Seminars in Surgical Oncology 7:81-86 (1991)
Papillary Carcinoma of the Thyroid BLAKE CADY, MD From the New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts
The clinical behavior and mortality rate of papillary carcinoma of the thyroid varies widely, and clinically insignificant microscopic foci of the disease are frequently found. Dietary iodine and radiation to the head and neck in childhood play a role in etiology. Needle aspiration cytology provides a highly accurate diagnosis. Ultrasound, radioactive iodine, and technetium scans are not specific and should only be used to complete diagnostic studies when aspiration cytology is negative for papillary carcinoma. The most important aspect of prognosis of an individual patient with papillary carcinoma of the thyroid is the age at which the disease is diagnosed, with an excellent prognosis, even in advanced primary disease or extensive lymph node involvement, in children and young adults. A multifactorial clinical risk group definition (AMES) is easy to use and reliably separates patients into low risk and high risk. Since 90% of patients with this disease rarely have metastases or late complications from the cancer, total or subtotal thyroidectomy is necessary in only 10% of cases for later use of postoperative radioactive iodine. More conservative surgical procedures are advised in low-risk patients. Papillary carcinoma incidentally found during operation for other conditions such as Graves disease or thyroiditis and reported first on the permanent pathology reports are always clinically insignificant and completely cured by removal; total thyroidectomy should be completely avoided. Postoperatively, thyroid hormone supplementation may be unnecessary after relatively conservative surgery in selected low-risk patients. Thyroid hormone must be maintained permanently after total or subtotal thyroidectomy. KEY WORDS:epidemiology, prognostic factors, operative and postoperative management, radioactive iodine scans, thyroglobulin
INTRODUCTION Papillary carcinoma of the thyroid has posed an enigma for the clinician in decision making; its clinical behavior and mortality rate based on age vanes widely, and clinically insignificant microscopic foci of the disease frequently occur. It has been difficult to understand the biological behavior and clinical evolution of individual cases in the past; over the past decade, numerous articles [ 1,2] have depicted the basic prognostic indicators for papillary carcinoma of the thyroid and reemphasized the clinical insignificance of microscopic forms, even small clinical masses of the disease, particularly in young people. The number of people at high risk from recurrence, metastases, and death from papillary carci0 1991 Wiley-Liss, Inc.
noma of the thyroid can be quite precisely defined [ 1,3]. At the same time, however, as more accurate prognostic indicators have been developed, there has been a general movement in the surgical endocrine and surgical oncologic communities to emphasize more radical surgery This trend toward more radical local surroutinely [4,5]. gery has occurred despite the markedly improved clinical presentation in recent years with smaller primaries, better survival, and fewer recurrences from even conservative surgical procedures [ 6 ] .It is important to understand some of the basic biologic data and clinical behavior of thyroid cancer and the subtleties of the prognostic indiAddress reprint requests to Blake Cady, M.D., 110 Francis Street, Boston, MA 02215.
82
Cady
cators to arrive at the most logical, practical, and safest surgical approach to the disease. The epidemiology of papillary carcinoma of the thyroid is not clearly understood, and the relative proportion of papillary carcinoma and follicular carcinoma varies throughout the world, apparently as a function of the basic iodine content of the diet [7]. As iodine deficiency occurs, the percentage of follicular carcinoma increases, and in societies where basic iodine supplementation has occurred or there is natural iodine in sufficient quantities, papillary carcinomas is the predominant type. The reasons for this varied pathology are not clearly established. Radiation therapy, even in very small doses anywhere in the head and neck area, has been found to be associated with later development of carcinoma of the thyroid [8] as well as with tumors of the salivary and parathyroid glands in long-term follow-up studies. Radiation therapy of the thymus gland and for acne of the face has ceased since 1960. As a result, we no longer see patients with a past history of low-dose radiation therapy during infancy and childhood. However, in patients who did have such radiation in childhood, the incidence of subsequent thyroid anatomic abnormalities such as masses and cold areas by radioactive scan and clinical palpation has been high [9]. When such thyroid glands are removed, a high proportion, perhaps 30%, will be found to harbor papillary carcinoma; more often than not, such a papillary carcinoma is a microscopic focus, not part of the palpable mass but in other thyroid tissue [lo]. With more recent extensive use of radiation therapy in the treatment of Hodgkins disease, subsequent papillary carcinomas of the thyroid are seen less frequently because the patients are older [ 11]. The developing thyroid gland is more subject to radiation genetic damage, a phenomena seen in radiation of breast and other tissues, and radiation after adulthood does not carry the high risk of later carcinoma. While it has been felt in the past that TSH stimulation of the thyroid gland has been one of the etiologic factors in the development of papillary carcinoma, it is difficult to prove in humans; patients are euthyroid, TSH values are not elevated, and rates vary by race in the same geographic area [ 12,133. However some animal models demonstrate a relationship between exogenous TSH administration or endogenous TSH elevation and increased incidence of papillary carcinoma of the thyroid.
