2024 Volume 71 Issue 4 Pages 357-362
In papillary thyroid carcinoma (PTC) patients with mediastinal lymph nodes (LN) and lung metastases, adding preoperative computed tomography (CT) to ultrasound is useful for planning surgery. We identified risk factors (RFs) for mediastinal lymph node metastasis (MLNM) and lung metastasis in PTC patients. Frequencies of MLNM and lung metastases were compared in 478 patients. Relative risk (RR) was calculated based on RFs. MLNM and lung metastases were detected in 1.2% and 3.3% of patients, respectively. cT3-4, cN1, central LN metastasis, and lateral LN metastasis were RFs for MLNM in all patients (p < 0.05, p < 0.05, p < 0.05, p < 0.01) and older patients (age: ≥55 years) (p < 0.01, p < 0.05, p < 0.05, p < 0.05). cT3-4, cN1, gross extrathyroidal extension, central LN metastasis, and lateral LN metastasis were RFs for lung metastasis in all patients (p < 0.01, p < 0.05, p < 0.01, p < 0.01, p < 0.01, respectively). cN1 and gross extrathyroidal extension, central LN metastasis, and lateral LN metastasis were RFs in older patients (p < 0.01, p < 0.01, p < 0.05, p < 0.01), while lateral LN metastasis was an RF for lung metastasis in those of <55 years of age (younger patients) (p < 0.05). No MLNM was observed in cT1-2cN0 PTC patients, who accounted for 50.5% of patients included in the MLNM analysis. No lung metastasis was present in cT1-2cN0 PTC patients, who accounted for 50.5% of the patients included in the lung metastasis analysis. PTC patients with cT3-4 and cN1 have an increased risk of MLNM and lung metastasis. RFs differed between older and younger patients. Preoperative neck and chest CT are not necessary for PTC patients with ultrasound-diagnosed as cT1-2cN0.
UNDER VARIOUS GUIDELINES, ultrasound (US) is strongly recommended for the preoperative evaluation of papillary thyroid cancer (PTC) [1-8]. However, it is difficult to assess distant metastasis or lymph node (LN) metastasis in the mediastinum or retro- and para- pharyngeal regions by US, although these findings are essential for deciding the extent of the operation.
To compensate for this disadvantage, combining computed tomography (CT) is recommended in some (but not all) advanced cases [1-7, 9]. The sensitivity for cervical LN metastasis of PTC improved from 51% to 69% with the addition of CT to US, but the specificity did not change [10]. According to analyses by the LN compartments, the benefit of CT is 13.1% for the patient, 8.9% for the central compartment, 21.3% for the lateral compartment, and 50.0% for the retropharyngeal/superior mediastinal compartment [11]. However, the quality of evidence supporting this recommendation is low, and no report has defined “advance cases.”
The present study identified the patients with PTC who can be expected to benefit from preoperative CT. We focused on cases with metastasis to the lung and mediastinal LNs. Since 2009, preoperative CT was performed for most patients in our institution. The characteristics of patients with lung and mediastinal LN metastasis were analyzed to identify clues for selecting patients who require preoperative CT and those who can avoid it.
We retrospectively reviewed the medical records of 478 patients who underwent preoperative CT and US during the initial operation for PTC at Tokyo Women’s Medical University from 2009 to 2017. Cases of CT performed in other institutes or PTC that could not be detected by US (cT0 or cTx) were excluded. Finally, 428 cases of neck CT and 420 cases of chest CT were included (Fig. 1). The thicknesses of the slices ranged from 0.5 to 5 mm. Neck CT was performed at least down to the level of the innominate vein to assess the invasion of the primary tumor and LN metastasis including the cervical and mediastinal areas. Contrast enhancement was observed in 321 patients (Fig. 1). LN metastasis was diagnosed by US if the LN showed the following findings: minor axis >1 cm, iso- to high-echoic level, or presence of calcification or cystic change. US was performed, and diagnosis was made by endocrine surgeons. LN metastasis was diagnosed using neck CT if LNs showed the following findings: minor axis >1 cm, presence of calcification or cystic changes, or positive enhancement. Mediastinal LN metastasis was defined as LN metastasis in the mediastinum recognized on neck CT and not US.
Inclusion and exclusion criteria
Mediastinal LN and lung metastases were diagnosed by radiologists using neck and chest CT scans. Postoperative radioactive iodine scintigraphy was used as the reference if performed.
