Tumori, 92: 178-180, 2006
AN UNUSUAL ASSOCIATION OF CEREBRAL MENINGIOMA, PARATHYROID ADENOMA AND THYROID PAPILLARY CARCINOMA Chiara Caliumi1, Dario Cotesta1, Luigi Petramala1, Monica Iorio1, Maurizio Salvati2, Sebastiano Filetti1, Giorgio De Toma3, Emilio D’Erasmo1, and Claudio Letizia1 1
Department of Clinical Sciences, 2Department of Neurosurgery, 3Department of Surgery, University of Rome “La Sapienza”, Rome, Italy
The case of a 50-year-old woman with cerebral meningioma and concomitant parathyroid adenoma and papillary thyroid carcinoma is presented. She complained of neurological symptoms characterized by right hemiparesis and dysarthria. Cerebral CT and MRI scans revealed a left voluminous frontal parasagittal lesion with the characteristics of a meningioma. Routine laboratory analysis revealed altered values of calciumphosphorus metabolism. Intravenous infusion of saline solution at 0.9% of NaCl resulted in a reduction of serum ionized calcium. A left craniotomy was performed and a fibroblastic meningioma of 5 cm in diameter was removed. Even though
the patient’s clinical condition was good, a calcium-phosphorus metabolism test confirmed high plasma levels of ionized calcium and parathyroid hormone. Thyroid and parathyroid ultrasonography revealed multinodular goiter and a parathyroid lesion confirmed by 99mTc-TCO4/99mTc-MIBI scintigraphy. A left superior parathyroidectomy and total thyroidectomy were performed. Histological examination revealed a parathyroid adenoma and a small papillary carcinoma of 0.4 cm in the right thyroid lobe. As far as we know, this patient is the third case of meningioma associated with parathyroid adenoma and papillary thyroid carcinoma described in the literature.
Key words: cerebral meningioma, papillary thyroid carcinoma, parathyroid adenoma.
Introduction
Endocrine tumors have sometimes been associated with other non-endocrine tumors. In the literature several associations, such as multiple endocrine neoplasia (MEN), have been well described and widely studied from the point of view of genetics (MENIN gene, RET proto-oncogene, neurofibromin, mutation of VHL gene, etc.)1-5. Although precise information has been found about some multiple-organ neoplasms, none has ever been found about the pathogenesis of other associations of endocrine and non-endocrine multiorgan lesions6. In fact, in the literature only four cases of endocrine and non-endocrine neoplasms have been described6-9. Here we describe a case of an unusual association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma. Case report A 50-year-old woman was admitted to our hospital with neurological symptoms characterized by right hemiparesis and dysarthria. Brain CT scan revealed a left voluminous frontal parasagittal lesion with the characteristics of a meningioma. The tumor was further confirmed by MRI of the brain. The patient had a clinical history of arterial hypertension and multinodular goiter treated with levothyroxine and she had undergone surgery for cholecystolithiasis several years earlier. She
had been in good health until, two months before admission to hospital, she began to suffer from asthenia and lethargy associated with migraine and gradually worsening motor slackening. The patient was checked and appeared to be in rather good general condition: she was alert, oriented, with normal breathing and her blood pressure was 150/100 mmHg with a regular heart rate of 90 beats/min. Neurological examination showed difficulty in speech and a strength deficit in the right side of the body. All routine laboratory tests were within the normal range except that of the calcium-phosphorus metabolism. Serum total calcium was high (13.4 mg/dL; normal range, 8.5-10.5 mg/dL) and serum phosphorus was low (1.7 mg/dL; normal range, 2.6-4.5 mg/dL). Ionized calcium values were very high (1.7 mmol/L; normal range, 1.11-1.33 mmol/L) and alkaline phosphatase was high (209 U/L; normal range, 39-111 U/L), as was 24hour urinary calcium excretion (400 mg/24 h; normal range, 50-300 mg/24 h). Intravenous infusion of saline solution at 0.9% of NaCl resulted in a reduction of serum ionized calcium to max 1.5 mmol/L. During her stay in the Internal Medicine Division the patient underwent MRI of the brain, which demonstrated a left voluminous frontal parasagittal meningioma of 6 cm in diameter, confirming the result of the CT scan that had been performed at the emergency department. The tumor on the MRI sequence showed a cystic component and closely adhered to the superior sagittal sinus, which appeared dislocated to the right side of the
Acknowledgments: The authors are grateful to Miss Lee Tanya O’Hara for linguistic revision of the manuscript. Correspondence to: Prof Claudio Letizia, MD, Dept of Clinical Sciences, Day Hospital of Internal Medicine and Arterial Hypertension, Policlinico Umberto I, 00161 Rome, Italy. Tel +39-06-49970944; fax +39-06-49970524; e-mail
[email protected] Received June 13, 2005; accepted August 11, 2005.