HISTOLOGY The term papillary carcinoma of the thyroid is utilized for carcinomas that have any papillary elements whatsoever, in contra-distinction to pure follicular carcinoma. It has been shown in a variety of reports that whatever the proportion of papillary elements in the cancer the bio-
logic behavior is identical [ 14,151 and clinical behavior differs from that of pure follicular carcinoma. Pathologically, papillary carcinoma may be marked by calcium deposits (psammonma bodies), evidence of desmoplastic reaction, multiple foci of disease, and frequent lymph node metastases. When routine lymph node dissections are performed in papillary thyroid carcinoma in young adults, in 75% or more lymph node metastases will be detected [ 14-16]. Distant metastases in papillary carcinoma of the thyroid are uncommon, are usually pulmonary, and may rarely occur in bone, liver, and brain [ 171. In contrast, follicular carcinoma seldom has lymph node metastases, is rarely multifocal, does not have calcification or desmoplastic reaction, and metastasizes more commonly to bones and liver as well as to lung [ 14-16].
CLINICAL PRESENTATION The clinical presentation of papillary carcinoma of the thyroid is almost always as a mass in the neck, either the primary lesion in the thyroid gland itself or frequently in young people as a metastatic lymph node palpable in the ipsilateral neck even at some distance from the thyroid gland itself. At least 25% of young adult patients and children will present with the lymph node as the first evidence of disease [ 141. While most of these patients on further diagnostic workup will be found to have a palpable or at least a detectable mass in the thyroid gland by radioactive scan, a proportion of such patients will have a small clinical focus in the thyroid lobe that will be discovered only at the time of surgical thyroidectomy . Only on very rare occasions will a papillary carcinoma of the thyroid present with a metastastic lesion other than a cervical lymph node. The appearance of lymph node metastases in the cervical area of young people with papillary carcinoma of the thyroid is common enough that whenever abnormally large lymph nodes in the cervical area appear, the possibility of papillary carcinoma of the thyroid must be kept in mind. These lymph nodes are usually softer and smaller than those of Hodgkins disease and of metastatic lymph nodes from squamous cell carcinomas of the upper aero-digestive tract.
