Apparent Lymph Node Metastasis Research Articles

Cutoff Age Between Pediatric and Adult Thyroid Differentiated Cancer: Is 18 Years Old Appropriate?

Background: The characteristics of pediatric differentiated thyroid cancer (DTC) are substantially different from those of adult DTC. This study investigated whether the cutoff age of 18 years, as recommended by the American Thyroid Association (ATA) management guidelines for pediatric DTC, is appropriate based on clinical characteristics and outcomes. Methods: The medical records of 288 patients aged <21 years with DTC, who underwent initial surgery between 1979 and 2014, were retrospectively reviewed. Disease-free survival (DFS) rates and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan-Meier method. As per the International Incidence of Childhood Cancer Report and the ATA management guidelines, cutoff ages of 14 and 18 years were analyzed in this study. Results: The age distributions of the subjects were as follows: 53 patients were aged <15 years (18.4%), 118 patients were aged 15-18 years (41%), and 117 patients were aged 19-20 years (40.6%). The DMFS rates were significantly different between the two cutoff ages. The DMFS was also significantly different between patients aged >15 years and patients aged 15-18 years; however, no significant difference was observed between patients aged 15-18 and 19-20 years. Multivariate analyses showed that clinically apparent lymph node metastasis (cN1) and gross extrathyroidal extension were significant factors related to DFS and DMFS. Although age as a continuous variant was not a significant factor related to either DFS or DMFS, when the cutoff age was set as 14 years rather than 18 years, differences in patient characteristics related to DMFS and DFS stood out. Conclusions: This study found that age was not significantly related to clinical outcome. However, in the younger patient group, more patients had factors that related to DFS and DMFS. Due to the indolent biological behavior of DTC, age at presentation or thyroidectomy does not always represent the age at occurrence, but patients aged <15 years had distinct clinical manifestations. Age <15 years rather than <19 years may therefore be a more suitable cutoff age in pediatric DTC.

Abstract #997055: Metastatic Papillary Thyroid Carcinoma without Identifiable Primary Tumor

Papillary Thyroid Carcinoma (PTC) with clinically apparent lymph node metastasis, but without an identifiable primary carcinoma lesion, is rare but can occur. We report such a case of occult PTC presenting as a cystic cervical lymph node metastasis.

Pregnancy During Active Surveillance of Papillary Thyroid Microcarcinoma

Abstract Introduction: Most patients diagnosed with papillary thyroid microcarcinoma (microPTC) classified as low risk and therefore eligible for active surveillance (AS) are women. Although age is a predictor of tumor progression (more frequent among young people), young adults are “appropriate” candidates for AS. Consequently, a proportion of patients with low-risk microPTC eligible for AS are women of childbearing age and knowledge of the effect of pregnancy on tumor progression is therefore important. In the Japanese population, Ito et al. observed this progression in only 8% of pregnancies. None of the series on the outcomes of AS in western populations has so far reported the behavior of microPTC in women who became pregnant during AS. Methods: We have submitted patients with low-risk microPTC to AS. Our management has been not to interrupt AS, i.e., not to indicate surgery when the patient wishes to become pregnant. We report here the results of five patients who became pregnant during AS and their follow-up up to 6 months after delivery. Results: The patients were 26 to 36 years old (median 29 years) when they became pregnant. None of them had a history of radiation exposure, one had a family history of PTC, one had associated Hashimoto’s thyroiditis, and all of them had only one tumor focus and were considered “appropriate” (but not “ideal”) candidates for AS. In fact, when pregnancy was diagnosed, the patients continued to exhibit the criterion for AS according to our initial protocol (tumor ≤ 1.2 cm, no apparent lymph node metastases [LNM] or extrathyroidal extension [ETE] on ultrasonography [US]). All women were monitored by monthly measurement of TSH and levothyroxine (L-T4) was administered during pregnancy to maintain TSH between 0.1 and 1 mIU/L. US was performed when pregnancy was diagnosed (between 6 and 9 weeks of gestation), around 22 weeks, at the end of pregnancy, and 6 months after delivery. During the evaluations, none of the patients had apparent LNM or ETE on US. None of the patients exhibited tumor growth, defined as an increase in diameter ≥ 3 mm. Tumor growth ≥ 50% was observed in only one patient, with a small reduction after delivery. Conclusions: Our preliminary results suggest that pregnancy is not associated with a high risk of progression of low-risk microPTC and that the desire to get pregnant or pregnancy should not be an exclusion factor for AS.

