Clinical Oncology (1996) 8:261-263 © 1996 The Royal College of Radiologists Clinical Oncology Case Report Medullary Carcinoma of the Thyroid Misdiagnosed as Differentiated Thyroid Carcinoma A. M. Moody, J. Sharpe, C. Fisher and C. L. Harmer Royal Marsden Hospital, London, UK Abstract. Four patients are presented, who were initially diagnosed and treated for differentiated thyroid carcinoma, but subsequently discovered to have medullary carcinoma. We suggest that tumour histopathology needs to be carefully reviewed in all cases of thyroid cancer, especially those having atypical clinical or pathological features. This should be completed prior to further therapeutic intervention, such as the administration of ablative radioactive iodine. Keywords: Medullary carcinoma; Radioactive iodine; Thyroid carcinoma INTRODUCTION Differentiated carcinoma is the most frequently occurring malignant neoplasm of the thyroid gland, comprising papillary, follicular and mixed histologies. The definitive treatment is surgery, with any unresectable or metastatic tumour treated with iodine-131, which is taken up by 80% of tumours [1]. Disease recurrence can be detected by the tumour marker thyroglobulin. Prognosis is excellent for the majority of tumours, which occur in the young and are of early stage. In contrast, medullary cancer of the thyroid (MTC) is rare, accounting for 3%-9% of thyroid cancers [2]. It is derived from the parafollicular or C cells; it does not take up iodine-131 and is managed by radical surgery, with external beam radiotherapy used for unresectable disease. It too has useful tumour markers: carcinoembryonic antigen (CEA) and calcitonin. Twenty per cent of cases are familial, comprising part of the multiple endocrine neoplasia syndrome type II. Prognosis, however, is worse, with a 50% 5-year survival [3]. Since differentiated carcinoma is so much more common, there can be a tendency for misdiagnosis, especially as poorly fixed MTC can have papillary features. This is important to recognize, since MTC will not take up iodine-131 and patients so treated will be exposed to unnecessary whole body irradiation. We report here four patients who were seen at the Royal Marsden Hospital and who were initially misdiagnosed and managed as differenti- Correspondence and offprint requests to: Dr A. M. Moody, Senior Registrar, Clinical Oncology Centre, Box 193, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK ated carcinoma of the thyroid, but were subsequently shown to have MTC. CASE REPORTS Patient 1 This woman presented in 1975, aged 27, with a 'pea-sized' lump in the right side of the thyroid, which was excised. At operation the tumour was found to be invading the trachea and there was a positive neck node. The diagnosis was stated to be papillary carcinoma stage TAN1. Completion thyroidectomy was then performed and was histologically negative. She was referred to the Royal Marsden Hospital and treated with an ablative dose of 3000 MBq of iodine131, followed by a further dose of 5500 MBq. On the later scan there was no localization of isotope in the neck or elsewhere. The patients remained well on review until 1982, when she developed a 1 cm mass at the medial end of the lobectomy scar. A diagnostic scan of iodine-131 was negative, but a CT scan confirmed the palpable mass and showed posterolateral extension around the trachea. At operation, only part of the tumour was removable. The resection specimen stained positively for calcitonin. The original histological specimen was then reviewed and found to stain positively for amyloid. The diagnosis was revised to MTC. The CEA level was normal but calcitonin was elevated at 5.13/zg/dl (upper limit of normal 0.08/*g/dl). There was no family history of thyroid abnormality and screening of family members was negative. She received radical dose megavoltage radiotherapy. The calcitonin remained at a similar level with a slightly elevated CEA, but there was no clinical evidence of tumour recurrence until 1987, when she developed an enlarging mass in the right side of the neck. Palliative chemotherapy was given with no response and she then underwent major resection with reconstruction. However, her disease progressed locally and she died in 1992. Patient 2 This woman presented, aged 55, in 1982 with a small nodule in the left lobe of the thyroid. She underwent resection for what was reported to be papillary cancer. An ablative dose of iodine-131 was given. She was referred to the Royal Marsden Hospital in 1983 and given a diagnostic dose of iodine-131, which showed only a small amount of 262 A.M. Moody et al. DISCUSSION Fig. 1. Histological section from patient 2 showing pseudopapillary features (× 52). uptake in the neck. The histology review revealed MTC with pseudopapillary features (Fig. 1). She had no family history and remains well 10 years later with no recurrence. Patient 3 This woman presented in 1977 with thyrotoxicosis when aged 16. After initial conservative management, she came to subtotal thyroidectomy in 1981. The histopathology was reported as showing follicular carcinoma and she was treated with thyroxine in order to suppress endogenous thyroid stimulating hormone (TSH). In 1988, she had a mass excised from the right side of the