A Rare Case of Follicular Thyroid Carcinoma in a Patient With Thyrotropin-Secreting Pituitary Adenoma

A Rare Case of Follicular Thyroid Carcinoma in a Patient With Thyrotropin-Secreting Pituitary Adenoma

CASE REPORT A Rare Case of Follicular Thyroid Carcinoma in a Patient With Thyrotropin-Secreting Pituitary Adenoma Maurizio Poggi, MD, PhD, Salvatore ...

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CASE REPORT

A Rare Case of Follicular Thyroid Carcinoma in a Patient With Thyrotropin-Secreting Pituitary Adenoma Maurizio Poggi, MD, PhD, Salvatore Monti, MD, PhD, Chiara Pascucci, MD and Vincenzo Toscano, MD

Abstract: Objective: To report a rare case of a thyrotropin (TSH)secreting pituitary adenoma associated with thyroid carcinoma. Methods: We report the clinical history, imaging studies, and laboratory and pathologic data in a male patient affected by TSH-secreting pituitary adenoma and goiter; histologic evaluation revealed thyroid carcinoma. Results: A 50-year-old man complained of years of palpitations, hypertensive crisis, and excessive nervousness that tended to progressively worsen. The basal and dynamic hematologic evaluation showed the presence of high free thyroid hormone levels with inappropriate levels of TSH. The thyroid morphologic study using Doppler ultrasonography showed a gland of increased volume with multiple nodular lesions bilaterally. The nuclear magnetic resonance of the pituitary gland described a microadenoma. A total thyroidectomy was performed followed by neurosurgical treatment of the pituitary lesion. The definitive thyroid histologic examination showed the presence of minimally invasive follicular carcinoma of 17 mm diameter. The patient firmly refused surgical removal of the pituitary adenoma. He was started on replacement therapy with thyroxine. Twelve months later, the hematologic examinations showed normal thyroid hormone levels and a TSH of 6.97 uIU/mL. The pituitary nuclear magnetic resonance showed a stable lesion without difference in size. Conclusion: The clinical association between thyroid carcinoma and TSH-producing adenoma is rare, with the removal of the pituitary lesion being mandatory. Pituitary surgery, in this case, is impossible, showing that TSH-producing microadenoma could seldom have an indolent behavior. Key Indexing Terms: TSH-oma; Thyroid cancer; T3 suppression test. [Am J Med Sci 2009;337(6):462–465.]

T

he thyrotropin (TSH)-secreting pituitary tumors are a rare cause of hyperthyroidism. They account for about 1% of the functioning pituitary tumorsand for less than 1% of all the causes of hyperthyroidism.1 Since its first description by Jailer and Holub,2 even though it remains a rare cause of hyperthyroidism, its diagnosis must be excluded, especially in patients with a diffuse goiter and no extrathyroidal signs, like ophthalmopathy, which are suggestive of Graves disease. Furthermore, the presence of a pituitary lesion must be taken into consideration when patients have high levels of thyroid hormones without suppression of TSH levels. The presence of a TSH-secreting pituitary tumor is nearly always associated with a goiter, whereas cases describing its association with Graves disease are rare.3 Cases describing TSH-secreting pituitary adenomas and thyroid neoplasia are rare.4 – 6 In these cases, the importance of the high levels of TSH-stimulating activity on cancer prolifera-

From the Department of Endocrinology, Second Faculty of Medicine, University of Rome, “La Sapienza,” Azienda Ospedaliera Sant’Andrea – via di Grottarossa, Rome, Italy. Submitted May 19, 2008; accepted in revised form October 2,2008. Correspondence: Maurizio Poggi, MD, PhD, Department of Endocrinology, Second Faculty of Medicine, University of Rome, “La Sapienza,” Azienda Ospedaliera Sant’Andrea – via di Grottarossa 1035, Rome 00189, Italy (E-mail: [email protected]).

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tion has been hypothesized. Furthermore, these were mostly papillary thyroid cancer and only 2 cases have been described as being a follicular thyroid carcinoma.7,8 We describe a rare case of a pituitary TSH-secreting microadenoma associated with follicular thyroid carcinoma. The diagnosis of a TSH-secreting pituitary adenoma preceded that of the thyroid cancer, which was done postoperatively. The thyroid lesion was surgically removed; because the patient was reluctant to undergo a second surgery, and considering the small dimensions of the lesion, the pituitary adenoma is at the moment under a close follow-up.