Microscopic extrathyroid extension in papillary thyroid carcinoma: impact on response to therapy.

Objectives Evaluate the impact of microscopic extrathyroid extension (MEE) on outcome and therapy response in patients with cT1 and cT2 papillary thyroid carcinoma (PTC). Subjects and methods Retrospective study of 970 consecutive patients, who underwent surgery for PTC between 2000 and 2016. All patients had: tumours ≤ 4 cm, apparent complete tumour resection, without clinically apparent lymph node or distant metastasis at diagnosis and nonaggressive histologic variant. Results Based on the finding of MEE, 175 (18.0%) patients were upstaged to T3. They were older (53.9 versus 50.6 years; P = 0.004) and were more prone to have multifocal tumours (38.2% versus 24.8%; P = 0.001). Radioiodine ablation therapy (RAI) was administered more often to MEE patients (92% versus 40.5%; P < 0.001), as well as prophylactic lymph node resection (35.4% versus 28.6%, P = 0.048). They were more likely to have biochemical incomplete response (4% versus 0.3%; P = 0.03) at the end of the follow-up period. There was no significant association between MEE and recurrence rate, persistence of disease or disease-specific mortality. Conclusion These results support the changes made to the latest edition of the TNM staging system, regarding MEE. Although incomplete biochemical response is more common in these patients, it does not seem to affect their prognosis.

Active Surveillance in Adults with Low-Risk Papillary Thyroid Microcarcinomas: A Prospective Study.

The acceptance and results of active surveillance in patients with low-risk papillary thyroid microcarcinomas (PTMC) are unknown in populations other than the Japanese population. This was the objective of the present prospective study. We selected patients ≥20 years who had thyroid nodules ≤1.2 cm with intermediate or high suspicion for malignancy on ultrasonography (US), not located near the recurrent laryngeal nerve and without extrathyroidal invasion or apparent lymph node metastases, whose cytology was suspicious (Bethesda V) or diagnostic (Bethesda VI) of papillary thyroid carcinoma. Patients who opted for active surveillance were followed up by biannual US. Fifteen patients (18.7%) readily opted for surgery and 12 (15%) for active surveillance. Fifty-three patients (66.2%) delegated the decision or wished to know the doctor's preference before deciding. After the doctor had declared his/her preference for active surveillance, 50 patients decided to have this management and three to have surgery. Only 1/70 patients exhibited tumor progression (growth associated with a suspicion of extrathyroidal invasion) after 30 months of follow-up. Two patients decided to have surgery during follow-up, although the indication was not defined by the study. A>50% reduction in tumor volume was observed in three patients. The study shows that active surveillance can be well accepted if doctors were convinced that it is the best option for patients with low-risk PTMC. At least the short-term results reproduced those observed in other populations, with tumor progression being uncommon.

Long-term oncologic outcomes of papillary thyroid microcarcinoma according to the presence of clinically apparent lymph node metastasis: a large retrospective analysis of 5,348 patients.

PurposeActive surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) may reduce the risk of overtreatment of clinically insignificant cancer. However, the absence of predictor for the progression of PTMC resulted in treatment delay and potentially compromising cure of aggressive disease. Therefore, to anticipate potential damage of delayed surgery, we investigated the oncologic outcomes of patients with low-risk PTMC initially eligible for AS except clinically apparent lymph node metastasis (LNM), imitating delayed surgery with neck dissection.Materials and methodsA total of 5,348 patients, enrolled between 1987 and 2016, with low-risk PTMC initially eligible for AS were included regardless of LNM. We classified our study patients into two groups: Group I, lobectomy with prophylactic central cervical node dissection; Group II, total thyroidectomy with modified radical neck dissection for LNM. In addition, we investigated the oncological outcomes of patients with second-wave surgery due to lateral lymph node recurrence (Group III, subgroup of Group I).ResultsGroup I showed more favorable clinicopathological characteristics compared with Group II. In Group I, only 29 (0.58%) of 4,927 patients underwent second-wave surgery with neck dissection for lateral lymph node recurrences, whereas in Group II, all 22 (5.23%) of 421 patients underwent second-wave selective node dissection because of nodal recurrence. Disease-free survival rates were significantly different between Groups I and II (P<0.05). Of note, the recurrence rate of Group II was still significantly higher than that of Group III (5.2% vs 0%, respectively; P=0.021). In addition, Kaplan–Mayer survival analysis indicated poor disease-free survival rates in Group II compared with Group III (P<0.05).ConclusionThe long-term treatment outcome of PTMC without LNM was favorable even if the recurrence occurs during follow-up period compared with that of PTMC with LNM. It should be noted that AS might be able to cause poor prognosis due to clinically apparent LNM.