neck. In 1991, she developed a further small lymph node on the right and was referred to the Royal Marsden Hospital, where she received a therapeutic dose of radioiodine, but the scans showed no uptake. Meanwhile, the histopathological review revealed MTC. The C E A and calcitonin levels were elevated and continued to rise during 1992 to cacitonin 20/~g/1 (upper limit of normal 0.08 /*g/l) and C E A 119 /~g/1 (upper limit of normal 5/ug/1). A CT scan was negative but technetium-99m labelled pentavalent dimercaptosuccinic acid (DMSA) and radioiodine labelled meta-iodobenzyl guanidine (MIBG) scanning both showed uptake in the neck. By late 1992, there was palpable disease in the right side of the neck and she underwent completion thyroidectomy and right functional neck dissection, at which seven of 17 nodes were positive. The patient remains well and the turnout markers have fallen to calcitonin 0.51 #g/l and C E A 6 #g/1. The patient's mother has been treated at another centre for MTC. Patient 4 This 50-year-old man developed a node in the right side of the neck in November 1992. By January 1993 there was also swelling of the right lobe of thyroid. He underwent fine needle aspiration and Tru-cut biopsy, which suggested follicular carcinoma, although the material was difficult to interpret. He received two doses of radioiodine 2250 MBq and 3750 MBq in early 1993. A biopsy of the neck node then revealed MTC and the serum calcitonin was grossly elevated. He was referred to the Royal Marsden Hospital, where a CT scan unfortunately showed inoperable disease fixed to the great vessels. Following external beam radiotherapy, he has been reassessed for surgery and his disease is now operable. In patients 1 and 2, MTC was mistaken for papillary carcinoma, whilst in patients 3 and 4, it was mistaken for follicular carcinoma of the thyroid. In all four patients, the tumour architecture showed some features of neuroendocrine differentiation, most frequently in the form of nests and cords of small cells with bland nuclear morphology. When performed, calcitonin staining was positive (three out of four specimens) and there was congo red positive amyloid stroma three out of four specimens. One of the main diagnostic pitfalls appears to be the pseudopapillary architecture seen in two tumours [4], leading to an erroneous diagnosis of papillary carcinoma. The absence of features of papillary carcinoma (Orphan Annie nuclei, nuclear grooves andpseudoinclusions) should arouse suspicion and the diagnosis can then be established immunohistochemically. Less common than the pseudopapillar variant of MTC is the true papillary variant in which tumour cells are aligned along fibrovascular cores [5]. The diagnosis of MTC is made as previously outlined. In the tumours in which an incorrect diagnosis of follicular carcinoma was made, this seems to have occurred due to the presence of eosiniphilic material resembling colloid, which was located within tubular structures. Tubular and follicular variants of MTC have been described previously [6]. The diagnosis can be established with positive calcitonin and negative thyroglobulin stains. The possibility of entrapped normal thyroid should be considered in the event of positive thyroglobulin staining within a calcitonin-positive mass. MTC shows no marked variation in incidence with age and sex, whilst differentiated carcioma is commonest in young females. However, the predilection is not sufficiently marked for the advanced age of patients 2 and 4 and the male sex of patient 4 to cause undue suspicion. Eighty per cent of differentiated carcinomas of the thyroid take up radioiodine, but this proportion is even higher in young females [3]. Non-uptake of radioiodine in the presence of known clinical disease in patients 1 and 3 (both young women) would be particularly unusual and liable to arouse suspicion regarding the diagnosis. It is important that the correct diagnosis is made promptly, as the treatment of MTC and differentiated carcinoma of the thyroid is different. Surgery is the definitive initial management of both conditions. However, in differentiated thyroid carcinoma near total thyroidectomy with resection of involved nodes is adequate, whilst in MTC total thyroidectomy with dissection of the central lymph nodes of the neck is required, with the addition of modified radical neck dissection if the lymph nodes are involved [7]. Knowledge of the correct diagnosis would have affected the definitive surgical management of patients 1 and 3. The dose of replacement thyroxine for the two conditions is different; for MTC, sufficient thyroxine is administered to maintain the TSH in the normal range, whilst in differentiated thyroid carcinoma, higher doses of thyroxine are used completely to suppress the TSH. All four patients were treated with radioiodine, which is ineffective in MTC. This involved inconvenience for the patients and unnecessary expenditure. More importantly, they have been exposed to needless whole body irradiation from radioiodine. The early effects are negligible but there is a potential risk of late morbidity. Although there is no known risk of foetal abnormality, fertility rates after treatment may be marginally impaired and a small but significant