used either using THW or thyrogen stimulation but the sensitivity and reliability of modern Tg assays has made this less necessary. DRS may be less useful or reliable in the presence of Tg antibodies. Assignment to a low DRS group means risk of relapse is very low and less intense follow up is needed. Furthermore supersuppression of the TSH is not needed. Generally Tg levels <0.2 indicate low risk. Levels between 0.2 and 1 raise some concerns for possible residual thyroid tissue/disease with cautious monitoring. Tg >1 may indicate a higher risk and consideration of Thyrogen stimulation and other imaging and the need for further intervention. The presence of rising or emergence of Tg anti-
bodies should raise suspicions of relapse and these tests must be interpreted with caution.
Follow Up
Follow up visits are carried out to monitor for recurrence and to be able to offer intervention treatments. Follow up is a combination of clinical examination, biochemical monitoring of thyroid function to include TSH levels and the Thyroglobulin as a tumour marker. There is a limited role for US and no place for regular imaging with CT or MRI unless indicated by clinical fndings or Tg levels. The frequency of visits tends to be more often for frst 2 years and for low risk patients the frequency can be relaxed. Following the COVID pandemic there has been increasing use of telephone or video-conferencing for follow up with “remote” blood sampling. The use of the new generation thyroglobulin assays has made remote consultations more secure.
Blood tests monitoring—As mentioned above the routine testing will include thyroid function, (free thyroxine, TSH and T3) together with thyroglobulin and Tg anti-bodies. Calcium should also be checked and as appropriate Parathyroid Hormone and vitamin D levels.
The target levels of TSH have changed in past 5 years. Historically super suppression of TSH was the aim but recognition that the risks of osteoporosis and atrial fbrillation out weigh the perceived benefts of suppression. Suppressive doses of levothyroxine are still required for high risk cases and those with metastatic disease. Modern practice now shows that for low/intermediate risk cases suppression no longer required after 2 years and target levels can be allowed to rise to 1–3 IU/L. Lifelong monitoring of TSH levels are required even when patients are discharged from specialist care. The hospital consultant has a duty to advise the primary care physicians about target levels of TSH in long term.
Thyroglobulin is now established as a reliable post-operative tumour marker except where there are antibodies where results need to be inter-
preted with caution. Ironically TgAb may have a role in monitoring. The emergence of new rising levels of antibodies strongly suggests recurrence and should trigger scanning to look for disease hence its role as a surrogate marker. US and follow up iodine scans have a limited and more controversial role. It has been practice to do a thyroid US along with stimulated thyrogen at 9–12 months post surgery as part of dynamic risk stratifcation (DRS).
Limitations of Thyroglobulin
The monitoring of Tg is only reliable after total thyroidectomy but may have a limited if uncertain role after lobectomy. After lobectomy US has a more secure role is monitoring recurrence. Interference from Tg antibodies has already been discussed above leading to cautions about rising Tg Abs as surrogate marker for relapse.
Follow-Up
Who should carry out follow up? This will depend on local practice and experience. The important issue is that the specialist should have experience and expertise in managing thyroid cancer. It may be endocrinology, surgery, ENT, oncology or nuclear medicine based or a combined clinic. This usually refects local experience and expertise. The use of nurse-led clinics or remote telephone/video consulting has become more common especially since the COVID pandemic. Given the relative rarity in primary care, general practitioners cannot be expected to to have suffcient expertise to carry out postoperative care outwith the shared care setting which be required for those living in remote and rural locations. However for lower risk cases after 5 years care can be transferred back to primary care with recommendations from the specialist clinics. Higher risk cases or metastatic patients need long term specialist clinic follow up. For patients who live a long way from the specialist centre, shared care may be considered
with agreed protocols. The recommendations generally refect current practice.
Relapse
The management of recurrent disease is outwith the remit of the guideline. Patients should be discussed at the MDT to determine whether management is surgical or oncological or combined.
Other Topics
Molecular profling is still establishing its role differentiated thyroid cancer. It can be important in confrming diagnosis (eg braf mutation) as well as having some predictive behaviour. Most recently other markers including ras, tert, ret. and NTRK are more important in helping to select targeted agents for relapsed disease but new data is likely to show that combining molecular testing may have prognostic qualities.
At present there are limited criteria for referral to Clinical genetics for DTC. There are some families with patterns of associated malignancies and these should be discussed with local genetics clinics. There are already clear pathways for medullary thyroid cancer/MEN syndrome patients.
