EuropeanJournalof

Nuclear Medicine

Case report

Thyroid carcinoma mimicking a toxic adenoma G i o v i n a De R o s a 1, A m e r i c o T e s t a 1, M a u r i z i o M a u r i z i 2, M a r i a A n t o n i e t t a S a t t a 1, C l a u d i a A i m o n i 2, A l b e r t o A r t u s o 2, E v e l i n a S i l v e s t r i 3, V i t t o r i a R u f i n i 4, a n d L u i g i T r o n c o n e 4 1 Institute of Endocrinology; 2 Institute of ENT; 3 Institute of Pathology; 4 Institute of Nuclear Medicine, Catholic University School of Medicine, 1-00151 Rome, Italy Received November 13, 1989 and in revised form February 16, 1990

Abstract. A young woman with a thyroid papillary carcinoma behaving as an autonomously hyperfunctioning nodule is described. Only 17 similar patients have been seen in the past 25 years. It is emphasized that hyperthyroidism does not exclude malignant disease in hot nodules. This possibility suggests that all thyroid nodules, either cold or hot, require careful management. Therefore, in " a t risk" cases, surgery could be the most useful treatment. Key words." Hot nodule - Hyperthyroidism - Thyroid

carcinoma - Thyroid scintigraphy Eur J Nucl Med (1990) 17:179-184

(Cooper et al. 1978). The hyperthyroidism observed in these cases has been attributed to the autonomous functioning of extremely voluminous metastatic lesions, which themselves are, however, less active than the normal thyroid parenchyma (Becker et al. 1963 ; McLaughlinet al. 1970; Valenta et al. 1970). On the other hand, the existence of excessive functioning by the carcinomatous thyroid tissue has been well documented by autoradiographic studies (Ghose et al. 1971). During the past few years several cases of malignant primary tumours, imaged as hot on scintigraphy but with no metastatic lesions, have been described as being responsible for hyperthyroidism (Nemec et al. 1982; R6sler et al. 1984; Sobel et al. 1985; Nagai et al. 1987).

Case report Introduction Only a low percentage of all solitary thyroid nodules (varying from 6% to 20%) shows an increased function in comparison with the surrounding normal thyroid tissue (Dische 1964; Kendall and Condon 1969; Walfish 1985). Even though a differentiated thyroid carcinoma can accumulate iodine and secrete thyroglobulin, the fact that it may manifest as a hyperfunctioning nodule is considered to be very rare and is even completely excluded by some authors (Perlmutter et al. 1954; Miller and Hamburger 1965; Wolfstein 1978). Hyperthyroidism due to a thyroid carcinoma has been described for several years generally as a :result of a carcinoma associated with functioning metastases (McLaughlin et at. 1970; Ghose et al. 1971; Baumann et al. 1979; Kruter et al. 1981; Nakashima et al. 1981; Nemec et al. 1982) or, more often, the activation of metastases following ablation of the primary tumor and the thyroid parenchyma Offprint requests to: G. De Rosa

A 25-year-old school teacher, came under our observation in June 1988 with a 2-year history of a palpable thyroid nodule on the right side of her neck, which had increased in size over the past 6 months. She suffered from such localized symptoms as intermittent dysphonia, slight dysphagia and an irritating cough, as well as the following general symptoms: palpitations, excessive sweating with frequent hot flushes, tremulous hands, unfounded anxiety and easy irritability, insomnia and reduced menstrual flow. Despite a good appetite she had lost 5 kg over the past 8 weeks. There was no family history of thyroid disease, and the patient did not come from an endemic goitre area. She denied ever having been pregnant or any excessive use of medication, in particular oral contraceptives and iodides. There was no history of prior head or neck radiation. On physical examination, a 3-cm, smooth, hard nodule with welldefined margins was palpable in the medial right lobe of the thyroid; it was moderately firm and had no associated lymph nodes. The mass was not tender, did not

© Springer-Verlag 1990

180

Fig. 1A, B. Thyroid 1311-scintigrambefore (A) and after (B) administration of T3 showing a hot nodule in the right lobe; it almost completely inhibits the remainingthyroid parenchymaand is only partially inhibited by T3 (see text)