Preferentially examined sentinel nodes for sentinel node navigation surgery in gastric cancer.

The intraoperative examination of the sentinel nodes (SNs) is crucial for correctly performing SN navigation surgery (SNNS). Frozen-section diagnosis is ordinarily used; however, when several SNs are being assessed in gastric cancer, which has numerous regional lymph nodes, it is difficult to examine them all correctly within the short duration of surgery. In the present study, we aimed to determine the SNs that should be preferentially examined during SNNS in gastric cancer. A total of 824 SNs were examined in 113 patients with clinically determined T1-2 gastric cancer and no apparent lymph node metastasis. We focused on the accumulation of tracers expressed by hot nodes (HNs) using the radioisotope (RI) method and green nodes (GNs) using the dye-guided method and measured the radioactivity count of the HNs (RI count). We compared these parameters between 35 metastatic and 789 non-metastatic SNs. The percentage of metastasis-positive SNs that were radioactively 'hot' and dyed green was higher compared with that of the negative SNs (89 vs. 43%, respectively; P<0.01). The RI counts of the metastasis-positive SNs were higher compared with those of the negative SNs [median (range): 361 (0-10,670) vs. 53 (0-9,931), respectively; P<0.01]. The area under the receiver operating characteristic curve of the RI count was 0.69 (95% CI: 0.60-0.78). Therefore, when assessing several SNs, those with higher RI counts (HNs and GNs) should be preferentially examined. Further accumulation of cases is required to establish the cut-off value for the diagnosis of metastasis based on the RI count.

Clinical prognostic index for recurrence of papillary thyroid carcinoma including intraoperative findings

This study created a new staging system using a risk model that employed clinical factors that were associated with recurrence, verified by preoperative clinical information and intraoperative finding and was compared with other staging systems. A review was conducted of patients who have undergone thyroidectomy and followed-up between January 1, 1983 and September 31, 2007 at Yonsei University Wonju Christian Hospital. The final prognostic staging system was defined as University of Yonsei clinical staging system (Prognostic score = 0.03 × Age + 0.8 × (if male gender) + 0.5 × (if extrathyroidal tumor extension present) + 0.7 × (if clinically apparent lymph node metastasis present), Stage I, less than 1.50; Stage II, 1.50 to 2.29; Stage III, 2.30 to 3.29; Stage IV 4, 3.3 or more). Compared with the other staging systems, the proportion of variation explained (PVE %) was calculated for each. The University of Yonsei clinical staging system appeared to be first as an accurate prognosis predictor with 11.9%. New staging system can predict recurrence and has advantage can use preoperative clinical information and intraoperative finding. Those who are diagnosed as high risk patients using the new staging system should be treated with aggressive surgical treatment and close follow-up.

Three Distinctly Different Kinds of Papillary Thyroid Microcarcinoma should be Recognized: Our Treatment Strategies and Outcomes

