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THYROID CANCER COMPLICATING PREGNANCY

  • Author Footnotes
    * Creighton University School of Medicine, Nebraska Methodist Hospital Cancer Center, Omaha, Nebraska
    Peter C. Morris
    Footnotes
    * Creighton University School of Medicine, Nebraska Methodist Hospital Cancer Center, Omaha, Nebraska
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  • Author Footnotes
    * Creighton University School of Medicine, Nebraska Methodist Hospital Cancer Center, Omaha, Nebraska
      Thyroid cancer is the most common endocrine malignancy. It affects persons of all ages, but the prognosis is worse for elderly patients. A total of 16,100 cases were projected in 1997, with 11,400 occurring in women.
      • Parker S.
      • Tong T.
      • Bolden S.
      • et al.
      Cancer statistics, 1997.
      Well-differentiated thyroid cancer occurs predominantly in young women, and the age at diagnosis is an important prognostic variable. The female predominance of thyroid cancer makes its occurrence during pregnancy not uncommon. About 10% of thyroid cancers occurring during the reproductive years are diagnosed during pregnancy or in the first year after birth.
      Thyroid nodules in women are common. Two percent of women of childbearing age have a thyroid nodule. Fortunately, most are benign. The prevalence of cancer in a solitary nodule ranges from 10% to 20%.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      Most nodules are discovered by the patient or by the physician at a routine prenatal examination. The discovery of any abnormality during pregnancy causes much anxiety for the patient and her physician. Any evaluation or diagnostic procedure must take into account the pregnant state of the patient and the fetal concerns to decrease any potential risks.
      Single clinically detected thyroid nodules are three to four times more common in women than in men, with a peak incidence during the reproductive years. This distribution of thyroid nodules suggests a possible role for hormonal stimulation in their development.
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      • Tan G.
      • Gharib H.
      • Goellner J.
      • et al.
      Management of thyroid nodules in pregnancy.
      Occult microcarcinomas are found approximately equally in men and women, but clinically detectable disease is more common in women during the childbearing years of hormonal function, suggesting a role for hormonal influences in the growth of thyroid malignancies. Walker and Doherty
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      • Walker R.
      • Lawrence A.
      • Paloyan E.
      Nodular disease during pregnancy.
      report an increase in nodular thyroid disease during pregnancy. Mazzaferri
      • Mazzaferi E.
      Management of a solitary thyroid nodule.
      reports an 8% to 17% incidence of malignancy in thyroid nodules overall; however, Doherty and Rosen
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      • Rosen B.
      • Walfish P.
      Pregnancy and surgical thyroid disease.
      • Rosen B.
      • Walfish P.
      Pregnancy as a predisposing factor in thyroid neoplasia.
      report that 39% to 43% of nodules discovered in association with pregnancy are malignant, suggesting an increased incidence of thyroid cancer during pregnancy. Most nodules discovered during pregnancy are benign thyroid cysts or colloid (adenomatous) nodules. Those found to be malignant are usually slow-growing differentiated thyroid cancers. These are usually papillary or follicular carcinomas with a good prognosis in this age group. Variants of papillary thyroid cancer associated with a poorer prognosis are columnar cell, tall cell, and diffuse sclerosing types.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      These mainly occur in older patients. The virulent, medullary, and undifferentiated or anaplastic thyroid carcinomas are rare during the childbearing years, with the highest incidence in the fifth and sixth decades.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      These nodules have an extremely poor prognosis regardless of stage or treatment. The discussion that follows focuses on the more common differentiated thyroid cancers.
      The changes in thyroid function brought about by pregnancy are well-known.
      • Burrow G.N.
      Thyroid diseases.
      • Rosen B.
      Thyroid cancer and pregnancy.
      There is a marked increase in the production of thyroid-binding globulin by the liver as a result of the elevated estrogen. Thyroid-binding globulin doubles by the end of the first trimester. Total concentrations of triiodothyronine (T3) and thyroxine (T4) also double; however, free T4 declines slightly but remains in the normal range. Thyroid-stimulating hormone declines to the lower limit of normal. Thyroid stimulation during pregnancy is thought to be caused by the high levels of beta human chorionic gonadotropin (β-HCG), which also has known thyroid-stimulating activity.