Patients were divided into two groups according to age (<55 or ≥55 years), sex (male or female), primary tumor and LN metastasis evaluated by the 8th edition of the UICC TNM classification (cT1-2 or cT3-T4, cN0 or cN1), multifocality (unifocal or multifocal), gross extrathyroidal extension (presence of invasion of the recurrent laryngeal nerve, trachea, or esophagus), and LN metastasis in the central or the lateral region determined by US. Following the 8th edition of the UICC TNM classification, the analysis was performed separately for patients of <55 years and ≥55 years of age. The number of clinical LN metastases diagnosed by US was compared between groups with and without mediastinal LN metastasis and lung metastasis. Statistical analyses of the differences between the two groups were performed using Student’s t-test or the χ2 test. P-values of <0.05 were considered to indicate statistical significance. Relative risk was calculated to estimate the risk of mediastinal LN metastasis and lung metastasis. The JMP PRO software program, ver. 14.0.0 (SAS Institute, Cary, NC, USA), was used for the analyses. The institutional review board of Tokyo Women’s Medical University approved this clinical study (reference number: 4740) which was completed in accordance with the Declaration of Helsinki as revised in 2013.
There were 239 patients <55 years of age (younger group) and 190 patients of ≥55 years of age (older group). There were no marked differences in sex, multifocality, cN, LN metastasis in the central or lateral region, or operative procedure between the age groups. Gross extrathyroidal extension was more frequent in older patients than in younger patients (p = 0.01). The distribution of cT differed between the groups (p = 0.04).
Patient characteristics
| All patients n = 429 |
Age <55 years n = 239 |
Age ≥55 years n = 190 |
p value | |
|---|---|---|---|---|
| Median age, years (range) | 51 (15–89) | 40 (15–54) | 66 (55–89) | — |
| Female/Male | 291/138 | 167/72 | 124/66 | N.S. |
| cT1/cT2/cT3/cT4 | 228/135/56/11 | 121/80/37/2 | 107/55/19/9 | 0.04 |
| Stage I/II/III/IVA/IVB | 333/81/7/0/8 | 233/6/—/—/— | 100/75/7/0/8 | — |
| Unifocal/Multifocal | 338/91 | 194/45 | 144/46 | N.S. |
| Gross extrathyroidal extension (–)/(+) | 418/11 | 237/2 | 181/9 | 0.01 |
| cN0/cN1a/cN1b | 248/28/153 | 138/14/87 | 110/14/66 | N.S. |
| Central LN metastasis (–)/(+) | 320/109 | 177/62 | 143/47 | N.S. |
| Lateral LN metastasis (–)/(+) | 276/153 | 152/87 | 124/66 | N.S. |
| Operative procedure | ||||
| Total thyroidectomy Yes/No | 219/210 | 119/120 | 100/90 | N.S. |
| LN dissection Central/Central + Lateral | 232/197 | 127/112 | 105/85 | N.S. |
LN: lymph node, N.S.: not significant
Mediastinal LN metastasis was found on neck CT in 5 patients (1.2%): 1 younger patient (0.4%) and 4 older patients (2.1%). All but one patient required opening of the mediastinum to remove the LNs. Older patients had mediastinal LN metastasis more frequently (2.1%) than younger patients (0.4%), albeit without statistical significance. Preoperative cT3-4, cN1, central LN metastasis, and lateral LN metastasis were risk factors (RFs) of mediastinal LN metastasis, (p = 0.03, p = 0.01, p = 0.02, p < 0.01, respectively). All four factors were also RFs among older patients (p < 0.01, p = 0.03, p = 0.048, p = 0.01, respectively) but not for younger patients (Table 2). The relative risk for mediastinal LN metastasis in patients with cT3-4 and cN1 was 16.8 (95% confidence interval [CI]: 2.9–97.5). The relative risk for mediastinal LN metastasis was 28.7 (95% CI: 3.1–261.4) for older patients (Table 3). The mean numbers of preoperative LN metastases diagnosed by US in total and in the lateral region were significantly higher in patients with mediastinal LN metastasis than those without mediastinal LN metastasis (mean ± standard deviation (SD): 5.80 ± 3.96 and 1.72 ± 2.99, p < 0.01, 4.60 ± 3.91 and 1.17 ± 2.19, p < 0.01, respectively). The mean number of preoperative LN metastases by US diagnosed in the central region was not significantly higher in patients with mediastinal LN metastasis than those without mediastinal LN metastasis (mean ± SD): 1.20 ± 1.64 and 0.55 ± 1.27, p = 0.26. None of the patients without any risk factors, that is cT1-2cN0 patients had mediastinal LN metastasis. cT1-2cN0 patients accounted for 216 (50.5%) of all patients, 116 (48.7%) of younger patients, and 100 (52.6%) of older patients.
