Survival In Papillary Thyroid Cancer Research Articles

Causal inference between aggressive extrathyroidal extension and survival in papillary thyroid cancer: a propensity score matching and weighting analysis.

Extrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates. The study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan-Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients. In the Kaplan-Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles. Our study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.

B cells and tertiary lymphoid structures are associated with survival in papillary thyroid cancer.

The function of B cells in papillary thyroid cancer (PTC) is controversial. The role of B-cell-related tertiary lymphoid structures (TLSs) is still unclear. Whether B cells exert their anti-tumor effect through forming TLS in PTC needs further investigation. We detected the percentage of B cells in PTC tissues by multi-parameter flow cytometry. Paraffin-embedded tumor tissues of 125 PTC patients were collected and stained with Haematoxylin-Eosin (H&E) for inflammatory infiltration analysis in combination with clinical features. Multiplexed immunohistochemistry (mIHC) was performed to verify the TLSs in above inflammatory infiltration. Correlation of B cells and TLSs with prognosis was analyzed using the TCGA database. We observed that PTC patients with higher expression of B lineage cell genes had improved survival and the percentage of B cells in the PTC tumor tissues was variable. Moreover, PTC tumor tissues with more B cells were surrounded by immune cell aggregates of varying sizes. We furtherly confirmed the immune cell aggregates as TLSs with different maturation stages. By analyzing PTC data from TCGA database, we found the maturation stages of TLSs were associated with genders and clinical stages among PTC patients. Moreover, patients with high TLSs survived longer and had a better prognosis. B cells are associated with the existence of TLSs which have different maturation stages in PTC. Both B cells and TLSs are associated with the survival rate of PTC. These observations indicate that the anti-tumor effects of B cells in PTC are associated with TLSs formation.

Delay in Surgery and Papillary Thyroid Cancer Survival in the United States: a SEER-Medicare Analysis.

Delays in surgery and their impact on survival in papillary thyroid cancer (PTC) is unclear. We sought to investigate the association between time to surgery and survival in patients with PTC. A total of 8,170 Medicare beneficiaries with PTC who underwent thyroidectomy were identified within the SEER-Medicare linked data files between 1999-2018. Disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meir analysis, and Cox proportional hazards models were specified to estimate the association between time to surgery and survival. Among 8,170 patients with PTC, mean age 69.3 (SD+/- 11.4), 89.8% had surgery within the first 90 days, 7.8% had surgery 91-180 days from diagnosis, and 2.4% had surgery after 180 days. Increasing time to surgery was associated with increased mortality for OS in the >180-day group (aHR 1.24, 95% CI 1.01-1.53). Moreover, on stratification by summary stage, those with localized disease in the 91-180-day group increased risk by 25% (aHR 1.25 95%CI 1.05-1.51) and delaying over 180 days increased risk by 61% (aHR 1.61 95%CI 1.19-2.18) in OS. Those with localized disease in the >180-day group had almost four times the estimated rate of DSS mortality (aHR3.51 95%CI 1.68-7.32). When stratified by T stage, those with T2 disease in the >180 days group had double the estimated rate of all-cause mortality (aHR 2.0, 95% CI 1.1-3.3) and almost triple the estimated rate of disease-specific mortality (aHR 2.7, 95% CI 1.05-6.8). Delays in surgery for PTC may impact OS and DSS in localized disease, prior to nodal metastasis.

Histological Variants of Papillary Thyroid Cancer in Relation to Clinical and Morphological Parameters and Prognosis

The correlation of histological features of papillary thyroid cancer with clinical and morphological prognostic factors and cause-specific mortality was analyzed in a case-control study within a cohort of patients from the Altai Regional Oncology Center (25 cases with lethal outcome and 64 follow-up controls). Significant variability was revealed in the histological structure of papillary thyroid cancer with the prevalence of classic (62%) and less frequent follicular (19%), tall cell (8%), and solid (7%) variants. In comparison with the classic variant, the solid variant was more often associated with male sex and large tumor size; follicular and tall cell variant was associated with more frequent metastases to regional lymph nodes; follicular and solid variants were associated with an increased proportion of cases with disease stages III-IV. The main differences reflecting the effect of histological factor on the disease outcome were associated with the solid variant of papillary thyroid cancer that was detected in 21% of lethal cases and only in 2% of control subjects. The detection of this variant can be of importance as an additional prognostic factor of the postoperative survival in papillary thyroid cancer.

Iodine Maps from Dual-Energy CT to Predict Extrathyroidal Extension and Recurrence in Papillary Thyroid Cancer Based on a Radiomics Approach.

