Nodular Disease During Pregnancy

SURGERY IN THE PREGNANT PATIENT

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NODULAR DISEASE DURING PREGNANCY Regina P. Walker, MO, Ann M. Lawrence, MO, PhD, and Edward Paloyan, MO

Thyroid disease during pregnancy is a significant issue, especially because the incidence of autoimmune disease of the thyroid approaches 10% in women. Exposure to head and neck irradiation in childhood is one of the most significant factors in the development of thyroid neoplasia. However, genetic, environmental, and racial factors have prevailed throughout recorded history and will continue to prevail long after the radiation effect has waned. Well-differentiated thyroid carcinoma occurs predominantly in young women. s Pregnancy may be regarded as an enhancing factor in individuals genetically or environmentally predisposed to the development of thyroid neoplasia. The renal loss of iodine in certain developing countries and in mountainous areas of the world, due to the increase in the glomerular filtration rate that occurs in pregnancy, can lead to a relative iodine deficiency and the development of thyroid-stimulating hormone (TSH)induced goiters, especially if dietary supplements are not provided. Furthermore, elevated estrogen levels in pregnancy lead to the hyperproduction of thyroid-binding globulin by the liver, which results in a rise in the number of T4 binding sites, which is responsible for a decrease in Support for this article was provided by the Ira and Arie Crown Foundation, Gerald Ajemian, and the Chicago Association for Research and Education in Science.

From the Departments of Otolaryngology/Head and Neck Surgery (RPW) and Medicine (AML), Loyola University Medical Center, Maywood, Illinois; Department of Surgery, University of Illinois, Chicago, Illinois (EP); and Edward Hines, Jr, Department of Veterans Affairs Hospital, Hines, Illinois

SURGICAL CLINICS OF NORTH AMERICA VOLUME 75 • NUMBER 1 • FEBRUARY 1995

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T3 uptake and an elevated total serum T4 • However, free thyroid hormone levels (free T3 or free T4 ) corrected for the elevated thyroid-binding globulin are in the normal range in pregnancy. The role of TSH in the development of thyroid neoplasia in pregnancy is not well characterized. However, other stimulators of thyroid neoplasia occur in pregnancy in the form of chorionic TSH, and human chorionic gonadotropin (hCG) has a mild TSH effect. Other growth factors may also have a role in thyroid neoplasia, such as somatome dins, growth-stimulating immunoglobulins, placental lactogen, epidermal growth factor, and growth hormone itself. The survival of a placental allograft (the fetus) requires a state of altered immunologic tolerance that is regarded as a condition conducive to the growth of neoplasms and includes the presence of embryogenic antigens both in the placental allograft and in the neoplasms. 2 These immunologic changes which occur in pregnancy are reflected in a reduction in killer cells and helper T cells, the presence of serologic blocking factors, the presence of suppressor T cells and leukocyte migration and enhancement factors in amniotic fluid, alteration of surface antigenicity, and the natural immunosuppressive effect of estrogen, progesterone, and hCG.l, 2, 6

GENERAL PRINCIPLES AND RECOMMENDATIONS

Thyroid carcinoma of follicular cell origin (papillary or follicular) predominates in women in their childbearing years. The incidence of neoplasia in thyroid nodular disease in pregnancy approximates 80%, with half of these lesions considered adenomas and the other half carcinomas. 4

DIAGNOSIS AND TREATMENT

The work-up of patients with nodular disease of pregnancy should ideally be undertaken promptly during the first trimester to allow for appropriate operative treatment during the second trimester if it is indicated. The work-up should be performed in the following sequence: L Thyroid function studies, which should include TSH, free triiodothyronine, and antithyroid microsomal antibodies. 2. An echo gram of the thyroid and the cervical nodal basins with small parts ultrasound technology. 3. Needle aspiration cytology. Patients with solid lesions by ultrasonography and with "cellular"

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and/ or highly suggestive cytologies for neoplasia should be started immediately on appropriate doses of thyroid hormone, provided that thyroid function studies are within the normal range, and then thyroidectomy should be considered and planned for the early second trimester, after extensive consultations with the obstetrician and the husband and after full discussions and considerations of the religious and philosophical views of both prospective parents. Intrapartum thyroidectomy would require the full involvement of the obstetrician and an experienced anesthesiologist. Case Presentations