Recommendations for Future Research
The main issues that are topical are those likely to affect decision making about surgical procedures required, for example where total thyroidectomy can be replaced by hemi-thyroidectomy. This is covered by the HOT trial. Further work will clarify optimal doses of RAI and the use of personalised dosing is likely to become standard. Molecular profling will continue to evolve both for diagnosis and prognostic/predictive testing and selection of treatment for relapse. Other measures will be looked at to reduce long term morbidities.
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forgive us our faults, and keep us from the chastisement of fire; the patient and the truthful and the obedient and those who spend (benevolently) and those who ask forgiveness in morning times”.[70]
Let us now point out some drawbacks which hinder the path of the divine love.
Man from his infancy is accustomed to enjoy sensual delights which are firmly implanted in him. Blind imitation of the creed with vague conception of the deity and his attributes fails to eradicate sensual delights and evoke the raptures of divine love. It is the dynamic force of direct contemplation of his attributes manifested in the universe that can prove an incentive for his love. To use a figure: a nation loves its national poet, but the feeling of one who studies the poet will be of exceeding strong love. The world is a masterpiece; he who studies it loves its invisible Author in a manner which cannot be described but is felt by the favoured few. Another drawback which sounds like a paradox, should be deeply studied. It is as follows: when we find a person writing or doing any other work, the fact that he is living will be most apparent to us: that is to say, his life, knowledge, power and will will be more apparent to us than his other internal qualities, e.g. colour, size, etc. which being perceived by the eye may be doubted. Similarly stones, plants, animals, the earth, the sky, the stars, the elements, in fact everything in the universe reveals to us the knowledge, power and the will of its originator. Nay, the first and the foremost proof is our consciousness, because the knowledge that I exist is immediate,[71] and more apparent than our perceptions. Thus we see that man’s actions are but one proof of his life, knowledge, power and will, but with reference to God the whole phenomenal existence with its law of causation and order and adaptability bears testimony of him and his attributes. Therefore, He is so dazzlingly apparent that the understanding of the people fails to see Him just as the bat pereeaes at night fails to see in daylight, because its imperfect sight cannot bear the light of the sun, so our understanding is blurred by the effulgent light of his manifestations. The fact is that objects are known by their opposites but the conception of one who exists everywhere and who has no opposite would be most difficult.
Besides, objects which differ in their respective significances can also be distinguished but if they have common significances the same difficulty will be felt. For instance if the sun would have shone always without setting, we could have formed no idea of light, knowing simply that objects have certain colours. But the setting of the sun revealed to us the nature of light by comparing it with darkness. If then light, which is more perceptible and apparent would have never been understood had there been no darkness notwithstanding its undeniable visibility, there is no wonder if God who is most apparent and all pervading true light (Nur)[72] remains hidden, because if he would have disappeared (which means the annihilation of the universe), there would have been an idea of him by comparison as in the case of the light and darkness. Thus we see that the very mode of his existence and manifestation is a drawback for human understanding. But he whose inward sight is keen and has strong intuition in his balanced state of mind neither sees nor knows any other active power save God omnipotent. Such a person neither sees the sky as the sky nor the earth as the earth—in fact sees nothing in the universe except in the light of its being work of an all pervading True One. To use a figure: if a man looks at a poem or a writing, not as a collection of black lines scribbled on white sheets of paper but as a work of a poet or an author, he ought not to be considered as looking to anything other than the author. The universe is a unique masterpiece, a perfect song, he who reads it looks at the divine author and loves him. The true Mowahhid is one who sees nothing but God. He is not even aware of his self except as servant of God. Such a person will be called absorbed in Him; he is effaced, the self is annihilated. These are facts known to him who sees intuitively, but weak minds do not know them. Even Ulamas fail to express them adequately or consider the publicity of them as unsafe and unnecessary for the masses.
THE UNITY OF GOD[73]
There are four stages in the belief in the unity of God. The first is to utter the words: “There is no God but God” without experiencing any impression in the heart. This is the creed of the hypocrites. The a second is to utter the above words and to believe that their meaning is also true. This is the dogma of ordinary Muslims. The third is to perceive by the inward light of the heart the truth of the above Kalima. Through the multiplicity of causes the mind arrives at the conception of the unity of the final cause. This is the stage of the initiates. The fourth is to gaze at the vision of an all-comprehensive, all-absorbing One, losing sight even of the duality of one’s own self. This is the highest stage of the true devotee. It is described by the Sufis as Fanafittauhid (i.e. the effacement of one’s individuality in contemplating the unity of God).[74] To use a simile these four stages may be compared with a walnut which is composed of an external hard rind, an internal skin, the kernel, and oil. The hard rind, which is bitter in taste, has no value except that it serves as a covering for some time. When the kernel is extracted the shell is thrown away. Similarly the hypocrite who, uttering the Kalima, is associated with the Muslims and safely enjoys their privileges, but at death is cut off from the faithful and falls headlong into perdition. The internal skin is more useful than the external in as much as it preserves the kernel and may be used, but is in no way equal to the kernel itself. Similarly the dogmatic belief of the ordinary Muslim is better than the lip service of the hypocrite, but lacks that broad clear insight which is described as “He whose heart Allah has opened to Islam walks in his light”.
