The Multiplicity of Thyroid Nodules and Carcinomas
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《新英格兰医药杂志》
About 5 percent of adults in the United States have palpable thyroid nodules. Most of these nodules are at least 2 cm in their longest dimension, and their frequency doesn't change much with age. Ultrasonography, unquestionably the most sensitive thyroid-imaging test, reveals smaller nodules in many more people, and the frequency of these nodules does increase with age. A thyroid nodule may represent any of a variety of entities (see diagram).1,2 Among the nodules that are evaluated by biopsy, about 95 percent are benign. Since there is selection for biopsy, mostly on the basis of size (the criterion is usually 1 cm in the longest dimension), the proportion of all nodules that are benign is probably higher.
Common Varieties of Thyroid Nodules.
Benign thyroid nodules are most often hyperplastic nodules of a multinodular goiter, but some are thyroid adenomas, and a few are cysts. Some hyperplastic nodules and adenomas have mutations that result in constitutive activation of the thyrotropin receptor or of intracellular signaling, leading to hyperthyroidism. For this reason, thyroid function should be assessed by measurement of serum thyrotropin in all patients with a thyroid nodule, but the result will usually be normal.
There is no reliable noninvasive way to distinguish a benign thyroid nodule from a thyroid carcinoma — it cannot be done by means of palpation, imaging, or biochemical testing. Rarely, there is evidence of invasion (vocal-cord paralysis) or metastasis (cervical lymphadenopathy) or a family history of medullary thyroid carcinoma, making it likely that the nodule is a carcinoma. The presence of multiple nodules does not decrease the likelihood that one of them is a carcinoma, as was once thought. Serum calcitonin concentrations are high in all patients with medullary thyroid carcinoma, but this type of carcinoma is rare (see diagram), and the concentrations may also be high in patients with other thyroid disorders.
Thyroid biopsy is — with some caveats — a reliable way to distinguish a benign nodule from a carcinoma. Nodules that are papillary carcinomas, medullary carcinomas, or anaplastic carcinomas (about 5 percent overall) are usually identified through biopsy.1 These diagnoses are based on the cytologic appearance of individual cells. This is also the case for most benign nodules (75 percent). One caveat is that too few cells may be obtained (in 10 percent of cases). Another is that follicular adenomas and carcinomas (the remaining 10 percent of cases) cannot be distinguished from one another; the same is true for Hürthle-cell tumors. When too few cells are obtained, the biopsy is usually repeated, often with similar results. The distinction between a follicular adenoma and a follicular carcinoma is based on the absence or presence, respectively, of invasion of the capsule of the nodule or of blood vessels or lymphatics within the nodule. Tissue sections are needed in order to search for these findings; about one in five of these nodules proves to be a carcinoma.
The widespread use of thyroid biopsy has increased the proportion of surgically removed nodules that turn out to be carcinomas, but there is room for improvement. There are likely to be cellular or molecular differences among the common types of thyroid nodules, but so far, attempts to improve the diagnostic accuracy of biopsy on the basis of such differences have been unsuccessful. Advances are especially needed for distinguishing between follicular adenomas and both follicular carcinomas and the follicular-variant papillary carcinomas.
Papillary carcinomas are often multifocal. Most of the additional foci are microscopic; the frequency of detection no doubt depends on the diligence with which the thyroid is examined by a pathologist. Are these carcinomas intrathyroidal metastases from the primary tumor, spreading through lymphatics not only within the ipsilateral thyroid lobe but also through the thyroid isthmus to the contralateral lobe? Or are they individual carcinomas? That they are often found at autopsy in the absence of a large carcinoma is evidence that they are individual tumors.
Better evidence is provided by the results of the molecular studies reported by Shattuck et al. in this issue of the Journal (pages 2406–2412). The investigators asked whether different foci of papillary carcinoma in the same woman had the same X chromosome, whether maternally or paternally derived, as determined by the presence of a polymorphism in the X-linked androgen-receptor gene. For the results to be informative, the women had to be heterozygous for the polymorphism. Among the 10 women who met this criterion, there were 5 in whom different foci of carcinoma consisted of monoclonal populations of cells with one or the other polymorphism. In other words, these five women had two different papillary carcinomas. The carcinomas in the other five women could have been derived from a single clone or from independent clones in which the same X chromosome, whether maternally or paternally inherited, happened to be inactivated. All these carcinomas were 0.4 cm or larger, but it is likely that the more numerous smaller carcinomas (measuring 0.1 cm or less) are also independent.