CASE REPORTS A 50-year-old man was brought to our attention because of an episode of atrial fibrillation requiring hospitalization. During examinations, high levels of thyroid hormones were observed. On referring his medical history, the patient described having had in the last 10 years episodes of palpitations and hypertensive crisis with excessive nervousness. His thyroid function was studied in 1992 because of the referred tachycardia, and in that occasion only a thyroid nodular hyperplasia had been described with normal thyroid function. A cytologic examination of the nodules done about 10 years ago showed negative results. The family history was positive for thyroid nodules and cardiovascular disease. When admitted to the hospital, the patient appeared in good general condition with a high blood pressure and a normal and rhythmic heart rate, and atenolol at a dose of 60 mg/d was administered. The hematologic evaluation showed a normal glycemia (101 mg/dL) and low cholesterol levels (134 mg/dL). The thyroid function tests showed a free triiodothyronine (FT3) of 4.05 pg/mL (normal values 1.45–3.48), a free thyroxine (FT4) of 2.32 (normal values 0.71–1.85), and a TSH of 2.31 (normal values 0.49 – 4.67). The antibodies were within the normal range. TSH levels were not suppressed despite the high levels of FT3 and FT4 indicating the presence of an inappropriate TSH secretion syndrome. For this reason, the steroid hormone binding protein was evaluated and resulted in 38.10 nmol/L (normal values 13–71 nmol/L). A nuclear magnetic resonance of the sellar region showed a 3 mm area of reduced vascularization corresponding to the inferior and lateral left portion of the pituitary gland. The evaluation of the other pituitary hormones showed levels in the normal range. It was decided that the patient would undergo a suppression test with increasing doses of triiodothyronine, and an antiarrhythmic therapy with carvedilol 50 mg/d was started preventively. We chose this approach for its most sensitive and specific capacity in assessing the presence of a TSH-producing adenoma. In fact, a complete inhibition of TSH secretion after T3 administration has never been recorded in this kind of lesions that lost the sensitivity to thyroid hormone. The suppression test with increasing doses of triiodothyronine was conducted till a dose of

The American Journal of the Medical Sciences • Volume 337, Number 6, June 2009

TSH-oma and Thyroid Carcinoma

TABLE 1. Suppression test with T3 FT3 (pg/mL) FT4 (ng/mL) TSH (uIU/mL) Cholesterol (mg/dL) SHBG (nmol/L) BP (mm Hg) Fc B (min)

Basal

After 3 d T3 60 ␮g/die

After 3 d T3 100 ␮g/die

After 3 d T3 200 ␮g/die

3.82 2.06 1.72 163 30.7 125/80 80

7.03 2.34 1.98 151 37.5 150/100 88

8.04 2.07 1.72 140 41.5 150/90 92

18.37 2.44 1.48 125 42.1 140/90 90

FT3 indicates free triiodothyronine; FT4, free thyroxine; TSH, thyrotropin; BP, blood pressure; SHBG, steroid hormone binding protein.

200 ␮g/d. The results showed no TSH suppression and were diagnostic of a TSH-secreting microadenoma (Table 1). To complete the evaluation, the patient underwent a Doppler ultrasound of the neck. This showed a gland of increased volume with rounded profiles and with the inferior lobes going beyond the giugulo that invaded the anterior mediastinum. Numerous nodular lesions measuring between 8 and 15 mm were described in both lobes. In particular, a hypoechoic nodule with intranodular microcalcifications measuring 15 mm was described in the median portion of the right lobe. The vascular pattern showed no intranodular vascularization but only a slight perinodular vascularization. Considering the clinical story, the relevant size of the gland, and the pressure symptoms, with recent evolving appearance, described by the patient, a total thyroidectomy was planned. This was performed after a short period with antithyroid drugs. There were no complications postoperatively. The final histologic examination described a gland with a multinodular macrofollicular hyperplasia. In the posterior portion of the right lobe, a capsuled neoplasm of 17 mm was described that appeared to be a capsuled follicular oncocytic neoplasm with minimum signs of incomplete capsule penetration (Figure 1). The lesion was positive for galectin-3 and this was suggestive of early cancer (incipient follicular carcinoma with oncocytic features); a classification according to the TNM scheme was not possible because of the uncertainty regarding its potential malignancy. The patient was started on replacement therapy with increasing