The kernel is undoubtedly the desired object, but it contains some substance which is removed when oil is being pressed out. Similarly the conception of an efficient final cause is the aim and object of the devotees, but is inferior to the vision of the all-pervading Holy One, because the conception of causality involves duality.
But the objection may be urged: How can we ignore the diversities and multiplicities of the universe? Man has hands and feet, bones and blood, heart and soul,—all distinct—yet he is one individual. When we are thinking of a dear old friend and suddenly he stands before us, we do not think of any multiplicity of his bodily organs, but are delighted to see him. The simile, though not quite appropriate is suggestive, especially for beginners. When they reach that stage they will themselves see its truth. Words fail to express the beatitude of that highest stage. It can be enjoyed, but not described.[75]
Let us consider the nature of the third stage. Man finds that God alone is the prime cause of everything. The world, its objects, life, death, happiness, misery, all have their source in his omnipotence. None is associated with Him in this. When man comes to recognise this, he has no fear of anything, but puts his trust in God alone. But Satan tempts him by misrepresenting the agencies of the inorganic and organic worlds as potent factors independent in the shaping of his destiny.
Think first of the inorganic world. Man thinks that crops depend on rain descending from clouds, and that clouds gather together owing to normal climatic conditions. Similarly his sailing on the sea depends on favourable winds. Without doubt, these are immediate causes, but they are not independent. Man who in the hour of need calls for God’s mysterious help, forgets Him and turns to external causes as soon as he finds himself safe and sound. “So, when they ride in ships, they call upon Allah, being sincerely obedient to Him, but when he brings them safe to land, they associate others with Him. Thus they become ungrateful for what we have given them, so they might enjoy: but they shall soon know”.[76] If a culprit, whose death sentence is revoked by the king, looks to the pen as his deliverer, will it not be sheer ignorance and ingratitude? Surely, the sun, the moon, the stars, the clouds, in fact, the whole universe is like a pen in the hand of an omnipotent dictator. When this kind of belief takes hold of the mind, Satan is disappointed in covertly tempting man, and uses subtle means, insinuating thus: “Do you not see that the king has full power either to kill or favour you, and though the pen, in the above simile, is not your deliverer, the writer
certainly is”? As this sort of reflection led to the vexed question of free will, we have dealt with it already at some length.
At the outset, let us point out that just as an ant, owing to its limited sight will see the point of the pen blackening a blank sheet of paper and not the fingers and hand of the writer, so the person whose mental sight is not keen will attribute the actions to the immediate doer only. But there are minds, which, with the searchlight of intuition, expose the lurking danger of wrongly attributing power to any except the all-powerful omniscient being. To them every atom in the universe speaks out the truth of this revelation. They find tongues in trees, books in the running brooks, sermons in stones. The worldling will say: Though we have ears, we do not hear them. But asses also having ears do not hear. Verily there are such ears which hear words that have no sound, that are neither Arabic nor any other language, known to man. These words are drops in the boundless unfathomable ocean of divine knowledge: “If the sea were ink for the words of my Lord, the sea would surely be consumed before the words of my Lord are exhausted.”[77]
THE LOVE OF GOD AND ITS SIGNS[78]
Love of God is the highest stage of our soul’s progress and her summum bonum. Repentance, patience, piety, and other virtues are all preliminary steps. Although rare these qualities are found in true devotees and the commonality, though devoid of them, at any rate believe in them. Love of God is not only very rare: the possibility of it is doubted, even by some Ulamas who call it simply service. For, in their opinion love exists amongst species of the same kind, but God being ultra-mundane and not of our kind, His love is an impossibility and hence the much talked of ecstatic states of the “true lovers of God” are mere delusions. As this is far from truth and impedes the progress of the soul, by spreading false notions, we shall briefly discuss the subject. First we shall quote passages from the Quran and the Hadith testifying to the existence of the love of God.
