Prolactinoma and other head and neck tumors after scalp irradiation. (Case Report).

Abstract

Tumors of the thyroid and parathyroid glands may develop together or separately in patients who previously have been exposed to head and neck irradiation. Whether cranial irradiation confers an increased risk for pituitary adenoma remains unknown. We report the case of a 52-year-old woman who was treated during childhood for tinea capitis with scalp irradiation and later in life developed a prolactin-secreting tumor, a parathyroid adenoma, a benign thyroid lesion, and a basal cell carcinoma of the skin. She was treated successfully with bromocriptine and surgical removal of the parathyroid adenoma. Molecular analysis of the parathyroid tissue failed to demonstrate any abnormality of the multiple endocrine neoplasia Type 1 gene. This case report is the first to describe a prolactin-secreting tumor that developed in association with other endocrine neoplasia after head and neck irradiation. Our case suggests that multiple endocrine neoplasia may develop in a sporadic pattern after scalp irradiation.

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The multiple endocrine neoplasia Type 1 (MEN-1) syndrome is characterized by the occurrence of parathyroid, endocrine pancreatic, and anterior pituitary tumors, and, to a lesser extent, other endocrine tumors (eg, carcinoid or adrenal tumors) in a single patient or in a familial context. (1) The diagnosis of MEN-1 is made, for the most part, on the basis of clinical criteria. Germline mutations in the MEN1 gene (2) are sought for objective assessment and confirmation of the clinical diagnosis. Somatic inactivating mutations and allelic loss targeting the MEN1 gene locus at 11q13 are indicative of the involvement of the MEN1 gene in the tumorigenic process of the relevant neoplasms. (3) The inclusion of thyroid adenomas as part of the MEN-1 syndrome is controversial. Thyroid adenoma is known to develop in approximately 5% of patients with MEN-1, (4) but compelling evidence for the involvement of the MEN1 gene in the pathogenesis of benign thyroid adenomas is lacking. Although head and neck irradiation is a kno wn risk factor for head and neck tumors, (5-9) it is unknown whether it confers an increased risk of pituitary adenomas. We report the case of a patient who was treated with scalp irradiation for tinea capitis during childhood. Later in life, she developed benign tumors of the parathyroid and pituitary glands, along with a benign thyroid nodule and basal cell carcinoma of the skin.

Discussion

After undergoing irradiation of the scalp, our patient developed two endocrine tumors, along with a benign thyroid lesion and a basal cell carcinoma of the skin on the face. Although none of these tumors are rare in the general population, their occurrence in the same patient suggests a common mechanism, either genetic or environmental. Somatic deletions (ie, allelic loss) of chromosome 11 genetic material at the MENI gene locus have been described in sporadic and MEN-I-associated parathyroid tumors. (10) The rate in MENI-associated parathyroid tumors approaches 100%, as would be expected with the MENI gene functioning as a tumor suppressor gene. (11) Our failure to detect allelic loss in the parathyroid adenoma in this patient may indicate, although not definitively, that the MENI gene was not involved in the tumorigenic process in this case. Parathyroid adenomas that occur after neck irradiation also have been reported, (12-14) and an increased incidence of thyroid and parathyroid tumors in the same patient after exposure to head and neck irradiation can be expected. (15,16) Because of the high incidence of benign thyroid nodules in the general population, however, we cannot rule out a casual association between the thyroid mass and the parathyroid adenoma in our patient.

Between 1948 and 1960, approximately 20,000 new immigrants to Israel, primarily children of North African origin, underwent scalp irradiation for the treatment of tinea capitis. (5-7) The five-field Adamson-Kienbok technique with lead shielding of the face and neck was used. Radiation was applied with superficial x-ray machines delivering beams of 70 to 100 kVp. The records of the specific dose that our patient received are not available; however, most patients received a single course of approximately 3.5 Gy in air per field delivered on 5 consecutive days. Actual doses to the thyroid and brain tissues were 4.3 to 16.8 cGy and 1.0 to 2.0 cGy. Follow-up of this cohort over 40 to 60 years revealed an increased risk of head and neck tumors. (5-9) Specifically, there were four- and twofold increases in the risk of thyroid cancer and thyroid adenomas among these patients.6'7

