Annals of Surgical Oncology

, 15:2287

Incidental and Nonincidental Papillary Thyroid Microcarcinoma

Authors

    • Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial HospitalChang Gung University
  • Sheng-Fong Kuo
    • Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial HospitalChang Gung University
  • Tzu-Chieh Chao
    • Department of General Surgery, Chang Gung Memorial HospitalChang Gung University
  • Chuen Hsueh
    • Department of Pathology, Chang Gung Memorial HospitalChang Gung University
Endocrine Tumors

DOI: 10.1245/s10434-008-9958-2

Cite this article as:
Lin, J., Kuo, S., Chao, T. et al. Ann Surg Oncol (2008) 15: 2287. doi:10.1245/s10434-008-9958-2

Abstract

Background

Subtotal thyroidectomy or lobectomy without radioactive iodide (131I) treatment is sufficient for postoperative treatment of incidental papillary thyroid microcarcinoma (PTMC). Aggressive surgical treatment with 131I therapy is indicated for nonincidental PTMC.

Methods

This is a retrospective analysis of 335 PTMC patients who received primary thyroid surgical treatment and long-term follow-up in a single medical center. All PTMC patients were categorized as incidental (group I) or nonincidental (group II). Group II patients (209 cases) were categorized as intrathyroid (group II A), neck lymph node or local regional soft-tissue invasion (group II B) and distant metastasis (group II C) groups.

Results

In group I, 105 of 126 cases received only subtotal thyroidectomy or lobectomy. None died of thyroid cancer. Histological evaluation revealed multicentric PTMC in 12 (9.5%) and 52 (24.9%) cases (P < 0.05) in groups I and II, respectively. In group II, 55 of the 209 patients (26.3%) presented with extrathyroidal involvement. Two cases of relapse occurred in group I and 20 in group II by the end of follow-up. One patient in group II B and two patients in group II C died of thyroid cancer. Nine out of ten patients in group II C were diagnosed with distant metastases before primary thyroid surgical treatment.

Conclusion

Subtotal thyroidectomy is effective surgical treatment for incidental PTMC. For nonincidental cases, aggressive treatment is essential for reducing the risk of cancer relapse or mortality following surgery.

Keywords

Nearly total thyroidectomyThyroglobulinMulticentric131I treatmentFollicular variant of papillary thyroid carcinoma

Increased incidence of papillary thyroid microcarcinoma (PTMC) is a major cause of the increasing incidence of thyroid cancer in developed countries.1,2 Identifying indolent PTMC or invasive PTMC during operation and postoperative follow-up period is essential. Incidental PTMC is defined as a postsurgical diagnosis of microcarcinoma with benign clinical course.3 To date, lack of long-term follow-up data has precluded comparison of incidental and nonincidental PTMC. Such information is critical for determining the effectiveness of less aggressive surgical procedures and postoperative radioactive iodide (131I) ablation for certain groups of PTMC patients. The goals of this study were to test the hypothesis that less aggressive surgical treatments such as lobectomy or subtotal thyroidectomy are adequate procedures for incidental PTMC and whether total thyroidectomy followed by 131I ablation therapy is effective for nonincidental PTMC. Further, this study elucidated clinical manifestations of incidental and nonincidental PTMC as well as prognostic factors in both groups.

Patients and Methods

From 1977 to 2006, 1,676 papillary thyroid carcinoma patients underwent surgical treatment and were followed up at Chang Gung Medical Center in Linkou, Taiwan. Among them, 335 cases were PTMC defined as papillary thyroid cancer no larger than 1.0 cm (≤1 cm) according to measurement at final histopathology. All patients received primary thyroid surgical treatment and long-term clinical follow-up at this medical center. During the operation, frozen sections from 235 patients were evaluated by pathologists. Initially, each specimen was assessed macroscopically to select the most significant nodules, to identify the most invasive tumors, and to plan the dissection of the surgical sample. Intraoperative frozen section examination was performed on the cut surface of the thyroid nodules including the interface between the nodule and adjacent thyroid tissue. Two or three frozen sections were regularly performed depending on the size of the nodules. Near-total or total thyroidectomy with unilateral selective neck dissection, including level II–IV and VI lymph nodes, was performed in patients with concurrent neck lymphadenopathy. Patients with PTMC whose malignancy was confirmed by frozen section underwent a near-total or total thyroidectomy. Near-total thyroidectomy was defined as total lobectomy in the lobe with the dominant nodule, with isthmectomy and near-total lobectomy on the contralateral side leaving approximately 2 g of thyroid tissue, adjacent parathyroid glands, and blood supply. Those with PTMC in the absence of extrathyroid invasion diagnosed by postoperative permanent section underwent follow-up if they had initially received subtotal thyroidectomy. Subtotal thyroidectomy was defined as removing more than 50% of the entire gland on both lobes. Forty-one cases received secondary thyroid operations for total thyroidectomy after histologically confirmed PTMC.

