Thyroid cancer

Abstract

We attempted to determine if women younger than 45 years of age who have isolated papillary thyroid cancer and whose tumors are smaller than 4 cm (T2N0M0) are at low risk for mortality and morbidity following thyroid lobectomy. To this end, we analyzed information on both women and men obtained from our review of the literature, and we integrated it with data compiled in the Delaware Cancer Registry. We performed a secondary analysis to determine if the risk of death and recurrence can be predicted on the basis of age, tumor size, sex, histology, and the type of operation. We found that among patients who had undergone either thyroid lobectomy or total thyroidectomy, mortality rates were 1.3% for those younger than 45 years of age and 15.6% for those 45 years and older (p<0.0001). With respect to tumor size, patients whose masses were smaller than 4 cm had significantly lower mortality (3.0%) and recurrence (11.1%) rates than did those whose tumors were 4 cm or larger (16.8 and 33.3%, respectively; p<0.0001). Other significant risk factors for death were male sex and the presence of follicular thyroid cancer (as opposed to papillary thyroid cancer). The risk of permanent hypocalcemia was significant among patients who had undergone total thyroidectomy, but not among those who had been treated with lobectomy. The subgroup of patients who had the lowest risk of mortality and morbidity was made up of women younger than 45 years who had a papillary thyroid tumor smaller than 4 cm that was limited to one lobe and who had undergone lobectomy. On the other hand, we found that lobectomy might carry a higher risk of recurrence (from a micrometastasis in the cervical lymph node) than does total thyroidectomy. Experienced surgeons whose rates of hypocalcemia and recurrent laryngeal nerve paralysis following total thyroidectomy are low offer their patients the unambiguous advantage of superior follow-up with thyroglobulin and radioactive iodine.

Introduction

Total thyroidectomy for papillary and follicular thyroid cancer is recommended for patients who are 45 years or older and for those who have large tumors, bilateral disease, and cervical or distant metastasis or other extrathyroidal spread. Conversely, few surgeons would argue that thyroid lobectomy is appropriate for patients younger than 45 years who have a tumor smaller than 1 cm (T1N0M0) that is limited clinically to one lobe. We set out to determine whether women younger than 45 years who have a papillary thyroid cancer smaller than 4 cm (T2N0M0) can be treated with thyroid lobectomy and experience low mortality and morbidity rates.

No prospective, randomized study has compared survival after total thyroidectomy, subtotal thyroidectomy, and thyroid lobectomy. Such an investigation would require decades of study and data accumulation. Because thyroid cancer deaths can occur decades after diagnosis, follow-up periods of 15 to 25 years are often necessary. (1,2) In conducting our study, we integrated data compiled in the Delaware Cancer Registry with information obtained through our own historical literature review. We analyzed mortality and recurrence rates as a function of age, tumor size, sex, histology, and the type of operation. We also determined the incidence of hypocalcemia and recurrent laryngeal nerve dysfunction according to the type of operation.

The literature is made up of widely divergent types of reports. (3,4) Narrative literature reviews describe series of studies, all of which have their particular strengths and weaknesses, that are discussed selectively and informally by one or more experts. A primary analysis contains original data, and a secondary analysis--such as the one we performed--contains a re-examination of previously published data. A meta-analysis is a statistical study of a collection of data obtained from many individual studies. Meta-analyses and quantitative retrospective analyses emphasize numbers over narrative, and they have greater statistical power than do other types of studies. Although meta-analyses are most useful when they include randomized, controlled trials, they have been used selectively in the otolaryngology literature to evaluate retrospective studies. (5)

Authors of numerous articles on differentiated thyroid cancer that appear in the endocrine and general surgery literature have advocated the use of total thyroidectomy, subtotal thyroidectomy, or lobectomy, depending on patient characteristics that predict survival and recurrence. However, the myriad classification systems in use make cross-comparisons difficult. In conducting searches of several databases covering the period from 1966 through 1998, we failed to find any meta-analysis or historical literature review that included data on all eight selected aspects of differentiated thyroid cancer that we wished to study; these eight aspects are mortality, recurrence, complications, age, tumor size, sex, histology, and type of operation.