The findings of Shattuck et al. have nothing to do with the pathogenesis of papillary carcinoma. (There are mutations and gene rearrangements that are specific for papillary carcinoma, but none have been found in more than about half the tumors, and such genetic changes may not be tumor-initiating events.) The fact that multiple nodules with the histopathological features of papillary carcinoma are monoclonal suggests that they are indeed carcinomas that can grow and spread. This evidence supports the clinical finding that patients with papillary carcinoma who undergo thyroid lobectomy are more likely than those who undergo near-total thyroidectomy to have recurrent carcinoma in the remaining lobe as well as elsewhere.3
The American Cancer Society estimates that thyroid carcinoma will be diagnosed in 25,690 people in the United States this year4; the annual estimate has been increasing faster than the population for several decades. Whether this is a true increase or an increase in ascertainment is not known. The proportion of these carcinomas that are papillary carcinomas is increasing as well. The average tumor size at detection is probably decreasing, because more tumors are being detected by means of imaging. That augurs well for the prognosis, because a larger tumor — along with older age and the presence of distant disease at the time of diagnosis — is the most important determinant of a poor outcome.3 This is not to say that treatment is unimportant; the outcome is better when treatment consists of near-total thyroidectomy and the administration of radioiodine, as compared with thyroid lobectomy and no radioiodine. The conclusion that both the average tumor size at diagnosis and treatment are changing for the better is supported by the slower increase in mortality than in the rate of new cases.
Whether the frequency of benign thyroid nodules — the "background" against which thyroid carcinomas are identified — is increasing more rapidly than the U.S. population is not known. If it is, the cause might be decreasing iodide intake, which is the best-known risk factor for multinodular goiter and which is known to have occurred in the United States in the past several decades.5 At the same time, the proportion of nodules that are carcinomas might decrease, increasing the need to find precise noninvasive methods of diagnosis.
Source Information
Dr. Utiger is a clinical professor of medicine at Harvard Medical School and Brigham and Women's Hospital, Boston.
References
Kaplan MM. Clinical evaluation and management of solitary thyroid nodules. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid: a fundamental and clinical text. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:996-1010.
Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. Cancer 2000;89:202-217.
Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86:1447-1463.
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
Hollowell JG, Straehling NW, Hannon WH, et al. Iodide nutrition in the United States: trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998;83:3401-3408.(Robert D. Utiger, M.D.)
Common Varieties of Thyroid Nodules.
Benign thyroid nodules are most often hyperplastic nodules of a multinodular goiter, but some are thyroid adenomas, and a few are cysts. Some hyperplastic nodules and adenomas have mutations that result in constitutive activation of the thyrotropin receptor or of intracellular signaling, leading to hyperthyroidism. For this reason, thyroid function should be assessed by measurement of serum thyrotropin in all patients with a thyroid nodule, but the result will usually be normal.
There is no reliable noninvasive way to distinguish a benign thyroid nodule from a thyroid carcinoma — it cannot be done by means of palpation, imaging, or biochemical testing. Rarely, there is evidence of invasion (vocal-cord paralysis) or metastasis (cervical lymphadenopathy) or a family history of medullary thyroid carcinoma, making it likely that the nodule is a carcinoma. The presence of multiple nodules does not decrease the likelihood that one of them is a carcinoma, as was once thought. Serum calcitonin concentrations are high in all patients with medullary thyroid carcinoma, but this type of carcinoma is rare (see diagram), and the concentrations may also be high in patients with other thyroid disorders.
Thyroid biopsy is — with some caveats — a reliable way to distinguish a benign nodule from a carcinoma. Nodules that are papillary carcinomas, medullary carcinomas, or anaplastic carcinomas (about 5 percent overall) are usually identified through biopsy.1 These diagnoses are based on the cytologic appearance of individual cells. This is also the case for most benign nodules (75 percent). One caveat is that too few cells may be obtained (in 10 percent of cases). Another is that follicular adenomas and carcinomas (the remaining 10 percent of cases) cannot be distinguished from one another; the same is true for Hürthle-cell tumors. When too few cells are obtained, the biopsy is usually repeated, often with similar results. The distinction between a follicular adenoma and a follicular carcinoma is based on the absence or presence, respectively, of invasion of the capsule of the nodule or of blood vessels or lymphatics within the nodule. Tissue sections are needed in order to search for these findings; about one in five of these nodules proves to be a carcinoma.