Following the operation, most patients underwent long-term thyroid hormone replacement or suppressive treatment. Cancer assessments involved a 2–5 mCi 131I whole-body scan and chest X-ray. Serum thyroglobulin (Tg) levels were assessed every 6–12 months. Postoperative serum Tg levels were detected by an immunoradiometric (IRMA) kit (CIS Bio International, France). After detecting metastatic or recurrent lesions surgery, external radiotherapy or 131I therapy was recommended. Persistent disease was defined as patients with cancer tissue that persisted after surgery or other adjuvant therapy. This group included patients with distant metastases detected by 131I whole-body scan within 1 year after the thyroid operation. Recurrence was defined as patients with recurrent cancer 1 year after primary thyroid surgery and 131I therapy.

All thyroid carcinomas were classified according to the World Health Organization (WHO) criteria.4 The study excluded patients that received initial surgical treatment elsewhere. Tumors were staged using International Union against Cancer (UICC) tumor–node–metastasis (TNM) criteria (6th edition).5 All PTMC cases were categorized as group I (incidental) or group II (nonincidental). Incidental PTMC was defined as cases of PTMC diagnosed in final histopathology of the thyroid surgery. Patients in this group had received thyroid operations due to other benign thyroid nodules or hyperthyroidism. Nonincidental PTMC was defined as thyroid carcinoma diagnosed before thyroid surgery or during surgery in frozen section. Group II cases were further categorized as II A (intrathyroid), II B (neck lymph node or local regional soft-tissue invasion) or II C (M1 in TNM staging).

The following data were extracted from admission recorded for analysis: age, gender, primary tumor size, ultrasonographic findings, fine-needle aspiration cytology (FNAC) results, thyroid function before operation, operative methods, histopathology, TNM staging, 1-month postoperative serum Tg levels, results of diagnostic and therapeutic 131I scans, postoperative chest X-ray findings, clinical status for analysis of distant metastases by noninvasive examinations, treatment results, cause of death, and survival status. Actuarial relapse-free survival rates were calculated by the Kaplan–Meier method and differences in survival rates were examined by Breslow and Mantel–Cox tests. Statistical significance was set at a P value of 0.05 or below.

Results

Of the 1,676 papillary thyroid carcinoma patients who had received regular follow-up, 335 (20.0%) were diagnosed as PTMC. Statistical analysis of PTMC patients with tumors larger than 1.0 cm revealed that this group had a higher percentage of females, a lower rate of diagnosis by FNAC, a shorter follow-up period, and a lower cancer mortality rate (Table 1). In contrast, age, percentage of patients receiving secondary thyroid surgery, and postoperative Tg levels did not statistically differ between these two groups. After a mean follow-up period of 8.7 ± 0.2 years, 4.1% (55/1,341 cases) of patients with larger tumor had died of thyroid cancer. Only three (0.9%) patients in the PTMC group had died of thyroid cancer (P < 0.05). Of the 335 PTMC, there were 22 cases (6.6%) with postoperative relapse diagnosed. This ratio was lower than in the larger tumor group.
Table 1

Clinical features of papillary microcarcinoma and larger papillary carcinoma

 

Microcarcinoma (N = 335)

Larger tumor (N = 1,341)

P value

Age (years)

43.0 ± 12.7

41.9 ± 14.5

0.1913

Female/male (ratio)

284/51 (5.6)

1,068/273 (3.9)

0.0333

FNAC (benign/follicular neoplasm/ malignancy)

139/55/72

140/280/801

0.0001

Frozen section (benign/deferred/malignancy)

47/13/175

52/39/1,133

0.0001

Total or near-total thyroidectomy

191 (57.0%)