“O you who believe, whosoever from among you turns back from his religion, then Allah will bring a people: He shall love them, and they shall love him, lowly before the believers, mightily against the unbelievers, they shall strive hard in Allah’s way and shall not fear the censure of any censurer: this is Allah’s grace, He gives it to whom He pleases and Allah is ample-giving, knowing.”[79]
“And there are some among men who take for themselves objects of worship besides Allah, whom they love. Allah and those who believe are stronger in love of Allah.”[80] These passages not only refer to the existence of the love of God but point to the difference in degree. The Prophet has taught us that the love of God is one of the conditions of faith. “None among you shall be a believer until he loves Allah and his apostle more than anything else.”[81]
True, as the Quran says “If your fathers and your sons and your brethren and your mates and your kinsfolk and property which you have acquired and trade, the dullness of which you fear, and
dwellings which you like, are dearer to you than Allah and His apostle and striving in His way, then wait till Allah brings about His command, and Allah does not guide the transgressing people.”[82]
A man came to the Prophet and said: “I love thee, O Apostle of God”. “Be ready for poverty.” replied the Prophet. “And I love Allah”, said the man. “Prepare to face tribulations”[83] replied the Prophet. The following tradition is narrated by the Khalif Omar: The Prophet one day saw Masah, son of Umair coming to him with a lambskin round his loins. “Look” said the Prophet to his companions, “how God has illumined his heart. I have seen him living in ease and well provided by his parents but now the love of Allah and His apostle has wrought a change in him.”[84]
The Prophet used to pray thus: “My God, give me thy love and the love of him who loves thee and the love of that action which will bring me nearer to thee and make thy love sweeter than cold water to the thirsty”.[85]
“Verily Allah loves those who repent and those who purify themselves.”[86] Say “If you love Allah, then follow me. Allah will love you and forgive you your faults, and Allah is forgiving, merciful”.[87] We have said before that love means yearning towards a desired object and that beneficence and beauty, whether perceived or conceived, equally attract our hearts. But in using the word love for God, no such meaning is possible as it implies imperfection. God’s love towards men is the love of His own work. Someone read the following verse of the Quran: “He loves them and they love him” in front of Shaikh Abu Said of Mohanna, who interpreted it saying: “He loves Himself because he alone exists. Surely an author who likes himself; his love is limited to his self.” God’s love means the lifting the veil from the heart of His servant, so that he might gaze at Him. It also means drawing him close to Himself. Let us give an illustration. A king permits some of his slaves to approach his presence, not because he requires them but because the slaves possess or are acquiring certain qualities which are worthy of being displayed before the royal presence. This privilege, this lifting of the veil, brings us nearer to the conception of God’s love. But it must be remembered
that approaching the divine presence should entirely exclude the idea of space, for then it would imply change in Him, which is absurd. Divine proximity means the attainment of godly virtues by abstaining from the promptings of the flesh and hence it implies approach from the point of view of quality and not of space. For example, two persons meet together either when both of them proceed towards each other or one is stationary and the other starts and approaches him. Again a pupil strives to come up to the level of his teacher’s knowledge who is resting in his elevated position. His uphill journey towards knowledge keeps him restless, and he climbs higher and higher till he catches a glimpse of the halo which surrounds his master’s countenance. The nature of divine proximity resembles this inward journey of the pupil; that is, the more a man acquires insight into the nature of things, and by subjugating his passions leads the life of righteousness, the nearer will he be coming to his lord. But it must be remembered that a pupil may equal his teacher, even be greater than he, but as regards divine proximity, no such equality is possible. God’s love means that which purifies the heart of his servant in a manner that he may be worthy of being admitted before his holy presence.
It may be asked: “How can we know that God loves a certain person?” My answer is that there are signs which bear testimony to it. The Prophet says: When God loves his servant, He sends tribulations, and when He loves him most he severs his connection from everything. Some one said to Jesus: “Why do you not buy a mule for yourself”? Jesus answered: “My God will not tolerate that I should concern myself with a mule”. Another saying of Mohammed is reported thus: When God loves any of His servants He sends tribulations, if he patiently bears them, he is favoured, and if he cheerfully faces them, he is singled out as chosen of God. Surely it is this joyous attitude of his mind whether evil befalls him or good, that is the chief sign of love. Such minds are providentially taken care of in their thoughts and deeds and in all their dealings with men. The veil is lifted and they live in wrapped communion.
As for the signs of a man’s love for God, let it be borne in mind that every body claims His love, but few really love Him. Beware of
self-deception; verify your statement by introspection. Love is like a tree rooted in the ground sending its shoots above the starry heaven; its fruits are found in the heart, the tongue and the limbs of the lover —in fact his whole self is a witness to love just as smoke is a sure sign of fire burning.
Let us, then, trace the signs which are found in the true lover.
