Thyroid carcinomas are the most common type of endocrine malignancies (1).  Initial symptoms may be nonspecific.  Typically, patients present with a recently discovered nodule in the neck or one of long standing.  Thyroid nodules are very common, with some estimates as high as 5 % of the population (2).   Malignant nodules have an incidence of 40 per one million patients (3).  Although this represents a low incidence, morbidity from thyroid cancer is the most devastating of all the endocrine organs, excluding ovarian tumors.  With proper identification, treatment, and surveillance, a malignancy of the thyroid discovered early can have a high success rate of treatment.

     The most common form of thyroid cancer is papillary carcinoma, accounting for as high as 80 % of all thyroid malignancies (4).  Paradoxically, the mortality rate from papillary carcinoma is the lowest of all thyroid cancers (5).  The peak incidence of papillary carcinomas is in the fourth and fifth decade with a female:male ratio of 2.6:1 (6,7).  Clinical studies have shown that increasing age is associated with an increased risk for papillary carcinoma (4).  The epidemiology of papillary carcinoma implicates prior irradiation to the head and neck areas, for treatment of other disorders, in the carcinogenesis of papillary carcinoma, with a linear dose exposure-incidence ratio (8).  Risk for radiation induced papillary carcinoma increases inversely proportionally to the age at which radiation exposure occurred (9).  Although papillary carcinomas may be seen within families, there is no established genetic linkage for hereditability for this disease.  Excess dietary iodine may be a predisposing factor for papillary carcinoma.  Increased TSH levels have also been suggested to be a causative factor for papillary carcinoma (8).  Molecular analysis indicates that the  ras oncogene may have an important role in causation of this tumor (10,11).

     The diagnosis of papillary carcinoma begins with a thorough history and physical examination.  Prior radiation exposure and familial cancer profile are important risk factors.  The physical characteristics of the thyroid gland, the number of nodules, and the presence of palpable cervical lymph nodes aid in estimating the probability of thyroid malignancy.  Serologic laboratory tests, other than routine thyroid functions, are not useful in diagnosis of thyroid cancers.

     Exogenous thyroid hormone, in doses sufficient to suppress endogenous TSH, may be used as a diagnostic maneuver and administered for a course of several months in an attempt to reduce the size of a thyroid nodule.  If the thyroid abnormality is TSH-dependent, regression with this therapy decreases the likelihood of malignancy, and many clinicians use this as a means for distinguishing benign from malignant nodules.

     Current radiologic methods for assessing the thyroid gland utilize either technetium-99m or iodine-123 to measure the functional capabilities of the thyroid nodule.  The absence of radionuclide concentration, i.e. a "cold nodule", is associated with a malignancy rate of 24%, while only 5 % of functioning nodules are malignant (1).  Ultrasonography is useful for quantification of tumor size and aids in distinguishing cystic from solid lesions.   The risk of cancer in a cystic lesion, approximately 5 %, is less than that for a solid lesion (6,8).

     Fine needle aspiration cytology is useful for determining the presence of malignancy, with 90 % reliability.  Important criteria for cytologic assessment of papillary carcinoma include the presence of true papillary formation, ground-glass nuclei, and psammoma bodies.  The presence of psammoma bodies may be a prognostic indicator of nodal metastases, as 53 % of nodules with psammoma bodies will have lymphatic involvement (6).

     Surgery for papillary carcinoma is dependent upon the clinical extent of disease, the histologic criteria of the tumor, and of the experience of the surgeon (5,12).  Consideration of the overall excellent prognosis for papillary carcinoma and the morbidity of recurrent laryngeal nerve injury and hypoparathyroidism may determine the advisability of total thyroidectomy or near-total thyroidectomy versus a subtotal thyroidectomy or simple thyroid lobectomy (3,5,13).  Papillary carcinoma has a high incidence of multi-centricity, supporting total thyroidectomy as the best operation (4).  Large series have shown reduced tumor recurrence rates in those patients who have undergone total thyroidectomy (12).  One retrospective study analyzed the theoretical advantage of total thyroidectomy and found that only 5 % of the patients with tumor recurrence would have benefitted from a more extensive operation than the initial procedure performed (1).  Because surgical resection of cervical lymph node metastases may be curative, aggressive surgical resection in the presence of extensive disease is indicated (9).