      • Mazzaferi E.
      Evaluation and management of common thyroid disorders in women.
      The thyroid gland may undergo a 20% to 30% increase in volume during pregnancy. In areas of low iodine intake such as Scotland, 71% of pregnant patients show goiter formation.
      • Rosen B.
      Thyroid cancer and pregnancy.
      The work-up of a thyroid nodule discovered in the pregnant patient is similar to that in the nonpregnant patient except for the fact that radionuclide scans are contraindicated. A history of rapid recent growth or of prior head and neck radiation exposure increases the suspicion that a thyroid nodule may be malignant. A history of treatment of Graves' disease with radioactive iodine does not increase the risk for thyroid cancer because doses greater than 5000 cGy ablate the gland completely. A complaint of a painful thyroid gland suggests thyroiditis, and a family history of Hashimoto's thyroiditis may be discovered. Radiation exposure increases the incidence of thyroid nodules to a range of 20% to 30%, and also increases the chance of malignancy in these nodules to 30% to 50%.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      On physical examination, a hard fixed nodule with cervical adenopathy is a sign of malignancy. Vocal cord paralysis, hoarseness, and dysphagia are rare but are signs of advanced disease. A dominate nodule, even of long duration, needs evaluation because of the slow growth pattern in most differentiated thyroid cancer.
      In general, extensive laboratory testing is not helpful.
      • Choe W.
      • McDougall R.
      Thyroid cancer in pregnant women: Diagnostic and therapeutic management.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      Mazzaferri
      • Mazzaferi E.
      Evaluation and management of common thyroid disorders in women.
      • Mazzaferi E.
      Management of a solitary thyroid nodule.
      suggests that the level of thyroid-stimulating hormone be obtained to identify unsuspected thyroiditis. Most patients with a malignant thyroid nodule have normal findings on thyroid function testing. Although medullary thyroid cancer is rare in young women, a serum calcitonin level should be obtained when this lesion is suspected. Serum calcitonin elevations are specific for medullary thyroid cancer. Other clinicians recommend, in addition to an assay for thyroid-stimulating hormone, determinations of free T3 and free T4, antithyroid antibodies, and serum calcium to rule out a parathyroid lesion.
      • Walker R.
      • Lawrence A.
      • Paloyan E.
      Nodular disease during pregnancy.
      Radionuclide thyroid imaging with 123I or 131I is contraindicated during pregnancy because of the ability of the fetal thyroid to concentrate iodine. Thyroid imaging does not reliably distinguish malignant nodules from benign nodules. Malignant nodules do not incorporate iodine as well as normal thyroid tissue and appear “cold” on the scan. Nodules that concentrate iodine or “hot” nodules are usually but not always benign. Cold nodules are found to be malignant 16% of the time.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      Ultrasound is safe in pregnancy but does not diagnose or exclude malignancy. Ultrasound is an accurate method for measuring a nodule and for determining the presence of more than one nodule. Ultrasound is accurate in categorizing nodules as cystic or solid. It has a low specificity for thyroid pathology and is unable to distinguish benign from malignant nodules. A solid nodule has a greater likelihood of being malignant, whereas a cystic nodule is more often benign.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      Ultrasound can be helpful in guiding fine-needle aspiration as well.
      Fine-needle aspiration is the most important diagnostic tool in the work-up of a thyroid nodule discovered in the pregnant patient. It is safe, inexpensive, and helps to distinguish those patients who can be observed safely during pregnancy from those who need surgery. False-negative results are reported in 1% to 6% of patients with a diagnostic accuracy of 70% to 97%.
      • Caruso D.
      • Mazzaferri E.
      Fine needle aspiration biopsy in the management of thyroid nodules.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      The results of a fine-needle aspiration may be malignant, suspicious, benign, or indeterminate. Hamburger
      • Hamburger J.
      Thyroid nodules in pregnancy.
      recommends strict criteria in the interpretation of the findings of fine-needle aspiration for the exclusion of malignancy. There must be at least six clusters of benign thyroid cells on two smears from separate aspirates from different parts of the nodule to exclude malignancy reliably. Biopsy specimens from lesions greater than 4 cm in size can be obtained with a cutting needle, allowing more accurate histologic analysis.