The occurrence of brain tumors, especially meningiomas and sarcomas, after exposure to head irradiation has been well documented.8 In fact, some have occurred after radiotherapy for pituitary tumors.(17,18) There is no information, however, regarding the development of prolactin-secreting tumors after radiation exposure. Furthermore, little is known about the molecular mechanisms involved in the development of prolactin-secreting tumors. As many as 12% of sporadic prolactinomas may harbor some mutation in the MENI gene." The dosage and type of radiation that apparently cause the development of meningiomas and sarcomas are much greater than the dosage our patient received. Nevertheless, the form of radiation received by our patient does sufficiently penetrate tissue to reach the pituitary gland. In the Israeli patient population followed after exposure to scalp irradiation, relative risk was 8.4 for neural tumors (9.5 for meningiomas, 2.6 for gliomas, and 3.4 for all others), (8) but no pituitary tumors previo usly were reported in this group.

The coexistence of several head and neck tumors in our patient strongly suggests a causal relationship between the previous exposure to scalp irradiation and the development of these tumors. To the best of our knowledge, this report is the first description of a prolactin-secreting tumor developing in association with other endocrine tumors after head and neck irradiation. The association of a pituitary tumor and parathyroid adenoma in this case suggests that a MEN-1-like condition may occur after exposure to radiation.

Acknowledgment

We thank Dr. Eitan Friedman of the Oncogenetic Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel, for his collaboration on the molecular analysis of the parathyroid tissue.

Accepted July 29, 2002.

References

(1.) Marx S, Spiegel AM, Skarulis MC, Doppman JL, Collins FS, Liotta LA. Multiple endocrinc neoplasia type 1: Clinical and genetic topics. Ann Intern Med 1998;129:484-494.

(2.) Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, et al. Germilne mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997;6:1169-1175.

(3.) Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, et al, Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 1997;16:375-378.

(4.) Matsuo K, Tang SH, Fagin JA. Allelotype of human thyroid tumors: Loss of chromosome 11q13 sequences in follicular neoplasms. Mol Endocrinol 1991;5:1873-1879.

(5.) Modan B, Baidatz D, Mart H, Steinitz R, Levin SG. Radiation-induced head and neck tumours. Lancet 1974;l:277-279.

(6.) Ron E, Modan B. Benign and malignant thyroid neoplasms after childhood irradiation for tinea capitis. J Natl Cancer Inst 1980;65:7-l1.

(7.) Ron E, Modan B, Preston D, Alfandary E, Stovall M, Boice JD Jr. Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 1989;120:516-531.

(8.) Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M, Chetrit A, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 1988;319:1033-1039

(9.) Modan B, Chetrit A, Alfandary E, Tamir A, Lusky A, Wolf M, et al. Increased risk of salivary gland tumors after low-dose irradiation. Laryngoscope 1998;108: 1095-1097.

(10.) Friedman E, Bale AE, Marx SJ, Norton JA, Arnold A, Tu T, et al. Genetic abnormalities in sporadic parathyroid adenomas. J Clin Endocrinol Metab 1990;71:293-297.

(11.) Shimon I, Melmed S. Genetic basis of endocrine disease: Pituitary tumor pathogenesis. J Clin Endocrinol Metab 1997;82:1675-1681.

(12.) Tisell LE, Carlsson S, Lindberg S, Ragnhult I. Autonomous hyperpara-thyroidism: A possible late complication of neck radiotherapy. Acta Chir Scand 1976;142:367-373.

(13.) Schachner SH, Hall A. Parathyroid adenoma and previous head and neck irradiation. Ann Intern Med 1978;88:804.

(14.) Fujiwara S, Sposto R, Ezaki H, Akiba S, Neriishi K, Kodama K, et al. Hyperparathyroidism among atomic bomb survivors in Hiroshima. Radiat Res 1992;130:372-378.