     Iodine-131 is an useful adjunct after surgical treatment for papillary carcinoma.  With small doses, it can be used to identify tumor recurrence or metastasis in a surveillance program, but with higher therapeutic doses, it is used for ablation of the remaining thyroid tissue after near-total or subtotal thyroidectomy or for unresected microscopic foci of tumor (4,9).  Mild toxicities may include nausea, vomiting, and sialoadenitis, with occasion bone marrow suppression (4).  Radiation-induced myeloproliferative disorders after long latency periods are rare.

     External beam radiation therapy may be indicated as an adjuvant in patients who have locally invasive aggressive papillary carcinomas.  Palliative treatment for bony metastases may also require this therapeutic modality.  In the presence of recurrent tumor unresponsive to I-131, secondary to poor uptake, external beam radiation treatment is necessary.

     Initiation of exogenous thyroid hormone after surgery and radioactive iodine ablation is important.  Because triiodothyroxine (T3) has a shorter half life than thyroxine (T4), the time required to reach equilibrium euthyroid state is less for replacement with T3 (3).  Thyroid hormone supplementation should be at doses sufficient to suppress serum TSH and thyroglobulin levels.

     The prognosis of papillary carcinoma is dependent upon several clinical and pathologic criteria.  The Mayo Clinic utilizes the AGES system, scoring for the patient's age, tumor grade, extent of tumor, and size of tumor (13).  A modification of this system for predicting the recurrence rate and cure rate, AMES, uses the criteria of age, metastasis to distant sites, extent of primary tumor, and size greater than 5 cm (14).  A more recent proposed predictive system, RAPE, evaluates tumor uptake of radioactive iodine, adenyl cyclase response to TSH, ploidy content of the tumor, presence of epithelial growth factor receptors, and the extent of treatment (3).  Patients with papillary carcinoma may be divided into a low risk category and a high risk category for recurrence and mortality from the disease.  The AJCC system (TNM) for papillary carcinoma recognizes age greater than 45, extra-thyroid invasion by direct extension, distant metastasis, and tumor size as staging criteria (15).  The WHO distinguishes between the variant histologies of papillary carcinoma which have either a benign or more malignant course.  Accepted designations for those variants of papillary carcinoma with good prognoses include micropapillary ( < 1 cm), encapsulated, solid, and follicular; those with poor prognoses include tall-cell, columnar, and diffuse sclerosing (16).  The presence of Hashimoto's thyroiditis is associated with a better prognosis (5,7,17).  No significant impact of lymph node involvement on tumor recurrence rate has been identified (5,14).   Local recurrence rates have been estimated to be between 5.8 % and 16 % (5,7,13).  Nodal metastases frequently involve the peri-tracheal lymph nodes (2).  Usual sites of distant metastases are 76 % lung, 24 % mediastinum, 23 % bone, and 15 % brain (13).

     Future prospects for treatment of papillary carcinoma are promising.  Studies using increased doses of iodine-131 or additional agents, such as lithium, to enhance the radiation effect are underway.  Bone marrow toxicity may be the limiting result of radioactive therapy in papillary carcinoma.  Progress in autologous bone marrow transplantation may allow the effects of radiation on bone marrow to be bypassed.  Concomitant use of adriamycin to enhance radioactive tumoricidal impact has not shown an increase in bone marrow toxicity (4).

     Astatine isotope 211 is a member of the same family as iodine.  This isotope is a high-energy alpha particle emitter, and is as effective as I-131 in concentrating within thyroid tissue.  Serious side effects include systemic lymphopenia, and Astatine 211 can damage follicles in ovary as well as cause loss of germ cells of the testes (4).  More research will be needed before this could be of clinical utility.