doses of thyroxine until the dose of 125 ␮g/day. Considering the risk of further growth of the pituitary lesion, the surgical removal of the microadenoma seemed necessary. We strongly recommended this second operation to the patients. The patient refused the second surgery for fear of the possible complications, especially the possibility, though very low, of panhypopituitarism. Not being able to convince the patient, a close follow up was decided. At 6 and 12 months after surgery, the patient underwent an admission in a Day Hospital. During the last admission in the hospital, the thyroid hormones were in the normal range (FT3 2.56, FT4 0.78), whereas the TSH levels were high (6.97). There was no detectable thyroglobulin and a normal antibody pattern (Tg ⬍0.5 ng/mL, TgAb ⬍20). The other pituitary hormones and the prolactin levels were in the normal range. The adrenal and gonadic functions were normal. An ultrasound of the neck, carried out to identify possible thyroid residue or suspicious lymph nodes, did not show any abnormality. The nuclear magnetic resonance of the pituitary region at 6 and 12 months after surgery described a lesion with the same dimensions. The results of the physical examination were normal with good blood pressure and cardiac rate control. It was, therefore, decided to continue with the same dose of replacement therapy (125 ␮g/day) and the next follow up visit was programmed at 6 months. The patient was advised to pay more attention to diet and to increase physical activity.

FIGURE 1. Histological pattern of the capsuled follicular oncocytic neoplasm with minimum signs of incomplete capsule penetration (Ematossilin-Eosin preparation, 10⫻ magnification).

We described a rare case of a TSH-secreting pituitary adenoma associated with a thyroid follicular carcinoma. To our knowledge, there are only a few descriptions of such associations, and of these, 2 are regarding an association with a follicular neoplasia (Table 2). Furthermore, our case is particular for 2 reasons: first, it concerns a patient with a pituitary microadenoma, which is a rare occurrence because normally these types of lesions are diagnosed at a more advanced stage9; and second, the neoplastic lesion was also discovered in an early stage. It is known that a chronic hyperproduction of TSH is important for the cell proliferation in adenomatous goiter and could be relevant for the development of neoplasia, especially in the early stage of tumorigenesis. These facts are suggested by clinical and experimental studies1,10 that showed how TSH is responsible for the activation of adenylate cyclase with the following increase of intracellular cAMP and stimulation of DNA synthesis. In our case, the thyroid neoplasm was removed before the capsular invasion was complete. The surgical removal of the lesion in this case may obtain a complete

DISCUSSION

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Poggi et al

TABLE 2. Other reported cases of association of TSH-oma with thyroid cancer Gessi et al8 Age 47 Gender Female TSH level at 139 onset FT3 FT4 0.96 FT4 Diameter of 4 mm TSH-oma

Ohta et al5

Kishida et al6

45 Female

Gasparoni et al5

27

Calle-Pascual et al7

37

Female

55

Female

Male

2.2

2.16

5.7

3.5

1.5 cm

9.5 pg/mL 4.05 ng/dL 1 cm

T3 5.7 pmol/L T4 23.1 pmol/L 1 cm

T4 3.4 ng/mL FT4 172 ⬎1 cm (exact dimension were not reported) Follicular

Present case 50 Male 2.31 4.05 pg/mL 2.32 ng/mL 3 mm

Type of Follicular Papillary Papillary Papillary Follicular Thyroid Ca Diameter of 8 mm 2 cm 3 cm 2 cm 5 cm 1.7 cm Thyroid Ca Treatment Thyroidectomy and Thyroidectomy and Hardy operation Thyroidectomy Thyroidectomy Thyroidectomy Hardy operation Hardy operation and and radiotherapy and radiotherapy and hemithyroidectomy and Hardy operation observation Hardy operation: classical transsphenoidal neurosurgery approach to the base of the skull.