transilluminate light and moved with swallowing. Careful inspection revealed lid-lag and stare but no proptosis. Blood pressure was 160/80 mmHg, heart rate 92/min, with a regular pulse. Laryngoscopy study revealed normal vocal chords. Routine laboratory work-up was normal, whereas thyroid function test results were outside the limits of normality: T3 (RIA) 219 ng/dl (normal 70180); T~ (RIA) 14.25gg/dl (normal 4.7 12); TSH (IRMA) undetectable. Consequently, a RAIU test and scintigraphy (1.85 MBq of ~3tI p.o.) were performed. The thyroid scintigraphy revealed an area of high uptake in the right lobe and isthmus, while the remaining parenchyma of the right lobe and the left lobe showed decreased activity (Fig. 1A). The thyroid uptake of 131I, already elevated at the 6th h (76% of the administered dose), had decreased only slightly at the 24th h (70%). After inhibition with T3 (100 gg daily for 8 days) the radioiodine uptake was partially modified but still remained elevated (60% at the 6th h; 76% at the 24th h), and the scintigraphic image of the gland remained substantially unchanged (Fig. 1 B). Thyroid ultrasonography revealed an ovoid-shaped mass at the isthmus of the gland, measuring 1.2 x 2.2 x 4.2 cm with well-defined margins and a homogeneous structure, which displaced the trachea laterally towards the left; the remaining thyroid parenchyma appeared to have a normal shape and size and a homogeneous structure (Fig. 2). The data available at that point were believed to be sufficient for making the diagnosis of an autonomously hyperfunctioning nodule. Thyroid surgery was performed in October 1988 after euthyroidism had been reached with propylthiouracil 100 mg t.i.d, administered for 3 months (T3 103 ng/dl, T4 6.2 gg/dl, TSH 1.36 gIU/ml) and followed by 8 drops per day for 10 days of Lugol's solution. Intraoperative biopsy and histological examination revealed a papillary carcinoma, and therefore a total thyroidectomy was performed. An early post-operative hypocalcaemia was controlled with calcium gluconate and 25-OH-cholecalciferol p.o. The definitive histological examination con-

Fig. 2. Ultrasonogram of the thyroid showing a nodule in the region of the isthmus of the right lobe; it has a homogeneousstructure, well-definedmargins and a maximum diameter of 4.2 cm. The remainingparenchymais within normal limits

firmed the diagnosis of a papillary thyroid carcinoma with focal areas of follicular carcinoma (Fig. 3). The surgical specimen was macroscopically 1.0 x 0.3 cm in size with indistinct margins and greyish in colour with a parenchyma-like consistency. The microscopical examination demonstrated a papillary carcinoma. The remainder of the nodular mass was found to be papillary and follicular carcinomatous tissue with numerous psammoma bodies. The shape and size of the neoplastic nuclei varied considerably with characteristic inclusion bodies. The immunohistochemical examination was positive for thyroglobulin in the neoplastic tissue. The samples taken from the parenchyma surrounding the nodular lesion demonstrated the presence of a carcinomatous area with a concomitant chronic inflammation. Forty days after surgery the patient underwent a whole-body scan following the administration of 222 MBq of 131I. The scintigraphy demonstrated numerous areas of hyperactivity in the anterior cervical region, extending from the base of the neck to the area under the chin. These could in part be attributed to residual thyroid tissue and in part to lymph node involvment (Fig. 4A). The patient was then given an integrated treatment with 3.3 GBq of 131I. A whole-body scan, performed 14 days after, did not reveal additional foci of abnormal radioiodine uptake. Moreover, a marked reduction of the previously demonstrated hyperactive areas was observed; only one area of elevated uptake in the upper cervical region persisted, even though it had decreased significantly: it corresponded to the area of greatest radioactive concentration in the metastases (Fig. 4 B). The patient subsequently received suppressive hormone therapy with a daily dose of 200 ~tg of L-thy-

181

Fig. 3. Papillary carcinoma; some psammoma bodies can be observed (hematoxylin and eosin staining, x 10)

Fig. 4. A Whole-body 1311-

scintigram performed 40 days after thyroidectomy, showing numerous areas of hyperactivity in the anterior cervical region, which can in part be attributed to residual thyroid tissue and in part to lymph node involvement. B Whole-body scintigraphy repeated 14 days after 3.3 GBq of 131I, showing a marked reduction of the hyperactive areas

roxine. After 3 m o n t h ' s follow-up the situation appeared unchanged with a thyroglobulin measurement of 7.1 ng/ ml and a C E A of 0.8 ng/ml. A new whole-body scan was scheduled to be followed by a second dose of 131I.