Death is a pleasure to him, for it removes the barrier of body and lets the fluttering soul free to soar and sing in the blissful abode of his beloved. Sufyan Thauri and Hafi used to say: “He who doubts dislikes death, because a friend will never dislike meeting a friend”. [88]
A certain Sufi asked a hermit whether he wished for death, but he gave no answer. Then the Sufi said to him: “Had you been a true hermit you would have liked death. The Quran says: If the future abode with Allah is especially for you to the exclusion of the people, then invoke death if you are truthful. They will never wish it on account of what their hands have sent on before, and Allah knows the unjust”.[89] The hermit replied: “But the Prophet says: ‘Do not wish for death’”. “Then you are suffering”, said the Sufi, “because acquiescence in divine decree is better than trying to escape it”.
It may be asked here: Can he who does not like death be God’s lover? Let us consider first the nature of his dislike. It is due to his attachment to the worldly objects, wife, children, and so forth, but it is possible that with this attachment, which no doubt comes in the way of his love of God there may be some inclination towards His love, because there are degrees of His love. Or it may be that his dislike is due to his feeling of unpreparedness in the path of love. He would like to love more so that he might be able to purify himself just as a lover hearing of his beloved’s arrival would like to be given some time for making preparations for a fitting reception. For these reasons if a devotee dislikes death, he can still be His lover, though of inferior type.
He should prefer, both inwardly and outwardly, God’s pleasure to his desires. For he who follows the dictates of his desires is no true lover, for the true lover’s will is his beloved’s. But human nature is so
constituted that such selfless beings are very rare. Patients would like to be cured but they often eat things which are injurious to their health. Similarly, a person would like to love God but very often follows his own impulses. Naaman was a sinner, who being repeatedly excused by the Prophet was at last flogged. While he was being flogged a certain person cursed him for his iniquity. “Do not curse him”, said he “he has a regard for God and his apostle”.
Experience tells us that he who loves loves the things connected with his beloved. Therefore another sure sign of God’s love is the love of his creatures who are created by and are dependent on him; for he who loves an author or poet, will he not love his work or poem? But this stage is reached when the lover’s heart is immersed in love and the more he is absorbed in Him, the more will he love His creatures, so much so that even the objects which hurt him will not be disliked by him—in fact the problem of evil is transcended in his love for him.
It may be objected here that it follows that he loves the evil-doers and sinners. But a deep insight into the nature of such love shows that he loves them as creatures of God, but at the same time hates their actions which are contrary to the command of his beloved. If this point is lost sight of, people are apt to be misguided in their love or hatred of His creatures. If they show their love towards any sinner, let it be in pure compassion, and not any sense of taking the sin lightly. Similarly their hatred should proceed from the consciousness of His stern law and justice and not from ruthless bigotry.
In one of the Hadisi-Qudsi[90] God has said: “My saints are those who cry like a child for my love, who remember me like a fearless lion at the sight of iniquities”.
A reverent attitude of mind is another sign of his love. Some hold that fear is opposed to love, but the truth is that just as the conception of beauty generates love, the knowledge of his sublime majesty produces the feeling of awe in us. Lovers meet with fears which are unknown to others.[91] There is the fear of being disregarded. There is fear of the veil being drawn down. There is the fear of their being turned away When the Sura Hud was revealed, in
which the awful doom of the wicked nations is narrated,: “Away with Samood, away with Midian,” the Prophet heaved a sigh and said: “This Sura has turned me into an old man.” He who loves His nearness will feel acutely the fear of being way from Him. There is another fear of remaining at a particular stage and not rising higher, for the ascending degrees of His nearness are infinite. A true lover is always trying to draw nearer and nearer to Him. “A thin veil covers my heart,” says the Prophet, “then I ask for His forgiveness seventy times in day and night.”[92] This means that the Prophet was always ascending the scales of his nearness, asking for His forgiveness at every stage which was found lower than the next one.
There is another fear of over confidence which slackens the efforts and mars progress. Hope with fear should be the guide of love. Some Sufis say that he who worships God without fear is liable to err and fall; he who worships him with fear turns gloomy and is cast off, but he who lovingly worships him with hope and fear is admitted by him and favoured. Therefore lovers should fear him and those who fear him should love him. Even excess of his love contains an inkling of fear: it is like salt in food. For human nature cannot bear the white heat of His love, if it is not chastened and tempered by the fear of the Lord.
Keeping love secret and giving no publicity to it is another sign of His love. For love is the beloved’s secret: it should not be revealed nor openly professed. However, if he is over-powered by the force of his love, and unwittingly and without the least dissimulation his secret is out, he is not to be blamed. Some Sufis say: He who is very often pointing towards Him is far from Him, because he feigns and makes a show of his love of Him. Zunnun[93] of Egypt once went to pay a visit to one of his brother Sufis, who was in distress, and who used to talk of his love openly. “He who feels the severity of pain inflicted by Him,” said Zunnun, “is no lover.” “He who finds no pleasure in such pain,” returned the Sufi, “is no lover.” “True,” replied Zunnun, “but I say to you that he who trumpets his love of Him is no lover.” The Sufi felt the force of Zunnun’s words and fell down prostrate before God and repented and did not talk again of his love.