PROGNOSTIC FACTORS The principal prognostic factor in papillary carcinoma of the thyroid is the age of the patient at clinical appearance of the disease [ 181. Prognosis in children and young adults, even with relatively advanced primary disease of the thyroid or bulky lymph node metastases, approaches 100% curability [17-201. In the 1930s, 40s, and 50s, the prognosis of such patients was less satisfactory; since 1960 the curability of papillary cancer has steadily increased so that it is very uncommon today for a younger
Papillary Carcinoma of the Thyroid
patient to die of disease even with long follow-up [20]. Uniquely in human cancers, lymph node metastases in papillary cancer of the thyroid have no bearing on overall prognosis [21]. Patients of younger ages, even with bulky and frequent lymph node metastases, have a prognosis that is not different from those who have negative lymph nodes [ 171. The prime determinant of prognosis within the older age group in papillary carcinoma is the extent of the primary carcinoma [3,21]. Thus, papillary carcinoma that invades outside the thyroid gland and into surrounding structures in older patients has a dire prognosis, but nowadays such a presentation occurs infrequently [6]. Large size indicates poor prognosis in older patients, but this has no impact or prognosis in younger patients (211. As evidence of the predominant prognostic effect of age that supersedes size or local disease extent in papillary carcinoma, we have reported that the cure rate of patients who had gross residual disease at the conclusion of surgery but were of young age was over 90%, whereas such patients in older age groups almost uniformly die of disease [18]. In addition, in old patients, pulmonary metastases from papillary carcinoma of the thyroid are highly lethal [17,18] in contrast to young patients. Recent attempts to increase prognostic accuracy in patients with papillary thyroid carcinoma have utilized flow-cytometry, which may have some correlation with outcome [ 17,221. That relationship, however, may not be as strong as such clinical features as age and extent of disease. Tables I and I1 illustrate data from our reports that correlate outcome with age and with a more recent expanded version of the risk group definition, (AMESAge, Metastases, Extent, and Size). Almost 90% of
83
cases fit into the expanded low-risk group definition, where less than 2% of patients will ever die of disease. The other 11% of the patients in the high-risk prognostic category have a death rate of almost 50%. Our prognostic categories apply to both papillary and follicular carcinomas, but the Mayo Clinic similarly developed a prognostic scale (AGES) for papillary carcinomas with exactly the same results (Table 111). Thus, the most important aspect of analysis of an individual patient with papillary carcinoma is the age at which the disease is discovered and diagnosed. Virtually no patient will die of disease if male, 40 or less, or female, 50 or less. As a matter of fact, recent articles indicate that in childhood papillary carcinomas of the thyroid few if any of these patients will die of disease, despite sometimes rather advanced clinical presentation [ 17,20,23]. Other clinical prognostic indicators are the size and extent of the primary cancer and the presence of distant metastases.
DIAGNOSIS Patients presenting with cervical lymph node metastases can almost always be diagnosed by needle aspiration of the lymph node itself. The cytologic appearance of aspirates of metastatic papillary carcinoma in lymph nodes is so characteristic that the diagnosis is highly accurate. If patients present with a mass in the thyroid itself, needle aspiration biopsy is the most accurate preoperative test that can be performed [24]. Again, needle aspirate cytology of papillary carcinoma is so characteristic that the preoperative diagnosis is almost always obtained in clinical nodules. Reports that cite low accuracy include cases where the palpable nodule was benign, but
TABLE I. Differentiated Thyroid Carcinoma: Lahey Clinic Foundation, 1961-1980, 310 Patients; Risk Group Definitions Total cases Incidence Feature Pathology type Papillary Follicular Size < 5 cm > 5 cm Extent of primary cancer Intraglandular or minor capsular Extraglandular or major capsular Age Younger Older Combination “AMES” Low risk High risk
Dead of disease Death rate # Cases (%)
# Cases
(”/.I
234 16
74 26
13 7
297 13
96 4
15 5
250
81
4
60
19
16
21
194 116
63 37
2 18
16
279 33
89 11
5 15
46
5.6 9 5 39 1.5
1
1.8
Ratio of death rates 1:1.6 1:8
1:17
1:16
1:26
84
Cady
TABLE 11. Differentiated Thyroid Carcinoma: Lahey Clinic Foundation, 1941-1980, 821 Patients; Changes in Combination Risk Group “AMES” Total cases
Recurrence
Incidence 1941-1950 Low risk High risk 195 1-1 960 Low risk High risk 196 1-1980 Low risk High risk
Dead of disease
(%I
# Cases
157 41
79 21
25 24
16 59
13 25
8.3 61
1.7
255 58
82 19
14 36
6 62
8
3.1 57
1:18
33
277 33
89 11
14 18
5 55
5 15
1.8 46
1:26
# Cases
Death rate (a)
Ratio of death rates
# Cases
Recurrence rate (a)
TABLE 111. Comparison of Risk Group Definitions Total cases Incidence #
(lo)
Dead of disease Death rate #
(%)
Ratio of death rates
Mayo Clinic, papillary carcinoma “AGES” (19461970) Low risk Hiah risk
737 121
“AMES” (1961-1980) Low risk High risk
277 33
86 14 Lahey Clinic, papillary and follicular carcinoma 89 11