Discussion The association of thyroid carcinoma and hyperthyroidism is presently not considered as exceptional as it was in the past, when it was c o m m o n l y believed that the condition of thyrotoxicosis could even be a definite guarantee against cancer of the thyroid. F r o m a nosographic point of view, the association of thyroid carcinoma and

hyperthyroidism must be considered a heterogeneous syndrome giving rise to three main combinations (Nemec et al. 1982; Wahl et al. 1982) (Fig. 5): (1) thyroid carcinoma corresponding to a hypofunctioning area within a diffuse or multi-nodular toxic goitre; (2) carcin o m a corresponding to an independent hypofunctioning area, either adjacent to or within an a u t o n o m o u s l y hyperfunctioning nodule (" hot a d e n o m a " ) ; (3) carcinoma corresponding to a hyperfunctioning nodule (" hot carcinoma"). A carcinoma present in thyroid glands which had been surgically removed because of either a diffuse or multi-nodular toxic goitre or a toxic a d e n o m a is described in the literature mostly as a chance finding (oc-

182

W

carcinomatouscold nodule in Graves' disease

Table 1. Thyroid carcinoma without metastases mimicking an autonomously hyperfunctioning thyroid adenoma (review of literature) independent .hot adenoma. and carcinomatous cold nodule

Patient

Clinical state

No. Sex Age

• cold carcinoma, in-hot adenoma.

.hot

carcinoma.

Fig. 5. Possible combinations of hyperthyroidism and thyroid carcinoma, with diagrams of their scintigraphic images

cult microcarcinoma) (Dische 1964; Olen and Klinck 1966; Wahl et al. 1982; Yeo et al. 1982; R6sler et al. 1984). Several cases of a carcinoma imaged as a cold area on scintigraphy and found either within a solitary toxic thyroid nodule or in the tissue surrounding the nodule have been reported, thus giving rise to the debate as to whether the origin of the carcinoma could be traced to a pre-existing adenoma (Meissner and Warren 1969; Lamberg et al. 1976; Vickery et al. 1985). The current opinion is that the two different lesions are independent of each other or, at best, are determined by a c o m m o n cause. The following situations are considered as favouring a thyroid carcinoma: exposure to ionizing radiation, a natural tendency towards goitre, a diet with a low iodine content, chemotherapeutic agents and pesticides (Paynter et al. 1988). Hyperthyroidism caused directly by carcinomatous tissue was first identified in 1946 by Leiter et al. and has not been reported very often since then. It is generally found in patients with a primary thyroid carcinoma accompanied by widespread functioning metastases (Baumann et al. 1979). It is more frequently reported in patients who, after having undergone a thyroidectomy, subsequently suffered from hyperthyroidism as a result of activation of the metastatic lesions (Cooper et al. 1978). After a careful analysis of the literature, 17 cases of primary thyroid carcinoma with no evident metastases, mimicking an autonomously functioning solitary nodule, are well described and documented (Table 1). In all the cases reported, the hyperactivity of the nodule was attributed to the carcinomatous tissue itself. Only 5 were reported before 1979, and none of them were reported before 1964 (Miller and Hamburger 1965). In all, only 12 patients presented a situation in which the carcinoma was claimed as resulting from a condition of thyroid toxicity. The remaining 5 patients were clinically euthyroid. In general, there was no history of previous irradiation to the head or neck or any other aetiopathogenetically favourable factors. Women were far more often affected than men (ratio female/male = 16/1), while there was no noticeable peak period with regard

Carci- Reference noma histology

1 1

F F

42 6

Hyperthyroidism fol Hyperthyroidism pap a

2

F F F F

59 54 16 19

Hyperthyroidism Euthyroidism Euthyroidism Euthyroidism

F F

64 52

Hyperthyroidism fol Hyperthyroidism fol

F F F F M F F F F

76 86 22 27 14 32 70 11 25

Hyperthyroidism Hyperthyroidism Hyperthyroidism Hyperthyroidism Hyperthyroidism Hyperthyroidism Euthyroidism Euthyroidism Hyperthyroidism

1 1 4

1 3 1 1 1

pap a pap pap pap a

Dische Sussman et al. Guinet et al.

(1964) (1968) (1972)

Hopwood et al. (1976) Abdel-Razzak (1979) and Christie Baumann et al. (1979)

fol pap a pap b Nemec et al. pap Sobel et al. pap pap" pap Fukata et al. fol Nagai et al. pap a Own data

(1982) (1985)

(1987)