Frequency of mediastinal LN metastasis
| All patients n = 428 |
p value | Age <55 years n = 238 |
p value | Age ≥55 years n = 190 |
p value | |
|---|---|---|---|---|---|---|
| Age <55 years | 1/238 (0.4%) | |||||
| Age ≥55 years | 4/190 (2.1%) | N.S. | ||||
| Female | 2/291 (0.7%) | 0/167 (0%) | 1/124 (1.6%) | |||
| Male | 3/137 (2.2%) | N.S. | 1/71 (1.4%) | N.S. | 2/66 (3.0%) | N.S. |
| cT1-2 | 2/362 (0.6%) | 1/200 (0.5%) | 1/162 (0.6%) | |||
| cT3-4 | 3/66 (4.6%) | 0.03 | 0/38 (0%) | N.S. | 3/28 (10.7%) | <0.01 |
| Unifocal | 4/337 (1.2%) | 1/193 (0.5%) | 3/144 (2.8%) | |||
| Multifocal | 1/91 (1.1%) | N.S. | 0/45 (0%) | N.S. | 1/46 (2.2%) | N.S. |
| Gross extrathyroidal extension (–) | 5/417 (1.2%) | 1/236 (0.4%) | 4/181 (2.8%) | |||
| Gross extrathyroidal extension (+) | 0/11 (0%) | N.S. | 0/2 (0%) | N.S. | 0/9 (0%) | N.S. |
| cN0 | 0/247 (0%) | 0/137 (0%) | 0/110 (0%) | |||
| cN1 | 5/181 (2.8%) | 0.01 | 1/101 (1.0%) | N.S. | 4/80 (6.1%) | 0.03 |
| Central LN metastasis (–) | 1/319 (0.31%) | 0/176 (0%) | 1/143 (0.7%) | |||
| Central LN metastasis (+) | 4/109 (3.7%) | 0.02 | 1/62 (1.61%) | N.S. | 3/47 (6.38%) | 0.048 |
| Lateral LN metastasis (–) | 0/286 (0%) | 0/152 (0%) | 0/124 (0%) | |||
| Lateral LN metastasis (+) | 5/142 (3.5%) | <0.01 | 1/86 (1.2%) | N.S. | 4/66 (6.1%) | 0.01 |
LN: lymph node, N.S.: not significant
Relative risk of mediastinal LN metastasis
| Mediastinal LN metastasis | Relative risk (95% confidence interval) | |
|---|---|---|
| All patients | ||
| cT3-4 and cN1 | 3/35 (8.6%) | |
| other | 2/393 (0.5%) | 16.8 (2.9–97.5) |
| Age <55 years | ||
| cT3-4 and cN1 | 0/17 (0%) | |
| other | 1/221 (0.5%) | 0 |
| Age ≥55 years | ||
| cT3-4 and c N1 | 3/18 (16.7%) | |
| other | 1/172 (0.6%) | 28.7 (3.1–261.4) |
LN: lymph node
Lung metastasis was found by chest CT in 14 patients (3.3%), including 6 younger patients (2.6%) and 8 older patients (4.3%). Abnormal findings were found in 133 patients (31.7%). Lung cancer was found in 3 patients (0.7%), and 130 (31.0%) other diseases that did not require treatment such as benign lung nodules, thymoma, mediastinal cyst, benign breast tumor, benign liver tumor, adrenal tumor, and aneurysm were found by chest CT incidentally. None of the lung nodules diagnosed as benign before the operation turned out to be malignant during follow-up (median: 57.6 [range: 0.1–138.5] months). Preoperative cT3-4, gross extrathyroidal extension, cN1, and LN metastasis in the central or lateral region were RFs of lung metastasis (p < 0.01, p = 0.048, p < 0.01, p < 0.01, p < 0.01, respectively) (Table 4). Among the younger patients, LN metastasis in the central region was an RF (p = 0.04) (Table 4). Among the older patients, gross extrathyroidal extension, cN1, and LN metastasis in the central or lateral region were RFs of lung metastasis (p < 0.01, p < 0.01, p = 0.02, p < 0.01, respectively) (Table 4). The relative risk for lung metastasis if the patient had cT3-4 and cN1 was 4.4 (95% CI: 1.5–13.3) (Table 5). The relative risk of lung metastasis if the patient had cT3-4 and cN1 in younger patients was 2.6 (95% CI: 0.3–20.6) (Table 5), and that in older patients was 5.6 (95% CI: 1.5–21.5) (Table 5). The total number of preoperative LN metastases diagnosed by US for patients with lung metastasis was significantly higher than those without lung metastasis, mean ± SD: 6.21 ± 5.06, and 1.61 ± 2.81, p < 0.01. The numbers of preoperative LN metastases diagnosed by US in the central and the lateral region for patients with lung metastasis were also significantly higher than those without lung metastasis, mean ± SD: 2.00 ± 2.63 and 0.50 ± 1.17, p < 0.01, and 4.21 ± 3.87 and 1.11 ± 2.09, p < 0.01, respectively. None of the patients without any risk factors, that is cT1-2cN0 patients had lung metastasis. cT1-2cN0 patients accounted for 212 (50.5%) of all patients. 115 (49.1%) of younger patients, and 97 (52.2%) of older patients.