      Tan and co-workers
      • Tan G.
      • Gharib H.
      • Goellner J.
      • et al.
      Management of thyroid nodules in pregnancy.
      report that fine-needle aspiration is a reliable diagnostic tool in pregnant and nonpregnant patients. Benign findings on a fine-needle aspiration allow for the continued observation of a nodule until completion of the pregnancy. If the sample is inadequate to exclude malignancy or has a benign appearance on aspiration cytology, suppression with thyroxine is warranted. Exogenously administered thyroid hormone will suppress most benign nodules but not most malignant ones. Unfortunately, successful suppression does not completely exclude malignancy because some malignant nodules also suppress.
      • Norton J.A.
      • Levin B.
      • Jensen R.T.
      Cancer of the endocrine system.
      Thyroxine is safe during pregnancy, although some physicians defer thyroid treatment until after delivery for medicolegal reasons.
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      • Hamburger J.
      Thyroid nodules in pregnancy.
      Levels of thyroid-stimulating hormone should be followed to ensure adequate doses of thyroxine are given to lower the level. Thyroidectomy for diagnosis is rarely indicated in the pregnant patient.
      Mazzaferri
      • Mazzaferi E.
      Evaluation and management of common thyroid disorders in women.
      suggests proceeding with fine-needle aspiration in all thyroid nodules discovered prior to 20 weeks' gestation. Fine-needle aspiration is performed after 20 weeks only in nodules that grow during suppressive therapy. Surgery for indeterminate findings on fine-needle aspiration can be delayed until after delivery in most patients unless the nodule is increasing in size. Doherty and co-workers
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      suggest that the work-up of a thyroid nodule should depend on the gestational age. They recommend delaying any work-up or biopsy until after delivery in patients first found to have a nodule beyond 20 weeks' gestation, except in patients with rapidly growing lesions. Fine-needle aspiration is performed on all patients prior to 20 weeks' gestation.
      The timing of surgery for nodules is controversial. Hamburger
      • Hamburger J.
      Thyroid nodules in pregnancy.
      recommends surgery if the findings of fine-needle aspiration are positive for cancer but does not state exactly when this treatment should be performed. In pregnant patients with differentiated thyroid cancer found after 20 weeks' gestation, definitive surgery is usually delayed until after delivery. Fortunately, undifferentiated cancer is rare in this age group, and treatment for these aggressive cancers must be individualized depending on the extent of disease. The prognosis is usually so poor in this situation that only a palliative procedure may be recommended.
      • Hamburger J.
      Thyroid nodules in pregnancy.
      For cancer found early in pregnancy, surgery during the second trimester is safe for the patient and her fetus.
      • Choe W.
      • McDougall R.
      Thyroid cancer in pregnant women: Diagnostic and therapeutic management.
      • Rosen B.
      • Walfish P.
      Pregnancy and surgical thyroid disease.
      • Rosen B.
      • Walfish P.
      Pregnancy as a predisposing factor in thyroid neoplasia.
      Cunningham and Slaughter
      • Cunningham M.
      • Slaughter D.
      Surgical treatment of diseases of the thyroid gland in pregnancy.
      reported on five patients operated on during pregnancy from 1956 to 1967. Three fetal deaths were attributed to the extent of the surgical procedure; however, more recent reports note no fetal complications using contemporary monitoring techniques.
      • Choe W.
      • McDougall R.
      Thyroid cancer in pregnant women: Diagnostic and therapeutic management.
      • Doherty C.
      • Shindo M.
      • Rice D.
      • et al.
      Management of thyroid nodules during pregnancy.
      • Hamilton N.
      • Paterson P.
      • Bierdahl H.
      Thyroidectomy during pregnancy.
      Because nearly all of these malignancies in young women are differentiated thyroid cancers with an excellent prognosis, delaying surgical treatment until after delivery for tumors found during the second trimester is advocated.
      • Hamburger J.
      Thyroid nodules in pregnancy.