It may be objected: Divine love is the highest stage, it would be better to manifest it, where is the harm? No doubt love is good and if of itself it is evident, there is no harm, but those who give themselves trouble to make it known are blameable. Let our hearts speak, let our deeds proclaim it, but not our tongue. Nay, he should always aim at making it evident before his beloved. The gospel says: “Take heed that ye do not give your alms before men to be seen: otherwise ye have no reward of your Father which is in heaven. Therefore, when thou doest thine alms do not sound a trumpet before thee as the hypocrites do in the synagogues and in the streets, that they may have the glory of men. Verily I say unto you they have their reward. But when thou doest alms let not thy left hand know what thy right hand doeth. That thine alms may be in secret, and thy Father which seeth in secret himself shall reward thee openly. Moreover when ye fast, be not as the hypocrites, of sad countenance: for they disfigure their faces, that they may appear unto men to fast. Verily I say unto you they have their reward. But thou, when thou fastest, anoint thine head and wash thy face, that thou appear not unto men to fast, but unto thy Father which is in secret; and thy Father which seeth in secret shall reward thee openly.”[94]
The essence of religion is love; some signs of which have been enumerated above. The love of God may be of two kinds. Some love him for his bounties, others for his perfect beauty irrespective of bounties. The former love increases according to the bounties received, but the latter love is the direct result of the contemplation of his perfect attributes and is constant even in tribulations. “These are His favoured few,” says Junaid of Baghdad.[95] But there are many who pose as his lovers and with much talk of his love lack the signs of true love. They are deluded by the devil, slaves of their passions, seeking a hollow reputation, shameless hypocrites who try to deceive the omniscient Lord their creator. They are all enemies of God, whether they are revered as divines or Sufis. Sahl of Taster who used to address everyone as “Friend”, was once asked by a person the reason of his doing so, as all men could not be his friends. Sahl whispered in his ear saying: “He will either be a believer
or a hypocrite; if he is a believer, he is God’s friend; if a hypocrite, the devil’s friend.”
Abu Turab Nakshabi has composed some verses describing the signs of love. Their translation is as follows:
Do not profess your love. Hearken to me: These are the signs of his love. The bitterness of tribulations is sweet to him, he is happy for he believes that everything proceeds from him; for praise or censure he cares not, the will of his beloved is his will. While his heart is burning with love his countenance is radiant with joy. He guards the secret of love with all his might, and no thought save of his beloved enters into his mind. Yahya bin Maaz Razi[96] adds some lines:
“Another sign is that he is up and ready like a diver at the bank of a river; He sighs and sheds tears in the gloom of night, and day and night he appears as if fighting for the sacred cause of his love. He entrusts his whole self to his love and gladly acquiescing abides in his love.”[97]
“RIZA” OR JOYOUS SUBMISSION TO HIS WILL[98]
Riza is the quintessence of love and is one of the highest stages of the favoured few. But some doubt its existence, saying, How can man be joyous for what is against his own will. He may submit to God’s will, but it does not follow that he also shares the feeling of joy. We shall discuss the nature of Riza and prove its existence.
Let us first turn to the Quran and the Hadis. “Allah has promised to the believing man and the believing women gardens, beneath which rivers flow, to abide in them, and goodly dwellings in gardens of perpetual abode and best of all is Allah’s goodly pleasure—that is the grand achievement”.[99] In this passage God’s pleasure (Rizwan) is described as best of all blessings. In another passage this blessing is also bestowed on those who joyfully submit to his will, “Allah is well pleased with them and they are well pleased with him; that is for him who fears his Lord.”[100] “Who fear the beneficent God in secret and come with a penitent heart, enter it in peace that is the day of abiding. They have therein what they wish and with us is more yet.” Some commentators while commenting on the words in italics say that three gifts will be given in paradise: (i) a rare gift of which “no soul knows (in this world) what is hidden for them of that which will refresh the eyes”.[101] (ii) The salutation as mentioned in the Quran: “Peace (Salam) a word from the merciful Lord”.[102] (iii) His goodly grace and pleasure as mentioned in “wa Rizwanumminallahi akbar” (and best of all is Allah’s goodly pleasure).
The Prophet once asked some of his companions to point out the signs of the faith which they professed. “O apostle of God,” said the companions, “we are patient in tribulations, grateful in felicity and pleased with what is ordained”. “Ye are Muslims” said the Prophet.