     Immunologic research has been done with monoclonal antibodies conjugated with radio-isotopes.  Because the association of autoimmune thyroiditis and papillary carcinoma has a better prognosis, clinical studies to induce an immunologic response have been attempted, but with minimal responses thus far (4).

     Prospects for therapeutic developments may evolve at the molecular level.  The ras oncogene requires farnesylation for activation to bind to GTP (10,11).  Agents designed for enzyme inhibition of farnesylation or for blocking of GTP binding may be the logical extension of this research.

     Papillary carcinoma is the most common of the carcinomas of the thyroid gland, but it is also the one with the best prognosis.  At the present, diagnosis is best done by fine needle aspiration, and treatment by surgical resection.  With recent advances in molecular and cellular biology, diagnosis and therapy in the future may depend on micromolecular technologies.  The prognosis is promising for increased success in the treatment of papillary carcinoma.

REFERENCES

 1. Rossi RL, Nieroda C, Cady B, Wool MS. Malignancies of the thyroid gland: the Lahey Clinic experience. Surg Clin North Am 1985; 65: 211 - 230.

2. Block BL, Spiegel JC, Chami RG. The treatment of papillary and follicular carcinoma of the thyroid. Otolaryngol Clin North Am 1990; 23: 403 - 411.

3. Clark OH, Duh QY. Thyroid cancer. Med Clin North Am 1991; 75: 211 - 234.

4. Robbins J, Merino MJ, Boice JD Jr, Ron E, Ain KB, Alexander HR, Norton JA, Reynolds J. Thyroid cancer: a lethal endocrine neoplasm. Ann Int Med 1991; 115: 133 - 147.

5. Brooks JR, Starnes HF, Brooks DC, Pelkey JN. Surgical therapy for thyroid carcinoma: a review of 1249 solitary thyroid nodules. Surgery 1988; 104: 940 - 946.

6. Carcangiu ML, Zampi G, Pupi A, Castagnoli A, Rosai J. Papillary carcinoma of the thyroid: a clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer 1985; 55: 805 - 828.

7. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986; 61: 978 - 996.

8. Norton JA, Doppman JL, Jensen RT. Cancer of the endocrine system. In DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 3rd edition. Philadelphia: JB Lippincott, 1989: 1269 - 1344.

9. Simpson WJ. Radioiodine and radiotherapy in the management of thyroid cancers. Otolaryngol Clin North AM 1990; 23: 509 - 521.

10. Baxter JD. Advances in molecular biology: potential impact on diagnosis and treatment of disorders of the thyroid. Med Clin North Am 1991; 75: 41 - 59.

11. Karga H, Lee JK, Vickery AL Jr, Thor A, Gaz RD, Jameson JL. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73: 832 - 836.

12. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary carcinoma. J Clin Endocrinol Metab 1990; 71: 414 - 424.

13. Grant CS, Hay ID, Gough IR, Bergstralh EJ, Goellner JR, McConahey WM. Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 1988; 104: 954 - 962.

14. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988; 104: 947 - 953.

15. Beahrs OH, Henson DE, Hutter RVP, Myers MH, editors. Manual for Staging Cancer. 3rd edition, Philadelphia: JB Lippincott, 1988: 57 - 59.

16. Hedinger C, Williams ED, Sobin LH. Histological typing of thyroid tumours. 2nd edition. No. 11 in: International Histological Classification of Tumours, World Health Organization. Berlin: Springer-Verlag, 1988.

17. Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 1989; 63: 908 - 911.

18. Hamby LS, McGrath PC, Scwartz RW, Sloan DA, Simpson WG, Kenady DE. Management of local recurrence in well-differentiated thyroid carcinoma. J Surg Research 1992; 52: 113 - 117.