Frequency of lung metastasis
| All patients n = 420 |
p value | Age <55 years n = 234 |
p value | Age ≥55 years n = 186 |
p value | |
|---|---|---|---|---|---|---|
| Age <55 years | 6/234 (2.6%) | |||||
| Age ≥55 years | 8/186 (4.3%) | N.S. | ||||
| Female | 9/285 (3.2%) | 6/164 (3.7%) | 3/121 (2.5%) | |||
| Male | 5/135 (3.7%) | N.S. | 0/70 (0%) | N.S. | 5/65 (7.7%) | N.S. |
| cT1-2 | 8/355 (2.3%) | 3/197 (1.5%) | 5/158 (3.2%) | |||
| cT3-4 | 6/65 (9.2%) | <0.01 | 3/37 (8.1%) | 0.05 | 3/28 (10.7%) | N.S. |
| Unifocal | 12/331 (3.6%) | 5/190 (2.6%) | 7/141 (5.0%) | |||
| Multifocal | 2/89 (2.3%) | N.S. | 1/44 (2.3%) | N.S. | 1/45 (2.2%) | N.S. |
| Gross extrathyroidal extension (–) | 12/409 (2.9%) | 5/226 (2.6%) | 6/177 (3.4%) | |||
| Gross extrathyroidal extension (+) | 2/11 (18.2%) | 0.048 | 0/2 (0%) | N.S. | 2/9 (22.2%) | <0.01 |
| cN0 | 2/242 (0.8%) | 2/135 (1.5%) | 0/107 (0%) | |||
| cN1 | 12/178 (6.7%) | <0.01 | 4/99 (4.0%) | N.S. | 8/79 (10.1%) | <0.01 |
| Central LN metastasis (–) | 5/313 (1.6%) | 2/172 (1.2%) | 3/140 (2.14%) | |||
| Central LN metastasis (+) | 9/107 (8.41%) | <0.01 | 4/61 (6.6%) | 0.04 | 5/46 (10.9%) | 0.02 |
| Lateral LN metastasis (–) | 3/269 (1.12%) | 2/149 (1.3%) | 1/120 (0.8%) | |||
| Lateral LN metastasis (+) | 11/151 (7.28%) | <0.01 | 4/84 (4.76%) | N.S. | 7/66 (10.6%) | <0.01 |
LN: lymph node, N.S.: not significant
Relative risk of lung metastasis
| Lung metastasis | Relative risk (95% confidence interval) | |
|---|---|---|
| All patients | ||
| cT3-4 and cN1 | 4/35 (11.4%) | |
| other | 10/385 (2.6%) | 4.4 (1.5–13.3) |
| Age <55 years | ||
| cT3-4 and cN1 | 1/17 (5.9%) | |
| other | 5/217 (2.3%) | 2.6 (0.3–20.6) |
| Age ≥55 years | ||
| cT3-4 and cN1 | 3/18 (3.0%) | |
| other | 5/168 (16.7%) | 5.6 (1.5–21.5) |
Metastasis of PTC to the mediastinal region and the lung occurs infrequently but tends to happen in advanced cases rather than in early cases. Such an understanding can markedly influence surgical strategies, as mediastinal LN dissection requires sternotomy, and total thyroidectomy is mandatory for PTC with lung metastasis for postoperative radioiodine therapy.