Again the Prophet said: “Ye who are poor be pleased with what God has put you in and then you shall have your reward”.
Let us discuss the nature of Riza. Those who deny the existence of Riza, saying that man can be patient in sufferings but joyous submission to His will is not possible, really deny the existence of love and its all-absorbing nature. A lover always loves his beloved’s actions. Now this love of actions is of two kinds: (1) Redemption from the experience of pain caused in mental or physical suffering.
Experience shows that many warriors while enraged do not feel the pain of their wounds, and know it only when they see blood gushing from them. Even when a man is engaged in some action which absorbs his attention, the pain of a thorn pricking him will not be felt. If then in such cases—and there are many such—pain is not felt, will it not be possible that a devotee who is absorbed in him does not feel pain, which in his belief is inflicted by his beloved?
Or (2) although pain is felt, he would desire it just as a patient who feels the pain caused by the surgeon’s lancet is glad to be operated upon and is pleased with the surgeon’s action. Similarly he who firmly believes that tribulations are like God-sent curatives will be pleased with them and be thankful to God. Anyone who ponders over the nature of the above mentioned kinds and then in the light of them reads the lives and the sayings of the lovers of God, will, I believe, be convinced of the existence of Riza.
Saint Basher, son of Harith, narrates the story: In the Sharkia Lane of Baghdad, I saw a man who received a thousand stripes, but did not cry in his agony. He was then sent to prison and I followed him. “Why have you been punished so mercilessly?” I asked. “Because they have found out the secret of my love”. “But why were you so strangely quiet while you were punished so severely”, I asked in astonishment. “Because”, answered the poor fellow with a sigh, “She was looking at me from her balcony”. “Oh that you might see the true Beloved”, I murmured. Hearing this, his colour at once changed, and with a loud cry he fell dead.
The same saint tells another story: “While I was a student of Sufiism I went to Jazirai Abbadan,[103] where I saw a blind epileptic
leper, lying on the ground while worms were eating his flesh. I sat by his side and placed his head on my lap and spoke gently to him. When he came to his senses, he spoke: ‘Who is this stranger who comes between me and my Lord. Even if each and every limb is severed from my body, I will love Him.’ That scene of Riza, says the saint, I shall never forget; it is a life-long lesson for me.”
It is said that Christ once saw a blind forlorn leper who was praying: “Blessed art thou, O Lord, who hast saved me from such maladies which have overtaken many of us”. “Art thou not in misery” asked Christ, “Tell me which is that malady which has not overtaken thee”. “Thank God”, cried the leper, “I am not like him who does not know God”. “You are right”, said Christ, “Give me your hand”. And the breath of Christ instantly healed the leper, and he became one of his followers.
The Prophet’s companion Said bin Wakas,[104] lost his eyesight in old age, and resigning his post returned to Mecca. People flocked to him for blessing as he was known to be one whose prayers were always heard. Says Abdullah bin Said: “I was then a mere boy; I too went to pay my respects to the venerable Said. He spake kindly to me and blessed me. Then I said: ‘Uncle, how is it that you who are praying for everybody would not pray for the restoration of your eyesight?’ ‘My son’, answered Said with a smile, ‘to be pleased with His sweet will is better than eyesight’”.
Some people went to see Shibli[105] at Maristan, where he was imprisoned. “Who are you?” asked the saint. “Friends”, they all replied with one voice. Hearing this Shibli fetched some stones and began to throw them at them, and they all fled calling him a madman. “What’s this”, exclaimed Shibli, “You call yourselves my friends but if you are sincere, bear patiently what ye receive from me,” and then he sang: “His love has turned my brain. Have you ever seen a lover who is not intoxicated with love!”
These narratives point out that Riza or joyous submission to God’s will is possible and is one of the highest stages to which the souls of true devotees could aspire. People believe in eccentricities of Cupid’s votaries but give no ear to the ecstasies of the true lovers of
God. Perhaps they have no eyes to look at the manifestation of His beauty; no ears to listen to the music of His love, no heart to gaze at and enjoy His sweet presence. Perhaps they are proud of their learning and think too much of their good deeds but they have no idea of humble and broken hearts.