In this article, we report our analysis of data obtained from published articles in which the authors advocated lobectomy (defined as lobectomy or thyroid isthmusectomy), subtotal thyroidectomy, or total thyroidectomy (either total or near-total) for differentiated thyroid carcinoma as well as data obtained from articles in which the authors took no stance on a preferred treatment. Discussions of prognostic factors and their influence on the management of differentiated thyroid cancer are sparse in the otolaryngology-head and neck surgery literature. Our analysis is unique in that no other article on prognostic factors in differentiated thyroid cancer included integrated data sets obtained from multiple studies and a state cancer registry.

Materials and methods

We conducted a MEDLINE search for English-language articles dealing with differentiated thyroid cancer that had been published from 1966 through 1998. We also performed manual cross-checks, including perusal of articles listed in textbook bibliographies, in symposium publications, in Current Contents, and in review articles. Finally, we searched MEDLINE, HealthStar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CancerLit, and Current Contents from 1966 through 1998 using thyroid neoplasm and meta-analysis as controlled vocabulary, and we did not find any systematic review of prognostic factors in differentiated thyroid neoplasms.

In all, we reviewed abstracts of 231 articles. Inclusion criteria included retrospective studies (no prospective studies exist) on death, recurrence, and morbidity in differentiated thyroid cancer. We excluded studies that contained data from a single institution that had already been published in another article (and, therefore, had already been accounted for) and studies in which data were presented only in graph form, making extraction of actual whole numbers impossible. All usable data were extracted by the primary author (R.L.W.) and a research assistant (A.M.M.); we relied on interobserver agreement to reduce error and achieve consistency. We ultimately reviewed data contained in the "Materials" sections of 56 studies, and from these we selected 19 studies (6-24) for our analysis.

The selection of these 19 studies was not based on results, country of origin, or the type of operation advocated, if any. Nine of these studies were from North America, five from Asia, four from Europe, and one from Israel. For the treatment of selected differentiated thyroid carcinomas, thyroid lobectomy was favored in eight studies, (6,8-12,17,22) total thyroidectomy was advocated in seven, (7,13,16,18,20,21,23) and no preference was expressed in four. (14,15,19,24) Most studies included data obtained during more than 1 decade; nine studies included data from the 1990s, 12 included data from the 1980s, 17 from the 1970s, 13 from the 1960s, nine from the 1950s, and two from the 1940s. Six studies had been published from 1995 through 1998, five from 1990 through 1994, four from 1985 through 1989, and four from 1980 through 1984. Nine studies contained information on the mean length of follow-up (mean: 12.4 yr), six specified only a range of follow-up, and four did not mention the length of follow-up. The ave rage publication date of those studies in which lobectomy was advocated was 1988, and the average date of those in which total thyroidectomy was favored was 1992.

Our historical literature review was performed to examine the rates of death and recurrence in patients with differentiated thyroid tumors and to compare outcomes according to five parameters: (1) patients younger than 45 years vs patients 45 years and older, (2) tumors smaller than 4 cm vs tumors 4 cm and larger, (3) men vs women, (4) papillary vs follicular histology, and (5) thyroid lobectomy and subtotal thyroidectomy vs total thyroidectomy. We also made a three-way comparison of the incidence of permanent hypocalcemia and recurrent laryngeal nerve dysfunction in patients who had undergone lobectomy, subtotal thyroidectomy, and total thyroidectomy.

We also reviewed data published by Brierley et al, (25) who studied 10 different staging systems for predicting outcomes and found that none was significantly superior to the TNM classification system used by the American Joint Committee on Cancer and the International Union Against Cancer. Also, several studies have suggested that age is the single most important variable for survival. (17,22) Therefore, we selected age and tumor size as study parameters. We handled variations in others' reporting of age and tumor size in two ways: (1) when sources classified patients as either younger or older than 50 years, we excluded from our analysis all those who were younger; (2) when sources categorized tumor sizes as either smaller or larger than 5 cm, we excluded all that were smaller.

Finally, we conducted a retrospective review of data compiled from 1988 through 1997 in the Delaware Cancer Registry and integrated them into our quantitative retrospective literature analysis. Two independent bio-statisticians reviewed our data.

Results

Age. The mortality rate among patients younger than 45 years who had either papillary or follicular thyroid carcinoma (regardless of tumor size) was 1.3%; the rate for patients 45 years and older was 15.6%--a statistically significant difference (p<0.0001) (table 1). Recurrence rates in the two age groups were not significantly different.

