Nobuyuki Wada

Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection.

ObjectiveTo determine the frequency and pattern of lymph node metastasis (LNM) from papillary thyroid microcarcinoma (PTMC) and the results of node dissection, and to establish the optimal strategy for neck dissection in these patients. Summary Background DataMost PTMCs carry a favorable prognosis, but a few present with palpable lymphadenopathy. Patients with LNM are at risk for nodal recurrence, although they do not have higher mortality. The frequency and pattern of LNM from PTMC and the results of node dissection are not well established. MethodsThe frequency and pattern of LNM from 259 PTMCs were analyzed according to the size and location of the primary tumor. Of the 259, 24 with palpable nodes underwent therapeutic node dissection and the other 235 patients without palpable nodes underwent prophylactic node dissection. The authors compared the results of node dissection between the therapeutic group and the prophylactic group, and between PTMCs 5 mm or smaller and PTMCs larger than 5 mm. The authors also compared nodal recurrence between the prophylactic group and a no-lymph-node-dissection group (155 PTMCs). ResultsOverall, 64.1% (166/259) and 44.5% (93/209) had node involvement of the central and ipsilateral lateral compartment, respectively. Pretracheal (43.2%), ipsilateral central (36.3%), and ipsilateral mid-lower (37.8%) jugular were more commonly involved. LNM was more frequent in the therapeutic group than in the prophylactic group (95.8% vs. 60.9% for central compartment, 83.3% vs. 39.5% for ipsilateral lateral compartment). Nodal recurrence was more common in the therapeutic group than in the prophylactic group (16.7% vs. 0.43%), but did not differ between the prophylactic group and the no-dissection group (0.43% vs. 0.65%). The tumor size did not influence nodal recurrence. Nodal recurrence preferentially occurred in ipsilateral mid-lower jugular nodes. ConclusionsPatients who have PTMC presenting with palpable lymphadenopathy should have therapeutic node dissection. Prophylactic node dissection is not beneficial in those without palpable lymphadenopathy.

Does Intraoperative Quick Parathyroid Hormone Assay Improve the Results of Parathyroidectomy

Preoperative sestamibi (MIBI) and ultrasonography (US) are used to localize parathyroid tumors in patients with primary hyperparathyroidism (pHPT). The intraoperative quick PTH assay (qPTH) has been recommended to determine whether all hyperfunctioning parathyroid tissue has been removed. We questioned whether qPTH improves the results of parathyroidectomy in patients with pHPT. We analyzed 115 unselected patients with pHPT without a family history or multiple endocrine neoplasia but who had undergone parathyroidectomy. All 115 patients had successful operations without complications. Of these patients, 88 (77%) had solitary adenomas, 13 had double adenomas, 1 had triple adenomas, 12 had hyperplasia, and 1 had carcinoma. Overall, MIBI was correct in 72% (76/106), US in 49% (49/99), and qPTH in 80% (92/115). For preoperative studies showing a single tumor, MIBI was correct in 83% (73/88), US was correct in 71% (45/63), and combined MIBI and US were correct in 95% (37/39). Adding qPTH in this subgroup did not improve the successful focused approach: 70% for MIBI, 65% for US, and 87% for combined MIBI and US. However, adding qPTH improved the overall success of parathyroidectomy (MIBI 92%, US 86%, combined MIBI and US 97%), but at the cost of unnecessary further exploration (MIBI 13%, US 6%, combined MIBI and US 8%). We conclude that when the same solitary tumor is identified by both MIBI and US, a focused exploration can be done with a 95% success rate. Adding qPTH to MIBI or US can improve the success rate but at a significant cost. General exploration of all parathyroid glands, however, has the highest success rate (100%).

Microscopic regional lymph node status in papillary thyroid carcinoma with and without lymphadenopathy and its relation to outcomes

AimThe aim of this study was to evaluate microscopic nodal status in papillary thyroid carcinoma (PTC) with and without lymphadenopathy and its relation to outcomes.Materials and methodsWe retrospectively analyzed 134 patients with PTC who underwent initial thyroidectomy. Forty-two patients with lymphadenopathy underwent therapeutic modified neck dissection (MND) and 92 without lymphadenopathy underwent prophylactic MND. The frequencies, numbers, and percentages of lymph node metastasis (LNM) were determined to evaluate nodal status; then, whether each nodal status influence to outcomes was analyzed. Disease-free survival (DFS) and disease-specific survival (DSS) were assessed (Kaplan–Meier method and log-rank test).ResultsLymphadenopathy was significantly related to local recurrence and DFS, but not DSS. The frequency (100 vs 67.4%), number (15.8 vs 2.7), and percentage (49.7 vs 17.8%) were significantly higher in patients with lymphadenopathy than in those without lymphadenopathy (p < 0.0001). Similarly, these were significantly higher in patients who developed recurrence than in those who did not. Recurrence was frequent in older patients with lymphadenopathy. The frequency, number, and percentage were also higher in older patients who developed local recurrence.ConclusionsLymphadenopathy and microscopic nodal status are significantly related to recurrence. Only a few nodes seem to be involved pathologically when no lymphadenopathy.

Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas.

The purpose of the present study was to establish accurate prognostic markers to predict the post-operative recurrence of stage I lung adenocarcinomas (ADC). One-hundred and ninety cases of stage I ADC were examined for KRAS mutations and Ki-67 expression, and their associations with disease recurrence were analyzed. KRAS-mutated cases showed a significantly higher risk of recurrence than cases without mutations (5-year disease-free survival (DFS) 61.0% vs. 85.8%, P=0.017: adjusted Hazard ratio (HR) 4.55, 95% Confidence Interval (CI) 1.61-12.82, P=0.004). Ki-67 high-expressers (labeling index >10%) also showed a higher risk of recurrence than low-expressers (5-year DFS 68.7% vs. 93.2%, P<0.001: adjusted HR 3.84, 95% CI 1.18-12.45, P=0.025). Ki-67 high-expressers with KRAS mutations showed an additional higher risk of recurrence compared to low-expressers without mutations (5-year DFS 37.5% vs. 93.3%, P<0.001: adjusted HR 16.82, 95% CI 3.77-74.98, P<0.001) and their 5-year DFS was nearly equivalent to that of stage II non-small cell lung cancer (NSCLC) in our facility (37.5% vs. 37.2% for stage II NSCLC, p=0.577). The combined use of KRAS status and Ki-67 expression level could be an excellent prognostic marker to predict the post-operative recurrence of stage I ADC.

Anaplastic Thyroid Cancer: Cytogenetic Patterns by Comparative Genomic Hybridization

We studied chromosomal abnormalities by comparative genomic hybridization (CGH) and flow cytometry in anaplastic thyroid cancer (ATC), and when present in coexisting or previous differentiated thyroid cancer (DTC). Overall 10 frozen tissues from patients with ATC and 5 cell lines (1 ATC and 4 DTCs) were analyzed. We found chromosomal abnormalities in 5 of 10 ATC tissues, with 24 abnormalities (22 gains and 2 losses). Among 8 ATCs that were associated with prior or concurrent DTC, more chromosomal abnormalities were found in ATC associated with follicular thyroid cancer (FTC) than those associated with PTC (median numbers 9.5 and 0.5, respectively, p = 0.046) or no associated differentiated thyroid cancer. Gain of 1q was relatively common in ATCs (30%). By flow cytometry, we found aneuploidy in 6 of 10 ATC tissues and diploidy in 4. There was concordance between DNA aneuploidy and the presence of chromosomal abnormalities by CGH in 4 of the 5 ATCs (p = 0.048). We also found 26 chromosomal abnormalities in an ATC cell line, 14.3 in 3 FTC cell line, and 3 in a PTC cell line. In conclusion, chromosomal abnormalities are frequent in ATCs associated with FTC, but uncommon in those associated with PTC and in ATCs with no associated differentiated thyroid cancer. These findings support the concept that PTC and FTC have different genetic backgrounds and, even after the transformation to ATC, they may retain some of their cytogenetic characteristics.

PCNA and Ki-67 as Prognostic Markers in Human Parathyroid Carcinomas

Background: It is widely accepted that histological diagnosis of parathyroid tumors is established with great difficulty. Carcinomas cannot be reliably separated from adenomas by histology alone. In this study, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and Ki-67 was determined in 10 cases of parathyroid carcinomas, labeling indices (LIs) were calculated, and the results were correlated with the clinical outcomes.Methods: Ten cases of formalin-fixed, paraffin-embedded tissue with surgically resected parathyroid carcinoma were used. Immunohistochemical staining for PCNA and Ki-67 was performed and the LIs were calculated. We also examined whether LI could become a useful marker for parathyroid carcinomas.Results: Although nine patients with minimally invasive growth without recurrence of the tumor showed a low LI for both markers, one patient with a widely invasive neoplasm, and who died, had a high LI.Conclusions: These results suggested that the LI of PCNA and Ki-67, in addition to the histological appearance, may be markers of the biological behavior of parathyroid carcinomas. However, this study was on a small scale, so it may be valuable to repeat these studies in a larger group of patients with better defined histological criteria.

Pediatric differentiated thyroid carcinoma in stage I: risk factor analysis for disease free survival

BackgroundTo examine the outcomes and risk factors in pediatric differentiated thyroid carcinoma (DTC) patients who were defined as TNM stage I because some patients develop disease recurrence but treatment strategy for such stage I pediatric patients is still controversial.MethodsWe reviewed 57 consecutive TNM stage I patients (15 years or less) with DTC (46 papillary and 11 follicular) who underwent initial treatment at Ito Hospital between 1962 and 2004 (7 males and 50 females; mean age: 13.1 years; mean follow-up: 17.4 years). Clinicopathological results were evaluated in all patients. Multivariate analysis was performed to reveal the risk factors for disease-free survival (DFS) in these 57 patients.ResultsExtrathyroid extension and clinical lymphadenopathy at diagnosis were found in 7 and 12 patients, respectively. Subtotal/total thyroidectomy was performed in 23 patients, modified neck dissection in 38, and radioactive iodine therapy in 10. Pathological node metastasis was confirmed in 37 patients (64.9%). Fifteen patients (26.3%) exhibited local recurrence and 3 of them also developed metachronous lung metastasis. Ten of these 15 achieved disease-free after further treatments and no patients died of disease. In multivariate analysis, male gender (p = 0.017), advanced tumor (T3, 4a) stage (p = 0.029), and clinical lymphadenopathy (p = 0.006) were risk factors for DFS in stage I pediatric patients.ConclusionMale gender, tumor stage, and lymphadenopathy are risk factors for DFS in stage I pediatric DTC patients. Aggressive treatment (total thyroidectomy, node dissection, and RI therapy) is considered appropriate for patients with risk factors, whereas conservative or stepwise approach may be acceptable for other patients.