Papillary microcarcinoma (PMC) of the thyroid generally follows a benign clinical course. However, treatment strategies remain controversial. According to our previous retrospective review of 178 patients with PMC who underwent surgery between 1976 and 1993, the most significant risk factors affecting cancer-specific survival were clinical symptoms at presentation due to invasion or metastasis. Distant metastasis and cancer-specific death were never seen postoperatively for 148 cases (83%) of asymptomatic PMC without clinically apparent (>or=1 cm) lymph node metastasis or recurrent nerve palsy. Based on these results, we identified three biologically different types of PMC that should be treated differently. Type I comprises incidentally detected PMC without any symptoms, which is harmless and the lowest-risk cancer. Conservative follow-up with ultrasonography every 6 or 12 months is feasible. Type II involves the early stage of the usual low-risk papillary carcinoma. This can be treated by lobectomy when increasing size is noted during conservative follow-up. Type III comprises clinically symptomatic PMC, representing a high-risk cancer. Immediate wider resection followed by radioiodine treatment and suppression of thyroid-stimulating hormone is recommended. Since 1995, we have been conducting a prospective clinical trial of nonsurgical observation for asymptomatic PMC. As of 2008, 230 of 244 candidates (94%) have decided to accept this policy, whereas 56 patients underwent surgery for symptomatic PMC between 1976 and 2006. Nonsurgical observation for a mean of 5 (range, 1-17) years for 300 lesions of asymptomatic PMC revealed that 22 (7%) had increased in size, 269 (90%) were unchanged, and 9 (3%) had decreased. No patients developed extrathyroidal invasion or distant metastasis. Three patients (1%) who developed apparent lymph node metastasis and nine patients (4%) in whom tumor increased in size eventually received surgery after 1-12 years of follow-up. No recurrences have been identified postoperatively. Conversely, 10-year cause-specific survival for symptomatic PMC was 80%. Multivariate analysis identified extrathyroidal invasion, large lymph node metastasis (>or=2 cm), and poorly differentiated component as significantly related to adverse outcomes. Nonsurgical observation seems to represent an attractive alternative to surgery for asymptomatic PMC. Almost 95% of asymptomatic PMC patients are type I, and another 5% are type II and can be treated with conservative surgery. A small number of PMCs with bulky lymph node metastasis or extrathyroidal invasion are high-risk type III and require aggressive treatment.

Excellent Prognosis of Patients with Solitary T1N0M0 Papillary Thyroid Carcinoma Who Underwent Thyroidectomy and Elective Lymph Node Dissection Without Radioiodine Therapy

The extent of surgery for papillary carcinoma significantly differs between western countries and Japan. Almost routine total thyroidectomy with radioiodine ablation therapy has been performed in western countries, whereas limited thyroidectomy has been adopted in Japan, especially for low-risk cases. In this study, the prognosis of patients with solitary papillary carcinoma measuring 2 cm or less without massive extrathyroid extension, clinically apparent lymph node metastasis or distant metastasis at diagnosis (T1N0M0 in the UICC TNM classification) was investigated to elucidate the appropriate extent of surgery for these patients. We investigated the prognosis of 2,638 patients with solitary T1N0M0 papillary carcinoma who underwent initial surgery between 1987 and 2004. Total or near total thyroidectomy was performed for 1,037 patients and the remaining 1,601 patients underwent more limited thyroidectomy. Elective central node dissection was performed for 2,511 patients, accounting for 96%, and 1,545 (59%) also underwent prophylactic lateral node dissection. Radioiodine ablation therapy was performed only for three patients. The 10-year disease-free survival (DFS) rate of our series was 97%. To date, recurrence was observed in 62 patients (2%) and 41 showed recurrence to the regional lymph nodes. Seventeen of 1,601 patients who received limited thyroidectomy (1%) showed recurrence to the remnant thyroid. Pathological nodal-positive patients showed a worse DFS, but the 10-year DFS rate was still high at 96%. Patients with total or near total thyroidectomy had a better DFS, but the difference disappeared if recurrence to the remnant thyroid was excluded. A number needed to treat (NNT) for total or near total thyroidectomy over hemithyroidectomy was 83 to prevent 1 recurrence. These findings suggest that solitary T1N0M0 patients have an excellent prognosis when they undergo thyroidectomy and elective lymph node dissection without radioiodine therapy. Regarding the extent of thyroidectomy, hemithyroidectomy is adequate for these patients, if a 1% risk of recurrence to the remnant thyroid is accepted.