remission of the disease. During preoperative staging, the neck Doppler ultrasound had described a multinodular goiter and, in particular, a hypoechoic nodule with intranodular microcalcifications, such a nodule did not show intranodular vascularization pattern. This is in accordance with many authors who consider the presence of intranodular microcalcifications in a hypoechoic nodule as important, and the importance of the vascularization pattern as doubtful.11 The early stage of the cancer could be correlated with the relatively recent appearance of the pituitary lesion, confirmed by the small dimension of the latter. The patient had also undergone a fine needle aspiration biopsy of the larger thyroid lesions about 10 years before, the findings of which revealed negative results. This, together with the small dimensions of the pituitary lesion, further supports the hypothesis that the TSH hypersecretion was a relatively recent finding, as shown by the thyroid hormones as a normal level. An important aspect is the possibility of an alternative treatment for the pituitary lesion. Until now, the surgical removal of TSH-secreting pituitary adenomas has always been considered important.9,12 Furthermore, in case of thyroidectomy, the surgical removal of the pituitary lesion has always been advised, either before or after this operation, so as to avoid the possible expansion of the lesion as in the Nelson Syndrome.12 This possibility, usually occurring 1 to 4 years after adrenalectomy, seems to be related to the loss of the feedback control at the hypothalamus and pituitary levels. Moreover, the necessity of neurosurgical approach is of importance for a more safe follow up. In this case, with a diagnosis of early cancer, the use of tyroxine only at replacement levels is indicated. The goal is to maintain a value of TSH in the low levels of normal range without reaching a great suppression, like in carcinoma of advanced stage. Unfortunately, the maintenance of the TSH-oma, does not allow us to achieve a low serum level of TSH. One year after thyroidectomy (and 2 years after first observation), no modifications in the lesions volume have been observed. We do not know if this will continue over the long period but, considering the patient’s trouble with regard to a second surgery, a careful monitoring is proposed. Furthermore, that the natural history of these kind of lesions, only

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when of such size, implies an increase in its volume is uncertain. The small dimensions of the lesion and the safe distance from important anatomical structure allow a watchful waiting. We do not know if the biological characteristics of the lesions, as suggested by its small dimensions and by its behavior in these 2 past years, are as indolent to allow us to avoid a second surgery. Furthermore, as reported by other authors regarding similar problems as in the Nelson Syndrome, the absence of an increased TSH secretion seems to support our watchful approach.13,14 It has, in fact, been underlined that the pituitary lesion expansion is preceded by a rapid and substantial increase in pituitary hormones levels. Therefore, even though a total thyroidectomy followed by the surgical removal of the pituitary lesion is the preferred approach, in our opinion, we cannot exclude a more watchful attitude, if the dimensions of the lesion allow it, when the neurosurgical approach is not feasible. REFERENCES 1. Beck-Peccoz P, Brucker-Davis F, Persani L, et al. Thyrotropinsecreting pituitary tumors. Endocr Rev 1996;17:610 –38. 2. Jailer JW, Holub DA. Remission of Graves’ disease following radiotherapy of a pituitary neoplasm. Am J Med 1960;28:497–500. 3. Koriyama N, Nakazaki M, Hashiguchi H, et al. Thyrotropin-producing pituitary adenoma associated with Graves’ disease. Eur J Endocrinol 2004;151:587–94. 4. Gasparoni P, Rubello D, Persani L, et al. Unusual association between a thyrotropin-secreting pituitary adenoma and a papillary thyroid carcinoma. Thyroid 1998;8:181–3. 5. Ohta S, Nishizawa S, Oki Y, et al. Coexistence of thyrotropinproducing pituitary adenoma with papillary adenocarcinoma of the thyroid—a case report and surgical strategy. Pituitary 2001;4:271– 4. 6. Kishida M, Otsuka F, Kataoka H, et al. Hyperthyroidism in a patients with TSH-producing adenoma coexisting with thyroid papillary adenocarcinoma. Endocr J 2000;47:731– 8. 7. Calle-Pascual AL, Yuste E, Martin P, et al. Association of a thyrotropin-secreting adenoma and a thyroid follicular carcinoma. J Endocrinol Invest 1991;14:499 –502.

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8. Gessi A, Vierhapper H, Feichtinger H. Non-suppressible TSH in a patient thyroidectomized due to follicular thyroid carcinoma. Exp Clin Endocrinol Diabetes 2006;114:389 –92. 9. Brucker-Davis F, Oldfield EH, Skarulis MC, et al. Thyrotropinsecreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999;84:476. 10. Mitsumori K, Onodera H, Takahashi M, et al. Effect of thyroid stimulating hormone on the development and progression of rat thyroid follicular cell tumors. Cancer Lett 1995;92:193–202.

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11. AACE/AME Task Force on Thyroid Nodules American Association of Clinical Endocrinologist and Associazione Medici Endocrinologi: Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules Endocrine Practice. 2006;12:63. 12. Beck-Peccoz P, Persani L. Medical management of thyrotropin-secreting pituitary adenomas. Pituitary 2002;5:83– 8. 13. Kemink SA, Smals AG, Hermus AR, et al. Nelson’s syndrome: a review. Endocrinologist 1997;7:5. 14. Pereira MA, Halpern A, Salgano LR, et al. A study of patients with Nelson’s syndrome. Clin Endocrinol 1998;49:533.

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