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Cancer in Pregnancy: Thyroid Cancer and Pregnancy

Introduction
Thyroid cancer is the most commonly diagnosed tumor of the endocrine glands 1. Furthermore, the well differentiated subtypes (papillary and follicular) have a female predominance, (often present with an indolent, asymptomatic course during pregnancy), and represent a significant proportion of all cancers in women of childbearing age 2, 3. The incidence of thyroid malignancy in pregnancy is unknown 4. Tumor types are similar to non-pregnant patients3.

Diagnosis
Thyroid gland changes that occur during pregnancy have been well described. An increase in size of the thyroid gland may occur due to glandular hyperplasia and increased vascularity. Other changes include increased thyroxin binding globulin (TBG), resulting in an increase in total T-3 and T-4. Free thyroid hormone levels remain unchanged 5-8. Thyroid stimulating activity has been demonstrated in the sera of normal pregnant women and has been shown to correlate with levels of human chorionic gonadotropin. The thyrotropic role of hCG is also supported by the observation that patients with trophoblastic tumors and hyperthyroidism have greatly increased hCG levels 9.

The influence of reproductive and hormonal factors on incidence of thyroid cancer remains controversial. Varying degrees of correlation have been found between well differentiated thyroid cancer and factors such as parity, miscarriage during first pregnancy, artificial menopause and oral contraceptive use 10-19 .

The effect of pregnancy on the incidence of carcinoma in solitary thyroid nodules is also unclear. A few recent studies suggest that thyroid stimulation during both pregnancy and lactation may result in transient increase in risk of papillary thyroid cancer20,21, especially among women diagnosed with thyroid cancer at a younger age22. In general, thyroid nodules are present in approximately 1-2% of young women with an estimated prevalence of thyroid cancer of 5-10% in those patients 2. Some series have reported a higher incidence of carcinoma in solitary nodules in pregnancy compared to the nonpregnant state, but this has not been substantiated in larger, well designed studies 23-25.

Similar to the nonpregnant population, the presenting signs and symptoms of a well differentiated thyroid carcinoma are nonspecific. A solitary thyroid nodule is a common presentation. Other patients may report an increase in size of a preexisting nodule, pain in the neck region or hoarseness. The approach to thyroid nodules in pregnancy should be similar to the approach with non-pregnant patients26, and reflect the clinical guidelines of both the American Thyroid Association and the American Association of Clinical Endocrinologists.

Physical examination should be directed to the evaluation of the following characteristics of the nodule: size, consistency, mobility, and associated lymphadenopathy. Other signs such as a Horner's syndrome may be present.

Thyroid function testing is usually normal in patients with cancer with the exception of medullary carcinoma where the serum calcitonin is elevated. Thyroiditis and a parathyroid lesion may be diagnosed with alterations in TSH, antithyroid antibodies, free T3, T4 and calcium levels.

Fine needle aspiration (FNA) is the procedure of choice for histologic confirmation of a malignancy and has a diagnostic accuracy of 70 percent to 97 percent 27,28. Ultrasound may be used to characterize the nodule (solid vs cystic), detect other nodules missed on physical examination, measure nodule growth during pregnancy, and to guide the fine needle aspiration. It has a low specificity for thyroid pathology. High-resolution, real-time ultrasound can be used to assess these patients29. Radionuclide scanning of the thyroid is rarely used in pregnancy.

For nodules detected prior to 20 weeks gestation, FNA is recommended. Benign or indeterminate cytology may be treated with observation or suppressive therapy using thyroxine until the pregnancy is completed. In general, malignant nodules do not suppress with exogenous thyroid hormone although this is not absolute. Thyroxine is considered safe in pregnancy and adequate therapy should result in a decrease in TSH. It has been suggested that FNA after 20 weeks gestation can be delayed until after pregnancy except for rapidly growing nodules or those that fail to suppress with thyroxine 25,30,31.

Therapeutic abortion
There is no evidence that therapeutic abortion increases survival.

Staging
In this population, most patients present with well differentiated, localized disease and extensive staging investigations are not indicated. Due to the iodine concentrating abilities of the fetus, radioactive iodine for diagnosis is contraindicated during pregnancy. Decisions regarding the use of radiological investigations must take into account the age of the fetus and the estimated dose of radiation delivered with the respective imaging study.