(15.) Cohen J, Gierlowski TC, Schneider AB. A prospective study of hyper-parathyroidism in individuals exposed to radiation in childhood. JAMA 1990; 264:581-584.

(16.) Christmas TJ, Chapple CR, Noble JG, Milroy EJ, Cowie AG. Hyper-Parathyroidism after neck irradiation. Br J Surg 1988;75:873-874.

(17.) Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M, et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992;304:1343-1346.

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RELATED ARTICLE: Key Points

* Little is known about the pathogenesis of prolactin-secreting pituitary tumors.

* Although genetic abnormalities--specifically those in the multiple endocrine neoplasia Type 1 gene--have been reported in some cases, environmental factors have not been well documented.

* This report suggests the possibility that radiation exposure confers an increased risk for developing prolactin-secreting pituitary tumors.

Case Report

A 52-year-old Jewish woman of Moroccan origin was referred to the Institute of Endocrinology at the Rabin Medical Center for evaluation of asymptomatic hyperprolactinemia of a few months' duration. Her medical history revealed that she had been treated with scalp irradiation for tinea capitis when she was 4 years old. A basal cell carcinoma of the face had been treated surgically when she was 47 years of age. Cessation of menstrual cycles accompanied by elevated gonadotropin level and low estrogen level had occurred when she was 48 years of age, when she had begun treatment with hormone replacement therapy. Her family history was remarkable for a sister with a nodular goiter and a brother with nephrolithiasis. No other data were available regarding her family history. A physical examination revealed a healthy-appearing woman. Her blood pressure was 130/90 nun Hg. A small thyroid nodule was suspected on the basis of palpation of the neck, and minimal galactorrhea was elicited from both breasts. A laboratory ev aluation showed hypercalcemia at a level of 11.5 mg/dl (normal, 8.0-1 0.5 mg/dl), a parathyroid hormone (PTH) level of 620 ng/L (normal, 12-72 ng/L), and mild hypercalciuria, with 24-hour urinary calcium excretion of 306 rug (normal, 100-300 mg/d). Her alkaline phosphatase level was elevated at 217 U/L, with 87% (192 U/L) of bone origin, and her prolactin level was 238 [micro]g/L (normal, 5-20 [micro]g/L).

Pituitary magnetic resonance imaging showed a round mass in the pituitary measuring 10 X 12 mm that was hypodense on T2-weighted images, with no involvement of the adjacent structures. A thyroid sonogram showed a 10-mm nodule on the left lobe and two smaller nodules (0.5 and 0.7 mm) on the right lobe. Another 12-mm lesion, which raised suspicion of a parathyroid adenoma, was found close to the left lobe. The sestamibi scan showed increased uptake on the lower left side, in accordance with the sonographic findings. Ultrasonography-guided fine-needle aspiration of the thyroid at two sites was consistent with a benign thyroid nodule.

The diagnosis was primary hyperparathyroidism in association with macroprolactinoma. Treatment with bromocriptine (2.5 rag bid) was started, and the patient was referred for parathyroidectomy. Surgical exploration of the neck revealed a single lower-left parathyroid adenoma measuring 1.3 cm, which was removed. Three weeks after surgery, the patient's calcium level was 8.8 mg/dl, and her PTH level, although still slightly elevated, had decreased to 92 ng/L. Eight months later, the patient's calcium level was 9.0 mg/dl, and her PTH level was 73.6 ng/L. The sestamibi scan was repeated, and it did not show a parathyroid adenoma. After 6 weeks of treatment with bromocriptine, prolactin levels decreased to 14.7 [micro]g/L, and after 8 months of treatment, almost complete resolution of the pituitary mass was noted on magnetic resonance imaging studies. Molecular analysis of the parathyroid tissue with the use of 1 1q13 MEN]linked markers (D11S4907 and PYGM) was informative but failed to demonstrate allelic loss at a ny of the tested sites. In addition, denaturing gradient gel electrophoresis analysis of the coding exons of the MEN] gene failed to show any migration abnormalities.

From the Endocrine Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva; the Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer; and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Reprint requests to Carlos A. Benbassat, MD, Endocrine Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel 49100.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9602-0209