BRAF Mutation in Papillary Thyroid Carcinoma in a Japanese Population: Its Lack of Correlation with High-Risk Clinicopathological Features and Disease-Free Survival of Patients

Recent studies have demonstrated that BRAF(V600E) mutation is a common event in papillary thyroid carcinoma and a majority of these lesions have shown a direct relationship between BRAF(V600E) mutation and aggressive characteristics, including a worse patient prognosis. However, there are no studies from Japan regarding this issue in a large series with adequate postoperative follow-up periods. We investigated BRAF(V600E) mutation in 631 patients with papillary carcinoma having median follow-up periods of 83 months. The prevalence of BRAF(V600E) mutation was 38.4%, and the rate was higher in carcinoma larger than 1.0 cm but did not successively increase with tumor size. Furthermore, the prevalence did not significantly increase in cases demonstrating high-risk biological features such as clinically apparent lymph node metastasis, massive extrathyroid extension, advanced age, distant metastasis at surgery, and advanced Stage. The disease-free survival of patients with BRAF(V600E) mutation did not differ from that of those without BRAF(V600E) mutation. These findings indicate that, although BRAF(V600E) mutation may play some roles in local carcinoma development, there is no evidence that BRAF(V600E) mutation significantly reflects the aggressive characteristics and poor prognosis of patients with papillary carcinoma in Japan.

A prospective monitoring study on the value of LDH and protein S-100B as indicators of progressive disease during adjuvant interferon a treatment in melanoma

7542 Background: Despite adjuvant interferon treatment, a significant number of patients with high-risk melanomas will develop progressive disease within the following years. Currently, the recommendations for blood tests in the follow-up of these patients are inconsistent. Methods: A prospective evaluation compared the value of lactate dehydrogenase (LDH) and protein S-100B serum tests (Sangtec 100 LIA mat) as indicators of progressive disease. Therefore, blood samples from 98 melanoma patients were taken 3-monthly and the upper institutional limits (LDH 240 U/l; S-100B 0,20 μg/l) were considered as cut-off points. A total of 1273 sera were analyzed. All patients belonged to prospective-randomized phase III trials (Dermatologic Cooperative Oncology Group; DeCOG) and were treated either if clinically lymph node negative (n=53) with two different Interferon a2b schedules or if clinically lymph node positive (n=54) in another interferon-based trial with observation controls. Results: During the median observation period of 30 months 52 out of 98 patients (53.1%) progressed to either stage III or IV according to the new AJCC melanoma classification. Neither S-100B nor LDH represented indicators of in-transit metastases. The detection of clinically apparent lymph node metastasis by abnormal serum values was feasible in only 11.8% (LDH) and 35.3% (S-100B) of the patients, respectively. Whereas S-100B elevations led to the detection of early distant metastasis (stage IV) in half of the patients (50.0%), only 15.4% of the patients demonstrated abnormal LDH concentrations. The rate of false-positive serum levels in currently disease-free patients did not differ between the two serum markers (S-100B: 13.0%, LDH: 10.9%). Conclusions: Now as before, loco-regional relapses in high-risk melanoma patients have to be detected by clinical examinations and lymph node ultrasound. However, S-100B serum tests are superior to LDH assessments as indicators of early distant metastasis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration DiaSorin DiaSorin

Clinical significance of lympho vascular space involvement and lymph node micrometastases in early-stage cervical cancer: A retrospective case-control surgico-pathological study

Objective Several studies have shown that lympho vascular space involvement (LVSI) and lymph node micrometastases (LNmM) may be risk factors for recurrence in early-stage cervical cancer with no apparent lymph node metastases. We performed a retrospective case-control study to reassess whether the presence of lymph node micrometastases and LVSI is predictive of subsequent recurrence following surgical resection of early-stage cervical cancer. Methods In a series of 292 patients diagnosed with early cervical cancer and treated by the same surgical procedure (laparoscopic-vaginal radical hysterectomy) during the same time period, two paired series were selected. The first series consisted of 26 cases who recurred in a median time of 36.8 months and the second series were 26 cases matched for age, histological sub-type, surgico-pathological stage and maximal tumor diameter, who did not recur after a median follow-up of 122 months. Sections taken from the hysterectomy specimens were reassessed for LVSI. All the lymph node blocks which have initially been considered as uninvolved were submitted to serial sectioning. Immunohistochemical staining using anti-cytokeratins AE1 and AE3 was used for identifying LNmM. Results LVSI was twice more frequent and LNmM ten-fold more frequent in the group of patients who recurred: 20/26 (77%) versus 9/26 (35%) and 11/26 (42%) versus 1/26 (4%) respectively. The relative risk of recurrence is 2.64 (1.67–5.49, P < 0.01) in the presence of LVSI and 2.44 (1.58–3.78, P < 0.01) in the presence of LNmM. All the patients with LNmM were LVSI positive. At bivariate analysis, the true LNmM (deposits more than 200 um in size) was the only independent risk factor. Conclusions LNmM is an important risk factor of tumor recurrence in patients with early cervical cancer with no apparent lymph node metastases. LNmM seems to occur only in LVSI positive tumors. These data may lead to improve management of early-stage cervical cancer to reduce the risk of recurrence in those cases.