The frequency of mediastinal LN metastasis in PTC patients is reported to be 5.4%–15.7% [12-14]; it was 1.2% in our study, which was lower than in previous studies because mediastinal LN detected by US was not included. RFs of mediastinal LN metastasis include tumor size >1 cm, pre-tracheal pathological LN metastasis, multiple lateral pathological LN metastases [12], age ≥45 years old [13], and the presence of a poorly differentiated lesion and distant metastasis [13]. PTC with cT3-4 tumor and cN1 was shown to be likely to have mediastinal LN metastasis in our study, which is consistent with previous reports [12-14]. None of the cN0 patients had mediastinal LN metastasis. A greater number of LN metastases is also an RF for mediastinal LN metastasis [13]. The mean number of clinical LN metastasis was larger in the mediastinal LN metastasis-positive patients than in the mediastinal LN metastasis-negative patients. Not only the presence of LN metastasis but the number of LN metastases was shown to be important. Central LN metastasis is assumed to be associated with mediastinal LN metastasis, as these regions are continuous anatomically. Against expectations, however, lateral LN metastasis was found to be more closely related to mediastinal LN metastasis. As the preoperative prediction of mediastinal LN metastasis is emphasized, clinical LN metastasis rather than pathological LN metastasis was adopted as a factor in our study. The analysis performed separately by age showed that the results for total PTC patients corresponded to the findings for older patients but not younger patients. The incidence of mediastinal LN metastasis in younger patients was too low to explore associated RFs; a separate analysis from older patients should be conducted.
cT3-4, the presence of gross extrathyroidal extension, cN1, and LN metastasis in the central or lateral region were RFs for lung metastasis. Pathological LN metastasis is reported to carry a risk of lung metastasis. Multivariable logistic regression indicated that mediastinal LN metastasis, N1a, and N1b were RFs for PTC lung metastasis (odds ratio [OR]: 7.5, 4.7, 16.4, respectively) [15]. The number of LN metastases is considered to influence the effect size. ORs for PTC lung metastasis of pathological metastasis involving 1–5 LNs, 6–10 LNs, 11–20 LNs, and ≥21 LNs were reported to be 9.9, 10.6, 13.8, and 25, respectively [15]. It makes sense that PTC with a larger primary tumor and more LN metastases, thus harboring more tumor cells, is likely to spread systemically.
Unexpected findings were detected in 31.6% of patients by chest CT. The malignant disease that required immediate treatment was found in 0.7%. For the remaining patients with benign disease, CT might have resulted in unnecessary follow-up and increased anxiety. This result agrees with the study by Kawano et al. [16], who found that cT1aN0 PTC patients did not have distant metastasis. It suggested that routine use of CT to detect PTC lung metastasis is not necessary for low-risk patients.
From the patient’s perspective, performing preoperative CT may be reassuring. On the other hand, CT scans have the disadvantage of increasing radiation exposure and detection of incidental diseases that do not need to be treated in 31% of the patients. Surgeons should be aware of this evidence and share this information with patients before performing CT. An analysis performed separately by age revealed that the results of total PTC patients corresponded to those of older patients, except for cT. However, cT3-4 and LN metastasis in the central region were found to be RFs in younger patients. Again, the results here differed between younger and older patients. As Machens et al. mentioned, PTC in older patients may have had more opportunities to acquire somatic mutations [15], which may have caused the observed differences in distant metastasis behavior from younger patients.
None of the patients with cT1-2cN0 PTC had mediastinal LN metastasis or lung metastasis. Preoperative neck and chest CT can be avoided for PTC patients who were diagnosed as cT1-2cN0 by preoperative US which accounts for around 50% of all patients.
Several limitations associated with the present retrospective study warrant mention. First, there was a lack of consistency in the pre-operative diagnosis of LN metastasis. The US diagnosis is largely dependent on the examiner’s ability. The quality of imaging is constant in CT so that the diagnosis can be made more objectively by CT than by US. To reflect real-world situations, CT without enhancement was included in this study; indeed, 23% of neck CT procedures did not involve contrast. Allergy to iodine, asthma, and renal dysfunction were reasons for avoiding iodine usage. As the contrast effect of LNs provides information on metastasis [11], the sensitivity of CT for LN metastasis might have been limited in cases without enhancement [9]. Second, a discrepancy between cN and pN is inevitable because microscopic LN metastasis is not rare, whereas there was only one case that was cN1b but pN0. Furthermore, cN and pN were confirmed by the LN compartment and not by each LN, as this study was retrospective. Finally, lung nodules were diagnosed by imaging and not confirmed by histopathology. PTC is a slow-growing cancer, so the median follow-up period of 57.6 months may not have been sufficient to rule out PTC lung metastasis.
PTC patients with cT3-4 and cN1 were shown to have a risk of mediastinal LN metastasis and lung metastasis. Those RFs did not apply to younger patients. Increased numbers of clinical LN metastases were also indicated as RFs. Preoperative neck and chest CT are recommended in such cases. Conversely, in patients with cT1-2 and cN0, preoperative neck and chest CT are not necessary.
None of the authors have any potential conflicts of interest associated with this research.
The manuscript has been posted on a preprint server, Research Gate (URL: https://www.researchgate.net. DOI: 10.21203/rs.3.rs-1979671/v1).