excess of cancer of the bladder and of acute leukaemia has been reported in patients receiving repeated doses [8]. An incorrect diagnosis is also liable to result in the omission or delay in delivering external beam radio- Misdiagnosis of Medullary Thyroid Carcinoma t h e r a p y , w h i c h is i n d i c a t e d m o r e o f t e n in M T C for unresect a b l e disease. T h e m a n n e r in w h i c h t h e s e misdiagnoses c a m e to light is of interest. I n p a t i e n t 1, t h e correct diagnosis was m a d e at r e b i o p s y 7 years after t h e original diagnosis. I n p a t i e n t 4, t h e misdiagnosis was d u e to a n i n a d e q u a t e initial s p e c i m e n b u t was c o r r e c t e d w h e n a d e q u a t e tissue was available. In p a t i e n t s 2 a n d 3, t h e diagnosis was revised o n r o u t i n e review at a s e c o n d centre. W e would r e c o m m e n d review by a p a t h o l o g i s t at a c a n c e r c e n t r e of t h o s e t u m o u r s with atypical clinical or p a t h o l o g i c a l features. Acknowledgements. W e are grateful to t h e referring consultants a n d to all t h e staff of t h e R o y a l M a r s d e n Hospital a n d e l s e w h e r e w h o were i n v o l v e d in t h e care of t h e s e patients. T h a n k s are also d u e to t h e D e p a r t m e n t s of P a t h o l o g y a n d Medical P h o t o g r a p h y at A d d e n b r o o k e ' s hospital for p r e p a r a t i o n of t h e figure. References 1. Pochin EE. Radioiodine for thyroid cancer. Semin Nucl Med 1971;1:503-15. 263 2. Bishop AE, Polak JM. Medullary carcinoma: Pathology and modern diagnostic procedures. In: Preece PE, Rosin RD, Maran AGD, editors. Head and neck oncology for the general surgeon. London: Saunders, 1991;11-26. 3. Harmer CL. Multidisciplinary management of thyroid neoplasms. In: Preece PE, Rosin RD, Maran AGD, editors. Head and neck oncology for the general surgeon. London: Saunders, 1991:55-90. 4. Rosai J, Carcangu ML, Delellis RA. Tumors of the thyroid gland. In: Atlas of tumor pathology, third series, fasc. 5. Washington DC: Armed Forces Institute of Pathology, 1990;230. 5. Kakudo K, Miyauchi A, Shin-Ichiro T, et al. C-cell carcinoma of the thyroid - papillary type. Acta Pathol Jpn 1979;29:63359. 6. Harach HR, Williams ED. Glandular (tubular and follicular) variants of medullary carcinoma of the thyroid. Histopathology 1983 ;7:83-91. 7. Buhr HJ, Kallinowski F, Herfath C. Surgical strategies and methods for the treatment of metastasising medullary thyroid carcinoma. In: Raue F, editor. Medullary thyroid carcinoma. London,Springer-Verlag 1992:147-66. 8. Edmonds CJ, Smith T. The long term hazards of the treatment of thyroid cancer with radioiodine. Br J Radiol 1986;59:4551. Received for publication May 1995 Accepted following revision November 1995 Book Review Survival Analysis: A Practical Approach by M. K. B. Parmar and D. Machin. Wiley, Chichester, 1995. Pages: 255; Price: £29.95; Hard cover. ISBN 0-471-93640-5. Survival is what treating cancer is all about. Patients want to know whether, with the treatment we propose, they are likely to live or die. The statistical analysis of survival has a long and distinguished history. Until about 40 years ago the life table method, as proposed by Halley in 1693, was the main method used for analysing survival over time. Techniques have evolved rapidly over the past 40 years and Parmar and Machin's book provides an excellent practical guide to recent developments. The book starts relatively gently, with an introduction to some basic concepts. The thicket of rates and ratios (hazard, odds and likelihood, and their interrelations) is soon encountered (by page 11). Thereafter, the going is tough, but rewarding. The authors have 'tried not to overwhelm the reader with details of statistical theory', but there are over 200 formulae embedded within the 232 pages of text. Hard going but, in the era of the 'stats package' and the 'laptop', it is useful to see the bones laid bare and to be made aware of the assumptions underlying the techniques. There are excellent discussions of the proportional hazards model and its extension into the derivation of prognostic indices. The data used to illustrate the various points are clinically relevant, with valuable interpretations and discussions of the important MRC studies in lung cancer and brain tumours, studies to which the authors have contributed so much. Any complaints I have are minor. It would be useful to have terms defined more explicitly, lifetables are mentioned on page 4, but not explained until page 47. Perhaps the index of statistical symbols might be expanded to include short definitions of important terms. I am not sure whether 'casual' on page 174 is correct or whether 'causal' was intended. The book fades away somewhat at the end. A concluding chapter on the uses and abuses of survival analysis, putting the practice into context, might be worth considering for the next edition. To return to the beginning; if we are going to learn how to improve our patients' chances of survival, we need to know, in some detail, how to analyse this survival. This book is an admirable guide to this difficult area and can be thoroughly recommended. A. J. MUNRO St Bartholomew's Hospital London