Tumor size. Among patients whose tumors were smaller than 4 cm (regardless of age), the mortality rate was 3.0% and the recurrence rate was 11.1% (table 2). Among those whose tumors were 4 cm or larger, the corresponding rates were 16.8 and 33.3%. The differences in both mortality and recurrence rates between the two groups were statistically significant (p<0.0001).

Sex. Female sex was a significant factor in a lower risk of death (mortality: 5.6% among women and 8.4% among men; p = 0.01), but not in recurrence (table 3).

Histology. Patients with papillary thyroid cancer had a significantly lower mortality rate than did those with follicular cancer--4.4 and 12.7%, respectively (p<0.0001) (table 4). However, those who had follicular cancer had a significantly lower rate of recurrence--6.4 and 12.9%, respectively (p = 0.02).

Type of operation. Regardless of age and tumor size, the mortality rate among patients who had undergone total thyroidectomy (4.7%) was significantly lower (p = 0.002) than the combined rate among those who had undergone either subtotal thyroidectomy or lobectomy (8.1%) (table 5). There was no significant difference between the two groups with respect to recurrence rates.

Hypocalcemia. The rates of permanent hypocalcemia were 6.4% following total thyroidectomy (during the 1990s), 1.9% following subtotal thyroidectomy, and 0% following lobectomy (table 6). All three differences were statistically significant (p<0.0001). (From the 1980s to the 1990s, the rate of permanent hypocalcemia following total thyroidectomy fell from 27.4 to 6.4%, and we used the latter figure for our comparison.)

Laryngeal dysfunction. We found no significant differences in the rates of recurrent laryngeal dysfunction among those who underwent total thyroidectomy, subtotal thyroidectomy, and lobectomy (table 7).

Discussion

We attempted to answer the question, Is thyroid lobectomy adequate for treating papillary thyroid cancer in women younger than 45 years of age whose tumors are smaller than 4 cm, are clinically limited to one lobe, and have not exhibited any cervical or distant metastasis or other extrathyroidal spread (T2N0M0)? We conclude that it is. Both mortality and recurrence rates were low in this group of patients.

The case for total thyroidectomy. Authors have proposed many reasons why total thyroidectomy should be performed as a treatment for differentiated thyroid carcinoma:

* Patients with clinically unilateral papillary malignancies have high rates of "multicentricity" and microscopic cancer in the opposite lobe. (8,16,26)

* Radioactive iodine scanning can be used to diagnose and treat any residual thyroid carcinoma and metastasis.

* Total thyroidectomy lowers the risk of recurrence. (8,16,26)

* Serum thyroglobulin levels can be measured during follow-up to screen for recurrent or metastatic disease in patients with well-differentiated cancer.

* Total thyroidectomy carries a low risk of causing hypoparathyroidism and recurrent laryngeal nerve injury. (16)

* The administration of high-dose radioactive iodine to ablate normal thyroid remnants can lead to sialadenitis, pulmonary fibrosis, and leukemia. (27)

* Total thyroidectomy eliminates the possibility of anaplastic transformation of the residual thyroid gland. (28)

* Total thyroidectomy alleviates patient anxiety, particularly with respect to recurrence and the need for additional surgery.

The case against total thyroidectomy. Other authors have challenged the appropriateness of total thyroidectomy for several reasons:

* The risk of permanent hypoparathyroidism can lead to fatigue, paresthesias, and irritability. (9)

* At best, contralateral recurrent laryngeal nerve damage can result in a breathy voice (unilateral recurrent laryngeal dysfunction); at worst, it can lead to airway obstruction (bilateral recurrent laryngeal nerve dysfunction).

* Among patients who undergo lobectomy for grossly unilateral papillary carcinoma, there is a lack of evidence that the high incidence of microscopic foci in the opposite lobe increases the risk of clinical recurrence. (6,8) Tollefsen et al reported that in papillary cancer, the rate of occult carcinoma in the contralateral lobe was 38%, (29) a rate eight times greater than the incidence of clinically recurrent carcinoma in the opposite lobe following initial lobectomy. This finding suggests that the presence of microscopic foci in differentiated thyroid cancer does not mean development of clinically significant cancer.