1,238 (92.3%)

0.0001

Thyroid reoperation

41 (12.2%)

193 (14.4%)

0.3090

Multicentric

64 (19.1%)

225 (16.8%)

0.3134

Tg levela (ng/mL)

40.9 ± 15.4

58.9 ± 7.1

0.2710

Follow-up period (years)

7.6 ± 0.3

8.7 ± 0.2

0.0012

Total mortality

11 (3.3%)

99 (7.4%)

0.0067

Thyroid-cancer-specific mortality

3 (0.9%)

55 (4.1%)

0.0041

Postsurgical relapseb

22 (6.6%)

165 (12.3%)

0.0001

FNAC, fine-needle aspiration cytology.

a Tg level: 4–6 weeks postoperative thyroglobulin level without thyroxin therapy.

b Postsurgical relapse: including persistent and recurrent cases.

Of the 335 PTMC patients, there were 126 cases in group I and 209 cases in group II (Table 2). Group I had a higher percentage of females than group II (female/male: 9.5 versus 4.4). Figure 1 illustrates the age, gender, and percentage distribution of 335 PTMC patients in different groups. Because the patients in group II were diagnosed before or during surgery, a higher fraction of cases had received near-total or total thyroidectomy than in group I. Histological examination showed that group II tended to have a larger tumor size (I/II: 4.5 ± 0.2 mm versus 6.8 ± 0.2 mm) and higher multicentric ratio of papillary thyroid carcinoma than group I. Otherwise, calculation cases of total thyroidectomy in group I and II illustrated multicentric percentage in both groups are 28.6% (6/21 cases) and 28.2% (48/170 cases), respectively. No statistical difference of multicentric ratio was noted between group I and II received total thyroidectomy. In group I, 49.2% (62/126 cases) of the cases were diagnosed as hyperthyroidism at the time of surgery. This percentage was higher than that in group II (10.5%). There were 19 cases diagnosed as follicular neoplasm and one case diagnosed as malignancy in group I by FNAC. All the 20 cases were proved as benign nodules. In final histopathological examination, PMTC was detected in other thyroid part. Of the group I cases, local-regional neck recurrence was detected in two patients, at 2.9 and 2.2 years after their first thyroid operation (Table 2). Both cases underwent redo surgery to remove the neck recurrence followed by 131I therapy. Both were relapse free by the end of follow-up. After 7.9 years of follow-up, three cases had died of thyroid cancer, and 20 cases in group II were relapsed.
Table 2

Presentations of papillary thyroid microcarcinoma in incidental (I) and non-incidental (II) groups

 

Group I (N = 126)

Group II (N = 209)

P value

Age (years)

42.3 ± 13.3

43.4 ± 12.4

0.5128

Female/male (ratio)

114/12 (9.5)

170/39 (4.4)

0.0241

Hyperthyroidism

62 {49.2%)

22 (10.5%)

0.0001

FNAC (benign/follicular neoplasm /malignancy)

65/19/1

74/36/71

0.0001

Frozen (benign/deferred/ malignancy)

44/0/0

3/13/175

0.0001

Total or near-total thyroidectomy

21 (16.7%)

170 (81.3%)

0.0001

Thyroid reoperation

18 (14.3%)

23 (11.0%)

0.3748

Post-op. 1 month Tga (ng/mL)

33.5 ± 9.5

45.1 ± 23.0

0.7165

Tumor size (cm)

0.45 ± 0.02

0.68 ± 0.02

0.0001

Multicentric

12 (9.5%)

52 (24.9%)

0.0005

Follow-up period (years)

7.1 ± 0.4

7.9 ± 0.3

0.1371

Total mortality

3 (2.4%)

8 (3.8%)

0.5453

Thyroid-cancer-specific mortality

0 (0%)

3 (1.4%)

0.2939

Postsurgical relapseb

2 (1.6%)

20 (9.6%)

0.0043

FNAC, fine-needle aspiration cytology.

a Tg level: 4–6 weeks postoperative thyroglobulin level.

b Postsurgical relapse: including persistent and recurrent cases.

https://static-content.springer.com/image/art%3A10.1245%2Fs10434-008-9958-2/MediaObjects/10434_2008_9958_Fig1_HTML.gif
Fig. 1

Age and gender distribution of 1,676 papillary thyroid carcinoma patients with tumors larger than 1 cm and 335 microcarcinomas.