Case 1. A 24-year-old woman, gravida I, para 0, had a 2.5-cm nodule in the left lobe of the thyroid noted by her obstetrician at 14 weeks' gestation. The family history was remarkable for the presence of autoimmune thyroid disease in the patient's mother and maternal aunts. There was no history of radiation exposure, and thyroid function studies, including free T3, TSH, and antithyroid microsomal antibodies, were in the normal range. An ultrasound examination showed that the nodule was solid, and aspiration cytology showed a pattern consistent with a neoplasm with some atypical cells, highly suggestive of a papillary carcinoma. The patient was started on TSH suppression with 0.1 mg of sodium levothyroxine. At 18 weeks' gestation, with intraoperative monitoring of the fetus and with the patient positioned on the operating room table with right lumbar elevation, a total left thyroid lobectomy was performed with autotransplantation of the left superior parathyroid gland and preservation of the left inferior parathyroid gland in situ with what appeared to be adequate blood supply. There was no grossly detectable cervical or superior mediastinal adenopathy. The permanent sections disclosed a grade 2 papillary carcinoma. The patient had an uneventful postoperative course; she was maintained on 0.125 mg of thyroxine, and TSH levels were maintained in the low normal range. A normal delivery ensued with a normal baby, euthyroid according to free T3 and TSH measurements during the first 4 weeks. The patient chose to nurse her baby and at 6 months' post-partum a total right thyroid lobectomy was performed with the autotransplantation of the right superior parathyroid gland and preservation of the right inferior parathyroid gland in situ with what appeared to be adequate blood supply. In addition to chronic inflammatory changes, there were two small foci (less than 5 mm) of papillary carcinoma in the right lobe. The patient had an uneventful postoperative course once more. Four months after the completion of total thyroidectomy, circulating TSH was undetectable, free T3 levels were at the upper limits of the normal range, thyroglobulin levels were undetectable, and serum calcium and phosphorus were in the normal range. The patient felt perfectly well with a resting pulse of 76 and a blood pressure of 110/70. The low transverse cervical scar, which had been slightly hypertrophic and hyperemic, blanched completely within 24 months with complete regression of the slight hypertrophy. Five years later and after another normal pregnancy and normal fetus and euthyroid baby, the patient is perfectly well with a normal thyroglobulin, intact parathyroid hormone, normal calcium/phosphorus, and no evidence of recurrence.

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Case 2. A 35-year-old woman, gravida 6, para 5, was referred at 28 weeks' gestation with a history of a small goiter for many years which was now enlarging rapidly, with a 3-cm nodule in the right lobe. There was extensive cervical adenopathy on the right side. Thyroid function studies disclosed that the patient's TSH was elevated and the nodule in the right lobe was solid. Aspiration cytology of the nodule and a separate aspiration of one of the cervical lymph nodes disclosed that the cytologic pattern of the nodule was consistent with neoplasia and the aspirated lymph node contained metastases consistent with a papillary carcinoma of the thyroid. The patient was started immediately on 0.15 mg of sodium levothyroxine and after a normal delivery of a normal fetus, underwent a total thyroidectomy and a modifed radical right neck dissection, with autotransplantation of the left superior parathyroid and preservation of the left inferior parathyroid and the right inferior parathyroid glands. The right superior parathyroid gland was included in the surgical specimen. The postoperative course was uneventful except that the patient required calcium carbonate supplementation for approximately 1 month for the treatment of mild hypocalcemia, although her serum phosphorus and intact parathormone levels were in the normal range and she was asymptomatic. This mother of now six children chose to nurse her new baby, with the usual perioperative precautions. Fourteen of 32 nodes contained metastases. Six months later after the patient had stopped nursing, thyroid hormone treatment was stopped. When TSH levels had risen to 55 !-LID/mL (normal, 0.3 to 5.0), the patient received 10 mCi of radioactive iodine for a total body scan. The 24- and 48-hour uptakes were less than 1% and showed a small amount of residual thyroid tissue bilaterally in the thyroid bed. Because it is our policy to treat only patients with an uptake of 3% or greater or with evidence of uptake outside the thyroid bed, no further treatment was contemplated except for the resumption of TSH suppression with appropriate doses of thyroxine. 3 With a follow-up of 6 years after total thyroidectomy and modified radical neck dissection, both the mother and her sixth child are doing quite well. Circulating thyroglobulin is undetectable, there is no evidence of recurrence, and parathyroid function is normal according to total calcium, inorganic phosphate, ionized calcium, and intact parathyroid hormone. Case 3. A 30-year-old woman, gravida 6, para 0, had a family history of autoimmune disease and a goiter that was detected at 6 weeks of pregnancy by her obstetrician. Upon examination, the right lobe was considerably larger than the left. Thyroid function studies disclosed an elevated TSH. An ultrasound examination confirmed the presence of a goiter, with the right lobe larger than the left without specific nodules but a disordered echographic texture of the thyroid compatible with a chronic inflammatory process such as Hashimoto's thyroiditis. Aspiration cytology of the right lobe showed a cytologic pattern consistent with chronic Hashimoto's thyroiditis. The patient was treated with progressively increasing doses of thyroxine, starting with 0.05 mg a day up to 0.125 mg by the time of delivery. Delivery was normal, as was the fetus, which was proved to be euthyroid with measurements of circulating TSH and thyroxine within the first 4 weeks after birth. Three months after delivery, on 0.125 mg of thyroxine, the patient's goiter was considerably smaller on physical examination. Ultrasonography confirmed