with an adjacent small focus of incidental papillary carcinoma. In these cases, there may be “false negative” aspirates, but that is a misinterpretation of the clinical situation [25]. Thyroid function tests have no role in the diagnosis of papillary carcinoma or any other thyroid carcinoma. They should not be performed as part of the process of evaluating nodules suspected of being carcinoma. Anatomic tests of the thyroid gland include ultrasound, radioactive iodine, and technetium scans. Lesions that are solid by echogram, cold or cool by radioactive iodine scan, and cold by technetium scan have a higher likelihood of being carcinoma. However, these tests are not specific, and since needle biopsy in papillary lesions is highly accurate and quite specific, more recent approaches to the diagnosis of masses of the thyroid emphasize immediate thyroid needle biopsy before the performance of thyroid function tests or anatomic studies such as ultrasound or radioactive scans of the thyroid gland. If aspiration cytology is negative for papillary carcinoma, and does not show microfollicular patterns indicating the need for surgery, functional and anatomic studies should be performed to complete diagnostic studies.
5 15
2 46
1:23
1.8 46
1:26
A simple chest X-ray is sufficient for detecting clinically apparent pulmonary metastases. If the chest X-ray is normal, radioactive diagnostic scans in the presence of an intact thyroid gland are not useful. Searches for distal metastases otherwise are without value in papillary carcinoma of the thyroid preoperatively. However if specific symptoms, such as bone pain, etc., occur, specific X-rays can be ordered.
OPERATIVE APPROACH Once the diagnosis has been established by needle aspiration or suspicious clinical presentation, the basic surgical approach should be exposure of the entire thyroid gland with removal of the thyroid lobe which contains the palpable mass or the suspected primary site in patients who present with a palpable cervical lymph node metastasis but inapparent primary cancer. A total or subtotal lobectomy on the ipsilateral side should be performed to include the isthmus also. The contralateral lobe of the thyroid should be palpated meticulously at the time of the surgical exposure. If a nodule is felt on the opposite lobe of the thyroid, it should be removed also since multifocal papillary carcinoma is common. Small
Papillary Carcinoma of the Thyroid
papillary carcinomas of the thyroid near the periphery of the gland or at the upper pole can easily be overlooked in preoperative anatomic localization scans. While numerous articles in the recent surgical literature advocate total thyroidectomy as the primary treatment of papillary carcinoma or even benign lesions of the thyroid, there is absolutely no evidence that such procedures increase the likelihood of cure in a disease that has such an excellent outcome [26-301. We have noted no advantage of total thyroid removal in terms of recurrence or control of local neck disease [21]. Since the prognosis of papillary carcinoma is so excellent in younger people, they will seldom, if ever, need radioactive iodine scans or therapy postoperatively. Therefore, the contralateral lobe of the thyroid gland does not need to be removed routinely for efficiency in the use of radioactive iodine postoperatively. However, in patients who are over the age of 45 or 50, who have extrathyroidal extension of the papillary carcinoma or bulky disease with a primary cancer over 5 cm in diameter, the contralateral lobe should be removed either totally or subtotally for the later use of radioactive iodine in detection and treatment of local recurrences and metastatic papillary carcinoma [30]. Since 90% of patients are in the good prognosis group and rarely have metastasis or late complications of the cancer, such a contralateral total or subtotal thyroid lobectomy is necessary in only 10% of cases. The major problems with total thyroidectomy as a treatment for this disease is that permanent hypoparathyroidism occurs with great frequency [20] even in experienced surgical hands [ 1,231 and is a devastating disease in young healthy people with a normal life span. For instance, the Mayo Clinic reports an incidence of permanent hypoparathyroidism of over 20% in total thyroidectomy in children and up to 30% in some situations [ 11, and Memorial Hospital reports higher rates of permanent hypoparathyroidism when total thyroidectomy is performed [23]. Foster’s collective series found that the overall rate of permanent hypoparathyroidism across the country when total thyroidectomy was attempted was about 20% [301. When more conservative surgical procedures are undertaken, the incidence of permanent hypoparathyroidism is essentially zero [27,29]. Long-term complications from the management of permanent hypoparathyroidism are severe, and this complication should be completely avoided by adopting a policy of conservative primary surgery of papillary carcinoma whenever it is in the good prognostic group. Patients in the poor prognostic group who have nearly a 50% risk of death may benefit from a bilateral surgical approach to the thyroid gland that avoids total thyroidectomy and will frequently need radioactive iodine therapy. Contralateral thyroid lobectomy should certainly be considered, but is not essential.