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AN UNUSUAL ASSOCIATION OF DIFFERENT TUMORS
cerebral hemisphere (Figure 1). A left frontal craniotomy was performed at our Neurosurgical Department, and a fibroblastic meningioma of 5 cm in diameter was removed. As the days passed, the patient’s speech improved and she recovered strength and motility in the right side of the body. Even though her clinical condition was good, the serum calcium level remained elevated. We decided to send her to day hospital where she was thoroughly examined. The calcium-phosphorus metabolism test confirmed the high plasma levels of total and ionized calcium (13.5 mg/dL and 1.62 mmol/L, respectively) and the intact parathyroid hormone (PTH-i) proved to be elevated (75 pg/mL; normal range, 10.6-54 pg/mL). Thyroid and parathyroid ultrasonography revealed an enlarged thyroid gland with many nodules and pseudonodules, while a solid, hypoechoic, homogeneous nodule measuring 3.3 x 1.3 x 1.8 cm with a regular border and the characteristics of a parathyroid adenoma was detected on the upper left thyroid lobe. Parathyroid 99mTc-TCO4/99mTc-MIBI scintigraphy was performed, which showed an area of abnormal tracer uptake in the upper left thyroid lobe (Figure 2). Ambulatory 24-hour blood pressure (AMBP) recording showed systolic and diastolic hypertension (first grade according to the WHO/ISH classification). The patient underwent MRI of the brain and pituitary gland, which showed an empty sella panel. The hormonal pattern of the pituitary, thyroid and adrenal glands turned out to be within the normal range. Six months after the neurosurgical intervention she was admitted to our Surgical Department and underwent a left superior parathyroidectomy and total thyroidectomy. Histological examination confirmed the parathyroid adenoma of 2.5 cm in diameter consisting of oxyphil cells and revealed a small papillary carcinoma of 0.4 cm in diameter in the right thyroid lobe. After the operation the calcium and PTH-i hormone serum levels returned to normal (8.4 mg/dL and 27 pg/mL, re-
Figure 1 - Celebral MRI: frontal parasagittal meningioma of 6 cm in diameter.
Figure 2 - 99mTc-TCO4/99mTc-MIBI scintigraphy scan: area of abnormal tracer uptake in the upper left thyroid lobe (parathyroid adenoma).
spectively) and the systolic and diastolic blood pressure dropped significantly at the AMBP. Assuming that these endocrine and non-endocrine tumors were genetically related, we investigated whether there were any defects in the RET proto-oncogene and the MENIN gene. No mutation or polymorphism of these genes were detected in our patient. At the moment the patient is in good health and is living a normal life. Discussion
So far, multiple endocrine neoplasia including MEN type 1, which primarily affects the pituitary, pancreas and parathyroid glands, and MEN type 2A and 2B, which affect the thyroid and parathyroid glands and the adrenal medulla, familial medullary thyroid carcinoma (FMTC) and the Carney complex10, which affects the adrenal cortex, the pituitary, thyroid gland and gonads, are the most well known syndromes due to their primary genetic defects11,12. MEN type 1 is caused by a mutation in the MENIN gene; MEN type 2 (MEN 2A and 2B) and FMTC are caused by mutations in the RET oncogene; the Carney complex is caused by mutations in the gene that codes for the regulatory subunit type 1A of protein kinase A (PRKAR1A) in at least half of the patients studied11. Other associations of endocrine and non-endocrine tumors are rare and few cases have been described in the literature. The case described above, showing an association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma, is the third such case described in the literature. In 1991 Cagnano et al.9 reported the first case of this triple association with the addition of pulmonary lymphangioleiomyomatosis, fibrous tumor of the lung, cavernous hemangioma of the liver and nodular stromal hyperplasia of the ovary. Nine years later, Yamakita et al.6 described the second case of this association along
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with thyroid follicular adenoma, temporal astrocytoma, hemangioma of the external auditory meatus and oral papilloma. Defects in genes encoding hormones, hormone receptors or polypeptides of the signaling pathways usually cause complex disease manifestations characterized by the involvement of several tissues and by variable expressions; also minor genetic alterations such as point mutations can affect the function of gene products and cause endocrine disease13. At the moment, the RET proto-oncogene is one of the most interesting models of human disease caused by mutations in a receptor tyrosine kinase gene. Somatic rearrangements of RET are involved in the etiology of a variable proportion of papillary thyroid carcinomas (as that found in our patient), the most common type of thyroid tumor. Moreover, germline RET mutations are associated with three variants of the inherited cancer
C CALIUMI, D COTESTA, L PETRAMALA ET AL
syndrome (MEN 2A, MEN 2B and FMTC). Finally, RET mutations or heterozygous deletions of the whole gene cause the autosomal dominant form of Hirschsprung’s disease, a congenital disorder of the enteric nervous system14-16. The tumors described in our case study cannot be included in the well-known MEN because no defects of the RET proto-oncogene and the MENIN gene were found in our patient. It could be that most of the tumor associations described in the literature are coincidental, even though the occasional incidence of such complicated lesions is really low. So far, we lack any precise information about the pathogenesis of the rare, unusual association of organ tumors. It is likely that other genetic defects or unknown mutations of the RET proto-oncogene, MENIN gene and PRKAR1A are involved and responsible for this particular tumor association.
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