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the significant decrease to a size smaller than normal and did not detect any nodules that may have been overlooked by the original ultrasound examination during pregnancy. The patient continues on thyroid replacement therapy. Case 4. A 28-year-old woman, gravida 3, para 3, was noted by her obstetrician to have a sudden enlargement of the thyroid gland at 3 months after delivery. Examination of the thyroid showed a diffusely enlarged, slightly sensitive thyroid gland. Thyroid function studies showed a moderate degree of hyperthyroidism and an ultrasound examination was compatible with a diffuse goiter and a disordered echotexture compatible with a chronic inflammatory process. The diagnosis of silent postpartum thyrOiditis, which occurs in 5% to 7% of pregnancies, was made, and the patient was treated with propylthiouracil (50 mg three times a day). During the subsequent 6 months, the doses of propylthiouracil were gradually decreased, and the patient became hypothyroid as the goiter increased in size. The hypothyroid state was documented and the patient was started on thyroxine replacement therapy. Three months later the goiter was considerably smaller and long-term thyroxine replacement therapy was instituted.

SUMMARY

The incidence of autoimmune disease of the thyroid approaches 10% in women. This autoimmune state, which predisposes to the development of thyroid neoplasia, especially in patients with subclinical hypothyroidism, combined with tumor growth and immunologic factors that occur in the pregnant state, account for the significant incidence of nodular thyroid disease in pregnancy. Thyroid carcinoma of follicular cell origin in a young woman can generally be expected to pursue a slow course with ample time for preoperative preparation and operative treatment. However, the pregnant state should be considered an exception and thyroid nodular disease with suspicious aspiration cytologic features should be managed with a certain degree of urgency. In an excellent article on the subject of pregnancy as a predisposing factor in thyroid neoplasia, Rosen and Walfish4 present a series of 30 patients with thyroid neoplasia arising during pregnancy. The incidence of thyroid carcinoma was 43% and the incidence of adenoma 37%, for an 80% overall incidence of neoplasia. Furthermore, during the course of the pregnancy, 20% of the patients showed marked increase in nodular growth, including a 26-year-old primiparous woman who developed a small nodule in the first trimester which proved to be cellular on needle aspiration biopsy. In spite of thyroid hormone treatment, the nodule grew markedly in the last trimester. At postpartum operation, the patient was found to have a papillary carcinoma with extensive unilateral neck and mediastinal node disease, which was clinically oc-

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cult. These authors stress the importance of the operative treatment of thyroid neoplasia of pregnancy, either in the second trimester or immediately after delivery. We agree.

References 1. Donegan WL: Cancer in pregnancy. Cancer 33:194--215, 1983 2. Gleicher M, Deppe G, Cohen B: Common aspects of immunological tolerance in pregnancy and malignancy. Obstet Gynecol 54:335-341, 1979 3. McHenry C, Jarosz H, Davis M, et al: Selective postoperative radioactive iodine treatment of thyroid carcinoma. Surgery 106:956-959, 1989 4. Rosen IB, Walfish PG: Pregnancy as a predisposing factor in thyroid neoplasia. Arch Surg 121:1287-1290, 1986 5. Silverberg E: Cancer in young adults. Cancer 32:32-42, 1982 6. Walfish PG, Chan JYC: Post-partum hyperthyroidism. Clin Endocrinol Metab 14:417447,1985

Address reprint requests to Edward Paloyan, MD Research Services Department of Veterans Affairs Edward Hines, Jr, Hospital Hines, IL 60141