      Although reproductive factors have been implicated in the development of thyroid cancer, there is no evidence that pregnancy worsens the prognosis of thyroid cancer found during an existing pregnancy or that subsequent pregnancies increase the risk for cancer recurrence. McTiernan and co-workers
      • McTiernan A.
      • Weiss N.
      • Daling J.
      Incidence of thyroid cancer in women in relation to reproductive and hormonal factors.
      reported that pregnancy had little effect on the general incidence of thyroid cancer. Other investigators have found no difference in recurrence rates in patients treated for thyroid cancer who subsequently become pregnant.
      • Breese M.
      Cancer of the thyroid in women of childbearing age.
      • Hill C.
      • Clark R.
      • Wolf M.
      The effect of subsequent pregnancy on patients with thyroid carcinoma.
      • Rosvoll R.
      • Winship T.
      Thyroid carcinoma and pregnancy.
      Rosen and Walfish
      • Rosen B.
      • Walfish P.
      Pregnancy as a predisposing factor in thyroid neoplasia.
      reported on 30 patients with thyroid neoplasia during pregnancy. There was a 43% incidence of cancer and a 37% incidence of adenoma. They concluded that thyroid neoplasia during pregnancy has a higher incidence of cancer and suggested that its course is aggravated by pregnancy. Citing no data whatsoever, Asteris and DeGroot
      • Asteris C.T.
      • DeGroot L.
      Thyroid cancer: Relationship to radiation exposure and to pregnancy.
      proscribe further pregnancy in these patients and recommend therapeutic abortion for cancers found during the first trimester. Herzon and co-workers
      • Herzon F.
      • Morris D.
      • Segal M.
      • et al.
      Coexistent thyroid cancer in pregnancy.
      reported on 22 patients with thyroid cancer diagnosed at the time of pregnancy. Six patients underwent successful surgery during pregnancy and delivered uneventfully. There were two recurrences overall and no deaths in this group of patients. When compared with nonpregnant patients, there were no differences in survival. Rosvoll and Winship
      • Rosvoll R.
      • Winship T.
      Thyroid carcinoma and pregnancy.
      also reported no growth acceleration of thyroid cancers as an effect of pregnancy, nor did the tumors complicate the pregnancy. They suggested that subsequent pregnancy is safe in these patients. In contrast, Hod and others
      • Hod M.
      • Sharonay R.
      • Friedman S.
      • et al.
      Pregnancy in thyroid carcinoma: A review of incidence, course, and prognosis.
      • Kobayashi K.
      • Tanaka Y.
      • Ishiguro S.
      • et al.
      Rapidly growing thyroid carcinoma during pregnancy.
      • Rosen B.
      • Walfish P.
      Pregnancy and surgical thyroid disease.
      have reported on cases in which pregnancy did seem to accelerate the growth of a thyroid cancer. It is speculated that high levels of serum HCG stimulated the growth of the thyroid cancers through the stimulation of thyroid-stimulating hormone receptors.
      • Kobayashi K.
      • Tanaka Y.
      • Ishiguro S.
      • et al.
      Rapidly growing thyroid carcinoma during pregnancy.
      Subsequent pregnancy after treatment with 131I seems to be safe. Impairment of gonadal function by 131I is temporary and reversible, and there does not seem to be an increased incidence of adverse pregnancy outcome.
      • Casara D.
      • Rubello D.
      • Saladini G.
      • et al.
      Pregnancy after high therapeutic doses of iodine-131 in differentiated thyroid cancer: Potential risks and recommendations.
      • Schlumberger M.
      • DeVathaire F.
      • Ceccarelli C.
      • et al.
      Outcome of pregnancy in women with thyroid carcinoma.
      The genetic risks after exposure to therapeutic doses of 131I are low. Casara and co-workers
      • Casara D.
      • Rubello D.
      • Saladini G.
      • et al.
      Pregnancy after high therapeutic doses of iodine-131 in differentiated thyroid cancer: Potential risks and recommendations.
      reported on 70 patients who became pregnant after treatment with 131I for thyroid cancer. There was no increase in stillbirths, malformations, early deaths, or malignancies in the offspring. They empirically recommend the avoidance of pregnancy for 1 year after the administration of 131I to ensure complete elimination of the radionuclide.
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