The widespread use of thyroid biopsy has increased the proportion of surgically removed nodules that turn out to be carcinomas, but there is room for improvement. There are likely to be cellular or molecular differences among the common types of thyroid nodules, but so far, attempts to improve the diagnostic accuracy of biopsy on the basis of such differences have been unsuccessful. Advances are especially needed for distinguishing between follicular adenomas and both follicular carcinomas and the follicular-variant papillary carcinomas.
Papillary carcinomas are often multifocal. Most of the additional foci are microscopic; the frequency of detection no doubt depends on the diligence with which the thyroid is examined by a pathologist. Are these carcinomas intrathyroidal metastases from the primary tumor, spreading through lymphatics not only within the ipsilateral thyroid lobe but also through the thyroid isthmus to the contralateral lobe? Or are they individual carcinomas? That they are often found at autopsy in the absence of a large carcinoma is evidence that they are individual tumors.
Better evidence is provided by the results of the molecular studies reported by Shattuck et al. in this issue of the Journal (pages 2406–2412). The investigators asked whether different foci of papillary carcinoma in the same woman had the same X chromosome, whether maternally or paternally derived, as determined by the presence of a polymorphism in the X-linked androgen-receptor gene. For the results to be informative, the women had to be heterozygous for the polymorphism. Among the 10 women who met this criterion, there were 5 in whom different foci of carcinoma consisted of monoclonal populations of cells with one or the other polymorphism. In other words, these five women had two different papillary carcinomas. The carcinomas in the other five women could have been derived from a single clone or from independent clones in which the same X chromosome, whether maternally or paternally inherited, happened to be inactivated. All these carcinomas were 0.4 cm or larger, but it is likely that the more numerous smaller carcinomas (measuring 0.1 cm or less) are also independent.
The findings of Shattuck et al. have nothing to do with the pathogenesis of papillary carcinoma. (There are mutations and gene rearrangements that are specific for papillary carcinoma, but none have been found in more than about half the tumors, and such genetic changes may not be tumor-initiating events.) The fact that multiple nodules with the histopathological features of papillary carcinoma are monoclonal suggests that they are indeed carcinomas that can grow and spread. This evidence supports the clinical finding that patients with papillary carcinoma who undergo thyroid lobectomy are more likely than those who undergo near-total thyroidectomy to have recurrent carcinoma in the remaining lobe as well as elsewhere.3
The American Cancer Society estimates that thyroid carcinoma will be diagnosed in 25,690 people in the United States this year4; the annual estimate has been increasing faster than the population for several decades. Whether this is a true increase or an increase in ascertainment is not known. The proportion of these carcinomas that are papillary carcinomas is increasing as well. The average tumor size at detection is probably decreasing, because more tumors are being detected by means of imaging. That augurs well for the prognosis, because a larger tumor — along with older age and the presence of distant disease at the time of diagnosis — is the most important determinant of a poor outcome.3 This is not to say that treatment is unimportant; the outcome is better when treatment consists of near-total thyroidectomy and the administration of radioiodine, as compared with thyroid lobectomy and no radioiodine. The conclusion that both the average tumor size at diagnosis and treatment are changing for the better is supported by the slower increase in mortality than in the rate of new cases.
Whether the frequency of benign thyroid nodules — the "background" against which thyroid carcinomas are identified — is increasing more rapidly than the U.S. population is not known. If it is, the cause might be decreasing iodide intake, which is the best-known risk factor for multinodular goiter and which is known to have occurred in the United States in the past several decades.5 At the same time, the proportion of nodules that are carcinomas might decrease, increasing the need to find precise noninvasive methods of diagnosis.
Source Information
Dr. Utiger is a clinical professor of medicine at Harvard Medical School and Brigham and Women's Hospital, Boston.
References
Kaplan MM. Clinical evaluation and management of solitary thyroid nodules. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid: a fundamental and clinical text. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:996-1010.
Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. Cancer 2000;89:202-217.
Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86:1447-1463.
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
Hollowell JG, Straehling NW, Hannon WH, et al. Iodide nutrition in the United States: trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998;83:3401-3408.(Robert D. Utiger, M.D.)