(1987) (1990)

fol, follicular carcinoma; pap, papillary carcinoma a Presence of neoplastic follicles b Presence of oncocytes

to age. In 5 patients the carcinoma was follicular, in the remaining patients it was papillary, with documented neoplastic follicles in 6; there was no undifferentiated carcinoma. Follicular differentiation and colloid production, both factors considered necessary in functioning malignancies (Becker et al. 1963), were not always present (Valenta et al. 1970; Sobel et al. 1985); Miller (1980), however, reported that their presence alone is not sufficient to guarantee those enzymatic systems involved in the thyroid hormonogenetic process. Several retrospective studies carried out either on hyperthyroid patients or on patients with solitary nodules who underwent thyroid operations reported quite frequently the possible relationship between the hot nodule and the malignant tumour (Kendall and Condon 1969; Georgiadis et al. 1971; Ashcraft and Van Herle 1981; R6sler et al. 1984). The prevalence of "hyperfunctioning carcinomas" among all hot thyroid nodules would therefore seem greater than is actually believed at present, although the true figures cannot easily be calculated. In fact, details on each single patient are seldom available from retrospective studies, and the carcinoma could often be found either within, or adjacent to, a hyperfunctioning adenoma (Meissner and Warren 1969; Lamberg et al. 1976; Hoving et al. 1981 ; K h a n et al. 1981). It is somewhat difficult to predict the incidence of malignant tumours in hot thyroid nodules, as demon-

183 strated also by our study. Several parameters have been proposed in this respect but have often been contradictory. The risk of malignancy in a hot nodule increases in accordance with the parameters for malignancy which are considered valid for all thyroid nodule diseases (Walfish 1985; De G r o o t and Sridama 1989), including youth, family history, conspicuous size of the nodule, its rapid growth, irregular outline, lack of mobility within the surrounding tissue and, of course, the presence of a local lymph adenopathy or distant metastases. Adjacent lymph nodes and distant metastases, however, very rarely manifest in the early stages of the tumour. On the other hand, unlike the malignancy parameters valid for low-uptake thyroid nodules, the probability o f malignancy in a hot nodule increases in young women, in those with an excessive production of T3 and in patients who show conflicting results between scintigraphy with 99mTc and that performed using 1311 (Kruter et al. 1981 ; Nemec et al. 1982; R6sler et al. 1984; Sobel et al. 1985; Spaulding and Lippes 1985). Cytological examination of the fine-needle aspirated thyroid content could be particularly useful for a diagnosis (R6sler et al. 1984; Sobel et al. 1985; Nagai et al. 1987), even though this procedure is usually recommended only for the diagnosis of those thyroid nodules with a normal or low uptake. In our case this was not taken into consideration as all indications pointed towards surgery. On the basis of our observations to date, including the subject in this study, it seems that the clinical course of a "hyperfunctioning thyroid carcinoma" reflects that of the low malignancy of the well-differentiated thyroid tumours. The elevated functional activity of the neoplasms should, furthermore, guarantee a greater efficacy of integrated metabolic radiotherapy with 131I, for both the primary tumour and its metastases. The rapid and marked regression of the localized lesions in our patient would seem to confirm this assumption. Nevertheless, there is still very little information available in the literature regarding the follow-up of these patients. The assay of serum thyroglobulin in monitoring the course of the neoplasm should prove to be effective as the "hyperfunctioning carcinoma" probably produces thyroglobulin in large quantities, independently of thyroid stimulating hormone (TSH) stimulation. The increase in incidence of " h o t carcinomas" observed over the past few years can be interpreted as a reality due to a greater exposure to aetiologicat factors, but on the other hand it could more likely result from a more continuous, profound and eager research in this field by physicians, as well as from a more systematic and better pathological study of the surgically removed thyroid tissue. In the past, a number of these patients were probably treated with radioiodine as toxic adenomas, which may ]have occurred in the studies by Guinet et al. (1972) and Miller (1978). Furthermore, it is possible that often the radio-metabolic treatment alone could have eliminated any malignant lesions in the initial phases of the disease (Lamberg et al. 1976).

In conclusion, the most widespread opinion at present is that a malignant tumour is unlikely to be present in a hot thyroid nodule (Walfish 1985). In the presence of an evident hyperthyroid condition, the diagnosis of a carcinoma is even less likely to be considered, and furthermore, a thyroid carcinoma associated with hyperthyroidism was not clinically apparent in most of the patients described. An approximate estimate is that there is a 2% incidence of malignancy in hyperfunctioning nodules (R6sler et al. 1984), but it might be an optimistic estimate (Dische 1964; Kendall and Condon 1969). In agreement with recent reports, our study suggests that in a thyroid nodule which images as hot, with clinical and ultrasonographic benign features, malignancy need not necessarily be excluded. Although this is a rare occurrence, it is clinically important enough to consider in every instance. We believe that it would be best to adopt a cautious approach in the management of all thyroid nodules, whether they be cold or not. A hot thyroid nodule should be removed without any delay when it grows rapidly and when the patient is a young woman. Nevertheless, a careful periodic control of the nodules is advisable for these patients as well by taking advantage of fine-needle aspiration cytology, as has been suggested by several authors (Wahl etal. 1982; Sobel et al. 1985).

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