85
When operations are undertaken for thyroid masses or for other conditions such as Graves disease or thyroiditis, and papillary carcinoma is neither suspected nor discovered on frozen section, but reported on permanent pathological reports, the cancers are always clinically insignificant. The surgeon should review the actual tissue slides with the pathologist and have a complete understanding of the lesion. Such incidental or very small cancers are completely cured by their removal; no further surgery should be performed, and completion of a total thyroidectomy should be completely avoided.
POSTOPERATIVE MANAGEMENT It has been customary since the late 1950s to administer thyroid hormone in doses sufficient to suppress endogenous TSH hormone in all patients with papillary carcinoma of the thyroid postoperatively. Such a recommendation continues as standard policy today, yet lowrisk thyroid carcinoma carries essentially no mortality. In patients with microscopic or small cancers even at older ages, routine administration of thyroid hormone is not necessary. Keep in mind the enormous number of incidental cancers discovered at autopsy or calculated to be present in our population [ 141. If patients have had relatively conservative surgery and have a residual thyroid lobe, enough thyroid tissue remains so that homeostasis can be maintained without administration of exogenous thyroid hormone. However, if bilateral total or subtotal thyroidectomy has been performed, the patient is compelled to maintain thyroid hormone administration permanently. Other postoperative management decisions regard the use of radioactive iodine (RAI) scans for the diagnosis of occult metastatic disease. Such RAI scans will not be successful in the presence of any normal thyroid gland. Thus, if radioactive iodine is to be used for detection of metastases, the residual thyroid gland has to be either removed surgically or destroyed radiotherapeutically by RAI before administering diagnostic RAI for the detection and treatment of metastatic disease. Since the occurrence of distant metastatic disease in young patients with papillary carcinoma is uncommon and seldom causes death, such RAI diagnostic scans should be performed and metastases treated if discovered. However, only a minority of metastatic papillary carcinoma in older patients will take up enough RAI to be successfully treated by this unique and specific tumor-seeking radioactive therapy. Thyroglobulin as a tumor marker has been utilized in following patients after initial surgery, but can only be accurate in the complete absence of normal thyroid tissue. Whether early detection of clinically occult metastatic disease is advantageous has not yet been proven, although it is theoretically attractive. Low-risk patients
86
Cady
seldom have metastases, and when discovered clinically, usually are of no clinical significance (cervical lymph nodes metastases) or can be treated successfully by RAI for pulmonary metastases. High-risk patients have an extremely poor prognosis if distant metastases appear at any stage, occult or clinical, and have over a 95% mortality rate even if apparently taking up RAI.