Pathology and biology
Although isolated case reports exist describing rapid growth of papillary cancer during pregnancy, they appear to be the exception rather than the rule32. There are no data supporting altered tumor biology or more aggressive course of cancer during pregnancy33-36.

Treatment
Surgery remains treatment of choice for well differentiated thyroid cancer. Due to the relatively indolent course but potential impact on long term survival, therapy during pregnancy can be tailored to the stage of pregnancy. For those presenting in the first trimester, surgery and general anaesthesia can be delayed until the second trimester to reduce the risks associated with surgery to the fetus. A few reports suggested that the risk of fetal loss related to surgery is minimal37.For those patients who present in the later stages of pregnancy with a well-differentiated tumor, surgery can usually be delayed safely until the post partum period 38.

The use of postoperative radioiodine therapy in patients with well differentiated thyroid cancer is controversial, although there is evidence that benefits include decreases in cancer death, tumor recurrence and development of metastatic disease 39-41. Radioiodine therapy is contraindicated during pregnancy as it can cross the placenta and cause fetal hypothyroidism and cretinism 6. It has been suggested that women receiving radioiodine not become pregnant for at least 12 months post therapy to ensure elimination of I-131, and confirm disease remission. This should help avoid the higher miscarriage rate seen in the first few months after radioiodine treatment43. A recent study suggested that even shorter period (7 women conceived within 6 months after the last administration of I 1311) does not result in demonstratable side effects in subsequent pregnancies 43.

Prior history of treatment for thyroid cancer in women of childbearing age does not seem to cause exacerbation of this disease during pregnancy or in the postpartum period. Delivery of a healthy child after thyroidectomy and complementary treatment should be expected45.

Post operative treatment with exogenous thyroid hormone in suppressive doses is suggested to decrease recurrences. This hormone is thought to be safe in pregnancy45.

Treatment for undifferentiated cancer is more problematic and must be individualized to the patient and extent of disease. These aggressive cancers have a much worse prognosis and will not be discussed in this brief review.

Treatment of metatastic follicular or papillary thyroid cancer is usually not curative. Palliation may occur with I-131, external beam radiation, suppressive exogenous thyroid hormone and investigational protocols including chemotherapy.

Radiotherapy

Chemotherapy
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus46. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy 47 and 25% for combination chemotherapy48. It is generally suggested that chemotherapy be avoided during first trimester, when cells are actively dividing. Use of these agents in the second and third trimesters has been associated with an increased risk of stillbirth, intrauterine growth retardation and low birth weight46,49,50. When chemotherapy is administered during pregnancy, timing of delivery of the infant should take into account the potential for bone marrow depression and associated problems such as bleeding or infections. Self limiting fetal haematopoetic depression after maternal exposure to chemotherapy has been described and the neonate should be monitored for complications of this 51. Long term neurodevelopmental complications of in utero chemotherapy exposure have not been extensively studied. Limited data exists to suggest that this may be normal in the offspring of patients with haematologic malignancies treated during various stages of the pregnancy 52. See also list of cytotoxic agents in pregnancy.

Prognosis
Although controversial, it appears that pregnancy does not alter the prognosis of well differentiated thyroid carcinoma. Most studies that have examined this issue suffer from methodological problems such as limited length of follow-up, variable follow-up, non-standardized treatments and inadequate control groups 24,33,53-56,59.

Fetal consequences
There is no evidence that fetal outcome is adversely affected by maternal thyroid cancer.

Lactation
Cytotoxic agents administered systemically may reach significant levels in breast milk and thus breast feeding while on chemotherapy is contraindicated. A similar situation exists for the use of radioiodine. See also Breastfeeding and anti-cancer chemotherapy.

Fertility
Fertility does not appear to be affected by thyroid cancer. Furthermore, a follow-up study of seventy female patients treated with high doses of iodine-131 for differentiated thyroid cancer who underwent a subsequent pregnancy failed to detect a significantly increased rate of birth defects or adverse fetal outcomes provided patients avoid pregnancy for a period necessary to ensure total elimination of the radionuclide 58. See also Fertility of children exposed in utero to chemotherapy.

References

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