* When all macroscopic disease has been removed during initial lobectomy, the need for remnant resection of recurrence is infrequent. (30)

* In young patients with papillary carcinoma of the thyroid, most cases of recurrence are attributable to regional lymph node flare-ups. Even delayed resection is not associated with an increase in the risk of death in these patients, a fact illustrated by the lack of mortality associated with palpable lymph node metastases, either at the initial evaluation or during follow-up. (31)

* The risk of toxicity from ablative radioiodine is low. (32)

* Anaplastic transformation of papillary thyroid carcinoma is rare (1/17,000 patients). (9)

* Many patients are classified as members of clinically low-risk groups that have high survival rates.

Predicting outcomes. Many scoring systems have been devised in an effort to predict outcomes based on patient and tumor characteristics other than age alone:

* Hay et al wrote that the four most important prognostic factors are age, tumor grade, extrathyroidal extension, and tumor size (AGES). (10)

* Cady and Rossi found that grade is difficult to classify because of variations in pathologic interpretations, and they suggested an alternative to AGES: age, distant metastasis, extrathyroidal extension, and tumor size (AMES). (12)

* Other scoring systems include the Ohio State University classification, (18) the EORTC (European Organisation for Research and Treatment of Cancer) system, (33) the age-related TNM system, (34) the MACIS (metastasis, age, completeness of resection, invasion, and size) classification from the Mayo Clinic, (35) the clinical class system devised by DeGroot et al, (36) the MSK (Memorial Sloan-Kettering) system, (37) the Noguchi system from Japan, (38) and the SAG (size, age, grade) system from Norway. (39)

The use of so many varied classification systems complicates the process of data comparison. The adoption of a uniform system would accelerate our understanding of prognostic factors.

The choice of surgical procedure. The decision as to which type of surgery to perform is sometimes clear and sometimes not:

* Total thyroidectomy is nearly universally recommended for high-risk patients.

* Thyroid lobectomy, the least drastic surgical alternative for treating differentiated thyroid malignancy, is a well-accepted choice for low-risk patients--that is, younger patients (<45 yr) whose tumors are smaller than 1 cm (T1N0M0). Among these low-risk patients, both Hay et al (40) and Mazzaferri (41) found that there was little difference in mortality rates between those who underwent total thyroidectomy and those who underwent lobectomy.

* There is no clear-cut choice for patients who are younger than 45 years who have tumors that are grossly limited to one lobe and between 1 and 4 cm in size (T2N0M0) and who have experienced no cervical or distant metastasis or extrathyroidal spread.

* Partial thyroidectomy for any type of thyroid cancer should not be considered. (22)

Recurrence. Reported data on the risk of recurrence following lobectomy and total thyroidectomy are conflicting. Hay et al (40) and Mazzaferri (41) reported that low risk patients who underwent total thyroidectomy had lower recurrence rates than did those who underwent lobectomy. However, Shaha et al (22) and Sanders and Cady (42) found no significant difference in recurrence rates among low-risk patients. Hay et al (40) and Sanders and Cady (42) reached conflicting conclusions despite the fact that they used the same classification system (AMES).

In conclusion, women younger than 45 years who have a papillary thyroid cancer smaller than 4cm that is limited clinically to one lobe and who have no nodal or distant metastasis or other extrathyroidal spread are considered to be at low risk for mortality and morbidity with thyroid lobectomy. Total thyroidectomy, in the hands of an experienced surgeon whose postsurgical rates of hypocalcemia and recurrent laryngeal nerve paralysis are low, provides women with T2N0M0 papillary thyroid cancer a potentially lower incidence of recurrence. An unambiguous advantage of total thyroidectomy is that it allows for precise follow-up with thyroglobulin and radioactive iodine scanning. Every patient's case is unique, of course, so therapeutic decisions should be made in consultation with the patient's endocrinologist, internist, or family physician.

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From the Department of Surgery, Christiana Care Health System, Wilmington, Del.

Originally presented at the Southern Section meeting of the Triologic Society; St. Petersburg, Fla.: Jan. 14-15, 2000.

Reprint requests: Robert L. Witt, MD, 2401 Pennsylvania Ave., Suite 112, Wilmington, DE 19806. Phone (302) 888-1980; fax: (302) 888-1982; e-mail: RobertLWitt@aol.com

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