REFERENCES 1. Hay ID, Grant CS, Taylor WF, McConaley WM: Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a nova1 prognostic scoring system. Surgery 102:1088-1094, 1987. 2. Carcangiu ML, Zampi G , Castagnoli A, et al.: Papillary carcinoma of the thyroid: A clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer 55:805-827, 1985. 3. Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947-953, 1988. 4. Clark 0: Total thyroidectomy. The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 3:366-370, 1982. 5 . Harness JF, Fung L, Thompson NW, Burney RE, et al.: Total thyroidectomy: Complications and technique. World I Surg 10:781-786, 1986. 6. Cady B, Rossi R, Silverman M. Wool M: Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 98:1171-1178, 1985. 7. Belfiore A, LaRosa GL, Padova A, Sava L, et al.: The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine deficient area. Cancer 60:3096-3102, 1987. 8. Fjalling M, Tisell L-E, Carlsson S , Hansson GL, et al.: Benign and malignant thyroid nodules after neck irradiation. Cancer 58~1291-1224, 1986. 9. Spitalnik PF, Straus FH:Patterns of human thyroid parenchymal reaction following low-dose childhood irradiation. Cancer 41:1098-1105, 1978. 10. Cerletty JM, Guansing AR, Engbring NH, Hagen TC, et al.: Radiation-related thyroid carcinoma. Arch Surg 1 13:1072-1076, 1978. 1 I . McHenry C, Jarosz H, Calendra D, McCall A, et al.: Thyroid neoplasia following radiation therapy for Hodgkins’s lymphoma. Arch Surg 122:68&686, 1987. 12. Sambade MC, Goncalves VS, Dias M, Sobrinho-Simoes MA: High relative frequency of thyroid papillary carcinoma in northern Portugal. Cancer 51:1754-1759, 1983. 13. Goodman MT, Yoshizawa CN, Kolonel LN: Descriptive epidemiology of thyroid cancer in Hawaii. Cancer 61:1272-1281, 1988.
14. Cady B, Sedgwick CE, Meissner WA, Bookwalter JR, et al.: Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Ann Surg 184:541-553, 1976. 15. Donohue JH, Goldfien SD, Miller TR, Abele JS, et al.: Do the prognoses of papillary and follicular thyroid carcinomas differ? Am J Surg 148:16&173, 1984. 16. Noguchi S, Noguchi A, Murakami N: Papillary carcinoma of the thyroid. 1. Developing pattern of metastasis. Cancer. 26: 105% 1060, 1970. 17. Zimmerman D, Hay ID, Gough IR,Goellner JR, et al.: Papillary thyroid carcinoma in children and adults: Long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 104:1157-1166, 1988. 18. Rossi RL, Cady B, Silverman ML, Wool MS, et al.: Surgically incurable well-differentiated thyroid carcinoma. Prognostic factors and results of therapy. Arch Surg 123:569-574, 1988. 19. Buckwalter JA, Thomas CG, Freeman JB: Is childhood thyroid cancer a lethal disease? Ann Surg 181:632-639, 1975. 20. Ceccarelli C, Pacini F, Lippi F, Elisei R, et al.: Thyroid cancer in children and adolescents. Surgery 1143-1 148, 1988. 21. Cady B, Rossi R , Silverman M, Wool MS, et al.: Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 98:1171-1178, 1988. 22. Komorowski RA, Deaconson TF, Vetsch R , Cerletty JM, et al.: DNA content in radiation-associated thyroid cancer. Surgery 104:992-996, 1988. 23. LaQuaglia MP, Corbally MT, Heller G, Exelby PR, et al.: Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1149-1 156, 1988. 24. Grant C: Long-term follow up of patients with thyroid FNA cytology. Surgery (in press). 25. Hall TL, Layfield LJ, Philippe A, Rosenthal DL: Source of diagnostic error in fine needle aspiration of the thyroid. Cancer 64:71%725, 1989. 26. Schroder DM, Chambors A, France CJ: Operative strategy for thyroid cancer. Is total thyroidectomy worth the price? Cancer 58:2320-2328, 1986. 27. Hoie J , Stenwig AE, Brennhovd 10: Surgery in papillary thyroid carcinoma: A review of 730 patients. J Surg Oncol 37:147-151. 1988. 28. Brooks JR, Stranes HF, Brooks DC, Pilkey JN: Surgical therapy for thyroid carcinoma: A review of 1249 solitary thyroid nodules. Surgery 104940-945. 1988. 29. Grant C, Hay ID, Gough IR, Bergstralh ET, et al.: Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 104:954-962, 1988. 30. Foster RS: Morbidity after thyroidectomy. Surg Gynecol Obstet 146:423429, 1978. 31. Cady B, Cohn K , Rossi RL, Sedgwick CE, et al.: The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 94:978-983, 1983.