Clinical features of three subgroups of nonincidental PTMC are illustrated in Table 3. Of the 154 cases in group II A, two had local lymph node recurrence 3.3 and 9 years after primary thyroid operation, respectively. At the end of follow-up, both of these cases were relapse free after secondary surgery. Forty-five cases in group II B were diagnosed with extrathyroid extension with or without lymph node metastases (12 cases) or regional lymph node metastases only (33 cases). Before operation, 30 cases had neck lymph node enlargement detected by physical examination or imaging studies. Mean age of patients in group II A and B was not statistically different. In contrast, lower female to male ratio, higher postoperative Tg levels without thyroxin therapy, and higher relapse rate were illustrated in group II B patients (Table 3). One patient in group II B died of thyroid cancer.
Table 3

Presentations of papillary thyroid microcarcinoma in three groups

 

Group II-A (N = 154)

Group II-B (N = 45)

Group II-C (N = 10)

P value

Age (years)

43.9 ± 12.0

41.7 ± 11.9

57.3 ± 12.7

b,c

Female/male (ratio)

136/18 (7.6)

29/16 (1.8)

5/5 (1.0)

a,b

FNAC (benign/follicular neoplasm/malignant)

58/29/53

12/7/16

4/0/2

> 0.05

Hyperthyroidism

18 (11.7%)

4 (8.9%)

0 (0%)

> 0.05

Frozen (benign/deferred/malignancy)

1/12/136

2/0/36

0/1/3

a,c

Total or near-total thyroidectomy

118 (76.6%)

43 (95.6%)

9 (90%)

a

Thyroid reoperation

8 (5.2%)

11 (24.4%)

4 (40%)

a,b

Multicentric

33 (21.4%)

15 (33.3%)

4 (40%)

> 0.05

Tumor size (mm)

6.6 ± 0.2

7.0 ± 0.4

7.7 ± 0.7

> 0.05

Post-op. 1 month Tga (ng/mL)

11.1 ± 12.9

31.0 ± 15.5

9,576 ± 59,27

a,b,c

Follow-up period (year)

7.8 ± 0.4

8.4 ± 0.7

7.1 ± 2.3

> 0.05

Total mortality

4 (2.6%)

2 (4.4%)

2 (20%)

b

Thyroid-cancer-specific mortality

0 (0%)

1 (2.2%)

2 (20%)

b

Postsurgical relapseb

2 (1.3%)

9 (20%)

9 (90%)

a,b,c

FNAC, fine-needle aspiration cytology.

a Tg level: 4–6 weeks post-operative thyroglobulin level.

b Postsurgical relapse: including persistent and recurrent cases.

a: Group II A versus group II B, P < 0.05.

b: Group II A versus group II C, P < 0.05.

c: Group II B versus group II C, P < 0.05.

Ten cases of PTMC with distant metastases in group II C had tumors from 0.5 to 1.0 cm in size (Table 3). Distant metastases were diagnosed before PTMC in primary tissue in nine of these ten cases. Another case was diagnosed as mediastinal and lung metastases by 131I after total thyroidectomy. This 38-year-old female presented with neck lymph node metastasis and PTMC. After 490 mCi 131I therapy, the patient had achieved relapse-free status by the end of follow-up. Among group II C, four cases presented with follicular variant of papillary thyroid carcinoma. This ratio is higher than in groups II A (7 cases) and B (2 cases). In comparison with other group II subgroups, group II C underwent aggressive surgical procedures and received therapy with the highest 131I accumulating dose. After a mean of 7.1 ± 2.3 years of follow-up, two had died of thyroid cancer, and seven had survival in non-disease-free status. Further, 40% of cases in group II C exhibited multicentric pattern (Table 3).

Discussion

Previous studies indicate that, depending on the detection method used, 2–22% of autopsies reported the incidental discovery of papillary thyroid carcinoma.69 In addition, in several autopsy studies, no gender differences were found. In our study, the percentage of females with PTMC was higher than that for females with larger tumor. Furthermore, the percentage of females with PTMC was higher in the incidental group than in the nonincidental group. Gender distribution in PTMC is different from autopsy series.