A certain nobleman of Bustam, comely in appearance and lordly in bearing, used to attend the sermons of saint Bayazid of Bustam.[106]
One day he said to the saint: “For thirty years I have been keeping fasts waking for the whole night and offering my prayers, but still I do not find in me the animating force of what you teach, although I believe in it and cherish love for you.” “Thirty years”: ejaculated the saint: “Why for three hundred years if you do as you have done till now you will not have a bit of it.” “How is that?” asked the astonished nobleman. “Because” answered the saint “the veil of your egotism has fallen heavily on your mind’s eye”. The chief then asked the saint to tell him of some remedy, but he declined saying that the chief would not like to take it. “But do tell me”, entreated the nobleman, “And I will try my best to follow your kind advice”. “Listen then”, calmly answered the saint, “This very moment go to the barber, get your head and beard shaven, take off this apparel, and gird your loins with a piece of blanket; gather children round you and tell them that whosoever gives you a slap with the hand will get a walnut; pass through the throngs in all the bazars, followed by those children and then show yourself to your intimate friends”.
“Subhan Allah” exclaimed the chief, “Do you say that to me”. “Hold thy tongue”, retorted the saint, “thy Subhan Allah is blasphemy.” “How is that”, asked the chief. “Because,” replied the saint, “you uttered Subhan Allah not for any reverence for the Holy Being but out of respect for your own vain self”. “Well”, said the chief, “tell me some other remedy, please”. “Try this remedy first”, continued the saint. “I cannot do so,” rejoined the chief. “There you are”, spoke the saint finally, “Did I not tell you that you would not like the remedy.”
Our egoistic tendencies impede the progress of our souls towards higher virtues, and hence some of us go the length of denying the possibility of their existence. Let the lives of the true lovers of God be our guide.
FOOTNOTES
[1] D. B. Macdonald: Muslim Theology London 1903. p. 215. This book gives the best account of Al Ghazzali’s work yet available in English.
[2] ibid p 240
[3] Quoted in E. G. Browne: Literary History of Persia 1903. Vol. I. p. 294.
[4] ibid. p. 293.
[5] I. Goldzieher: Vorlesungen uber den Islam Leipzig 1910. p. 185. See translation in the Indian Philosophical Review by the present writer: Vol 1 pp 260-6
[6] Op. cit. pp. 238-40.
[7] From Al Munqidh min ad’-Dalal
[8] Gazali. Paris 1902. pp. 44-45.
[9] See the English translation of the Guide by Friedländer; The Guide to the Perplexed, London, especially pp 225 ff Al Ghazzali’s works were so widely studied that it is hardly possible to suppose that Maimonides was not influenced by them The influence may have been direct, as Maimonides was not only a student in Spain but also physician in the court of Saladin in Alexandria Indirectly the influence may have come through the Jewish poet Yehuda Halevi.
[10] op. cit. p. 179.
[11] This list is taken from A Chronological List of Muslim Works on Religion and Philosophy which has been for a short time in preparation at the Seminar for the Comparative Study of Religions, Baroda, by Professor J. ur Rehman of Hyderabad, and Professor F. S. Gilani of Surat, Fellows of the Seminar. The list has been compared with that of Shibli in his Urdu life of Ghazali (Cawnpore 1902) whose classification is followed with slight modification.
[12] Ihya III 1
[13] This word is used both for Rasul and Nabi, but the Muslim notion of Rasul differs from that of Nabi. Malachi was a prophet (Nabi), but Moses was more than a prophet (Rasul) Thus in St Matthew XI 9 we have: “But wherefore went ye out? to see a prophet? Yea, I say unto you, and much more than a prophet”
[14] Abuhuraira’s report given in Bokhari and Muslim.
[15] Reported by Abuhuraira in Ahmad’s Masnav Egypt 1300 A H
[16] Quran XXXIII. 72.
[17] Quran XVII 85
[18] Ihya IV. 5.
[19] It is interesting to note here the following passage from a modern European author: “If we form a conception of a Perfect or Infinite Mind it is in this sense that we must speak of such a mind as free To speak of choice between alternatives is to suggest that another than the best might be chosen and this would be inconsistent with the idea of perfection.
A finite mind, limited in knowledge and power and distracted by desires other than the will to goodness, may yet have a partial measure of self-determination which is complete only in the infinite It is incompletely determined by forces external to itself And if it stand as it does stand between the realm of nature and the realm of goodness, conscious of the good and yet beset by many temptations to fall to a lower level, then the relative independence or partial spontaneity of such a mind may be exhibited in the power to direct its own path toward the goal of goodness or to allow it to lapse into evil. Its freedom will be neither complete independence of external determination nor complete agreement with the ideal of goodness; but it will exclude total subordination to the forces beyond itself, and it will give opportunity for choosing and serving the good. In spite of its restrictions human activity will be recognized as possessing a core of spontaneity”. W. R. Sorley: Moral Values and the Idea of God. Cambridge 1918 pp. 446-7.
[20] Ghazzali here anticipated Hume. “Seven hundred years before Hume, Ghazzali cut the bond of causality with the edge of his dialectic”. Journal of the American Oriental Society vol. XX. 103.