Preoperative change of thyroid stimulating hormone receptor antibody level: possible marker for predicting recurrent hyperthyroidism in patients with Graves' disease after subtotal thyroidectomy.

Abstract. To make the surgical treatment for Graves’ disease more ideal, it is important to elucidate factors related to postoperative thyroid dysfunction in addition to thyroid remnant. Because TSH receptor antibody (TRAb) is thought to be one of the essential causes of Graves’ disease, we investigated whether preoperative changes in serum TRAb levels are related to postoperative recurrent hyperthyroidism. Between 1987 and 1992 a total of 1520 patients with Graves’ disease were treated by subtotal thyroidectomy. Of these patients 335 visited Ito Hospital with no history of drug treatment of their disease and were treated surgically after several courses of antithyroid drug (ATD) therapy. There were 68 males and 267 females with a mean age of 25.8 years. The mean follow-up period was 48 months (range 12–84 months). Factors analyzed by univariate and multivariate analysis were as follows: age, sex, duration of ATD treatment, weight of resected thyroid, weight of thyroid remnant, preoperative titer of MCHA, TRAb at the time of initial examination (TRAb1), TRAb at the time of surgery (TRAb2), and ΔTRAb, the difference between TRAb1 and TRAb2 (ΔTRAb = TRAb1 − TRAb2). The chi-square test was used for univariate analysis and a logistic model for multivariate analysis. Of this group, 119 patients were euthyroid (35.5%), 50 were hyperthyroid (14.9%), and 166 were hypothyroid (49.3%). Significant factors related to recurrent hyperthyroidism were weight of thyroid remnant and ΔTRAb in both univariate and multivariate analyses. ΔTRAb is a possible new marker for predicting postoperative recurrent hyperthyroidism. If the preoperative TRAb level is not improved by ATDs in patients with Graves’ disease, the thyroid remnant should be made smaller.

Axillary Lymph Node Metastasis from Papillary Thyroid Carcinoma: Report of a Case

We report a case of axillary lymph node metastasis (LNM) from papillary thyroid carcinoma (PTC) in a 21-year-old man. The patient presented with bilateral cervical and right axillary lymphadenopathy, and computed tomography (CT) showed a primary tumor of the thyroid and gross lymphadenopathy from the neck to the right axilla. We performed a total thyroidectomy with therapeutic nodal dissection. The resection of the primary thyroid tumor and all the node metastases was curative. Pathological examination confirmed that the resected lesions were PTC and nodal metastases from the primary tumor. Six years after the operation, cervical, upper mediastinal, and axillary lymph node recurrence developed and multiple lung metastases were found on a CT scan. He was treated with radioactive iodine therapy. Axillary LNM from PTC is unusual and seems to be associated with a poor prognosis. Thus, comprehensive treatment strategies are needed to improve the outcome of patients with PTC who present with axillary LNM.

Chromosomal aberrations by comparative genomic hybridization in thyroid tumors in patients with familial nonmedullary thyroid cancer.

PURPOSE Nonmedullary thyroid cancer is the most common form of thyroid cancer and its familial form (FNMTC) is increasingly recognized as a distinct clinical entity. However, the genetic background of FNMTC is still poorly understood and the causative gene(s) have not yet been identified. METHODS Because comparative genomic hybridization allows for screening of the entire tumor genome simultaneously for chromosomal gains and/or losses without prior knowledge of potential aberrations, we used this technique in thyroid normal and neoplastic samples from FNMTC patients (1) to analyze whether chromosomal aberrations would correlate with inheritance pattern, and/or clinicopathologic features and (2) to compare comparative genomic hybridization (CGH) findings in familial tumors with those already known in sporadic differentiated thyroid cancers. RESULTS No common germline or somatic chromosomal aberrations were observed in patients with FNMTC because the frequencies and most locations of chromosomal aberrations in familial tumors were also common in sporadic tumors. However, some somatic aberrations were only found in familial tumors (gains in 2q, 3q, 18p, and 19p). Common aberrations in familial tumors corresponded to several locations of candidate genes already reported for sporadic thyroid tumorigenesis. CONCLUSIONS Our findings suggest that chromosomal aberrations in thyroid tumors in patients with FNMTC are not related to inheritance pattern but rather to tumorigenesis.