Tumor size and diagnostic method used for discovery determines if PTMC is overt, occult, incidental or nonincidental.3,6 The reported ratio of postoperatively diagnosed incidental PTMC to total PTMC varies according to differences in diagnostic procedures and facilities. Nonincidental PTMC may be diagnosed during ultrasound with FNAC for other benign thyroid disorders or during carotid artery ultrasonography.10 Several of the nonincidental PTMC patients in group II B were diagnosed during surgery by the presence of lymph node involvement, extrathyroid extension or frozen section. In 70.1% (235/335 cases) of subjects with PTMC in our study, frozen section was performed during thyroid operation. Although the cost effectiveness of frozen section remains controversial, diagnosis of PTMC by perithyroid soft-tissue involvement using frozen section during surgery is the most common determinant of surgical intervention.11

Several of our patients with PTMC presented with neck lymph node metastases. The enlarged lymph node may be diagnosed before or during surgery. Group II B in our study included patients with lymph node metastases with or without perithyroid soft-tissue invasion. All cases with perithyroid soft-tissue invasion were staged T4 in accordance with the TNM classification system (6th edition).5

Three (0.9%) cancer-specific mortalities from PTMC occurred in our study. Two presented with distant metastases and another with neck lymph node metastases. In contrast to a recent study of 317 cases12 which described a recurrence rate of 2.2% for PTMC, our study showed a slightly lower recurrence rate of 1.6% for incidental PTMC. For nonincidental PTMC, 9.6% (20/209 cases) demonstrated postoperative residual tumor or recurrence.

Most of the surgically treated cases at our hospital received preoperative thyroid ultrasound examination, which can preoperatively screen high-risk cases of PTMC. In an earlier study, total thyroidectomy was suggested for patients with PTMC due to other multifocal cancer, invasive pathological patterns, family history or radiation exposure.1315 Preoperative thyroid ultrasonography is often used with FNAC and is effective for early detection of nonincidental PTMC with extrathyroid extension. In our study, mortality in incidental PTMC cases was not cancer specific, and the relapse rate was very low even without further surgery. Stratification of PTMC patients reveals that patients with poorer prognosis tend to have larger tumors, a higher frequency of multicentricity in histology, and a lower frequency of surgery due to hyperthyroidism.

Multicentric PTMC was noted in 24.9% of the patients in the nonincidental group. In a recent report, multicentric PTMC did not statistically differ between intrathyroid nonincidental and local regional invasion groups.16 A Toronto series reported no statistical difference between PTMC and larger tumors in multifocal cases.17 Cases of nonincidental PTMC presenting with distant metastases usually have a much higher incidence of multifocal lesions and a high mortality rate.1820 Conversely, if distant metastases are detected by 131I scan after thyroid surgery, prognosis is improved.3 Local regional lymph node involvement is not uncommon in PTMC. Due to the poorer prognosis of these patients, most studies recommend aggressive surgical and postoperative 131I therapy.21,22

A high ratio of the follicular variant of papillary thyroid carcinoma (40%) in group II C was noted in our investigation. The clinical presentation and prognosis of the follicular variant papillary thyroid carcinoma is reportedly less aggressive than the classic papillary thyroid carcinoma.23,24 Few studies have examined PTMC with follicular variant. Recent studies conclude that the BRAF V600E mutation is associated with high-risk papillary thyroid cancer, particularly the follicular variant with invasive tumor growth,25 however, more data is needed for a definitive conclusion.

This retrospective study has some limitations. Preoperative ultrasound with FNAC and frozen section was not performed in all cases. In addition, of the 335 cases, only 191 cases underwent total or near-total thyroidectomy, therefore, the number of multicentric PTMC cases may actually be higher. For those patients who underwent subtotal thyroidectomy, recurrence may be difficult to identify by postoperative follow-up and evaluation with serum Tg levels and diagnostic and therapeutic 131I scans. A prospective study with long-term follow-up is needed for detailed analysis of these important issues.

Conclusion

The prognosis of incidental PTMC is generally excellent. Most cases do not require further surgical or adjuvant 131I therapy. However, aggressive surgery and postoperative adjuvant treatment is indicated for nonincidental PTMC patients presenting with distant metastases or local or regional invasion. Clinical course and therapeutic strategies for nonincidental PTMC patients depends on TNM stage at time of diagnosis.

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© Society of Surgical Oncology 2008