Low-risk differentiated thyroid cancer: the need for selective treatment.

The well recognized prognostic factors in differentiated carcinoma of the thyroid are age, grade, extracapsular extension, distant metastasis, and size of the tumor. Based on these prognostic factors, we have divided patients into low-, intermediate-, and high-risk categories. Clearly, there are significant differences in these three groups. This article analyzes in depth our data on low-risk thyroid cancer patients. A retrospective review of 1,038 patients with differentiated carcinoma of the thyroid was undertaken. Various prognostic factors and risk groups were analyzed. Univariate and multivariate analyses were performed, and the survival curves were plotted by the Kaplan-Meier method. The inclusion criteria for the low-risk group were age younger than 45 years, tumors < 4 cm in size, low-grade histology, absence of distant metastasis, and absence of extrathyroidal extension. There were 465 patients in the low-risk group. Four hundred three patients had papillary and 62 patients had follicular thyroid cancer. There were 120 male and 354 female patients. Two hundred seventy-eight patients (60%) presented with clinically apparent lymph node metastasis. With a median follow-up of 20 years, the 10- and 20-year survival in this select group was 99%. The local, regional, and distant recurrence rates were 5, 9, and 2% in this series. The analysis of the data showed statistical difference in local recurrence rate between partial lobectomy and total lobectomy (27 vs. 4%; p = 0.005). There was no statistical difference in local recurrence rate between total lobectomy compared with total thyroidectomy (4 vs. 1%; p = 0.10). The overall failure rate between partial lobectomy and total thyroidectomy (27 vs. 8%) was statistically significant (p = 0.04). There was no statistical difference in the overall failure rate between total lobectomy and total thyroidectomy (13 vs. 8%; p = 0.06). There was no survival difference between various histologies or nodal status. Patients with low-risk tumors have excellent long-term survival. Nodulectomy or partial lobectomy should be avoided. The intraoperative decisions regarding the extent of thyroidectomy should be based on gross clinical findings and risk group analysis.

Carcinoma of the gallbladder. A clinicopathology of 103 patients and a newly proposed staging.

Tissue samples from 103 patients with gallbladder carcinoma were examined, using 5-mm stepwise tissue sections. Three pathologic stages were used: Stage I; carcinoma invading not further than the muscle coat of the gallbladder, with or without extension along Rokitansky-Aschoff sinuses in the subserosa (11 cases); Stage II, carcinoma extending to the subserosal fibroadipose tissue of the gallbladder (73 cases); and Stage III: carcinoma invading the adjacent organs such as the duodenum, liver, and colon (19 cases). In the 11 patients with Stage I carcinoma, there was no apparent lymph node metastasis and all remained well for 3 months to 14 years after the initial operation. The cumulative 3-year survival rate of Stage I (100%) was significantly higher than of Stage II (40%) and Stage III (10%) (P less than 0.01, P less than 0.001). The Stage I tumors, therefore, can be defined as early carcinoma of the gallbladder. Dysplastic epithelium was seen in the mucosa adjacent to the malignant lesion in 57% of those with gallbladder carcinoma: 73% in Stage I, 59% in Stage II, and 42% in Stage III. Nine gallbladders had multiple foci of adenocarcinoma in a background of a diffuse dysplasia. Immunohistochemical study for carcinoembryonic antigen and carbohydrate antigen 19-9 resulted in positive staining of the dysplastic epithelial element adjacent to the invasive carcinoma and, in a similar fashion, in the carcinoma itself, thereby indicating a close relation between the epithelial dysplasia and adenocarcinoma of the gallbladder.