Accurate prediction of extrathyroidal extension and subsequent recurrence is crucial in papillary thyroid cancer clinical management. Our aim was to conduct iodine map-based radiomics to predict extrathyroidal extension and to explore its prognostic value for recurrence-free survival in papillary thyroid cancer. A total of 452 patients with papillary thyroid cancer were retrospectively recruited between June 2017 and June 2020. Radiomics features were extracted from noncontrast images, dual-phase mixed images, and iodine maps, respectively. Random forest and least absolute shrinkage and selection operator (LASSO) were applied to build 6 radiomics scores (noncontrast radiomics score_random forest; noncontrast rad-score_LASSO; mixed rad-score_random forest; mixed rad-score_LASSO; iodine radiomics score_random forest; iodine radiomics score_LASSO) respectively. Logistic regression was used to construct 6 radiomics models incorporating 6 radiomics scores with clinical risk factors and to compare them with the clinical model. A radiomics model that achieved the highest performance was presented as a nomogram and assessed by discrimination, calibration, clinical usefulness, and prognosis evaluation. Iodine radiomics scores performed significantly better than mixed radiomics scores. Both of them outperformed noncontrast radiomics scores. Iodine map-based radiomics models significantly surpassed the clinical model. A radiomics nomogram incorporating size, capsule contact, and iodine radiomics score_random forest was built with the highest performance (training set, area under the curve = 0.78; validation set, area under the curve = 0.84). Stratified analysis confirmed the nomogram stability, especially in group negative for CT-reported extrathyroidal extension (area under the curve = 0.69). Nomogram-predicted extrathyroidal extension risk was an independent predictor of recurrence-free survival. A high risk for extrathyroidal extension portended significantly lower recurrence-free survival than low risk (P < .001). Iodine map-based radiomics might be a supporting tool for predicting extrathyroidal extension and subsequent recurrence risk in patients with papillary thyroid cancer, thus facilitating clinical decision-making.

Site-Specific Metastasis and Survival in Papillary Thyroid Cancer: The Importance of Brain and Multi-Organ Disease.

Introduction-heterogeneity in clinical outcomes and survival was observed in patients with papillary thyroid cancer (PTC) and distant metastases. Here, we investigated the effect of distant metastases sites on survival in PTC patients. Methods-patients with a diagnosis of PTC and known metastases were identified using the Surveillance, Epidemiology, and End Results database (1975-2016). Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on thyroid cancer-specific survival (TCSS) and overall survival (OS). Results-from 89,694 PTC patients, 1819 (2%) developed distant metastasis at the initial diagnosis, of whom 26.3% presented with the multiple-organ disease. The most common metastatic sites were lung (53.4%), followed by bone (28.1%), liver (8.3%), and brain (4.7%). In metastatic patients, thyroid cancer-specific death accounted for 73.2%. Kaplan-Meier curves showed decreased OS in patients with metastases to the brain (median OS = 5 months) and liver (median OS = 6 months) compared to lung (median OS = 10 months) and bone (median OS = 23 months). Moreover, multiple organ metastasis had a higher mortality rate (67.4%) compared to single organ metastasis (51.2%, p < 0.001). Using multivariate analysis, risk factors that significantly influence TCSS and OS were male gender (HR = 1.86, 95% CI = 1.17-2.94, p < 0.001, and HR = 1.90, 95% CI = 1.40-2.57, p = 0.009), higher tumor grade (HR = 7.31, 95% CI = 2.13-25.0, p < 0.001 and HR = 4.76, 95% CI = 3.93-5.76, p < 0.001), multiple organ involvement (HR = 6.52, 95% CI = 1.50-28.39, p = 0.026 and HR = 5.08, 95% CI = 1.21-21.30, p = 0.013), and brain metastasis (HR = 1.82, 95% CI = 1.15-2.89, p < 0.001 and HR = 4.21, 95% CI = 2.20-8.07, p = 0.010). Conclusion-the pattern of distant metastatic organ involvement was associated with variability in OS in PTC. Multi-organ metastasis and brain involvement are associated with lower survival rates in PTC. Knowledge of the patterns of distant metastasis is crucial to personalize the treatment and follow-up strategies.

Does Aggressive Variant Histology Without Invasive Features Predict Overall Survival in Papillary Thyroid Cancer?: A National Cancer Database Analysis.

We aimed to clarify whether aggressive histology of papillary thyroid cancer (PTC) impacts overall survival (OS). Aggressive variants of PTC (AVPTC) are associated with invasive features. However, their behavior in the absence of these features is not well characterized. Patients treated from 2004 to 2015 for classic PTC (cPTC) or AVPTCs were identified from the National Cancer Database. Patients were further stratified based on presence of at least 1 invasive feature-extrathyroidal extension, multifocality, lymphovascular invasion, nodal or distant metastasis. Demographics, treatments, and OS were compared. A total of 170,778 patients were included-162,827 cPTC and 7951 AVPTC. Invasive features were more prevalent in AVPTC lesions compared to cPTC (70.7% vs 59.7%, P < 0.001). AVPTC included tall cell/columnar cell (89.5%) and diffuse sclerosing (10.5%) variants. Patients with invasive features had worse OS irrespective of histology. Furthermore, when controlling for demographics, tumor size, and treatment variables in patients with noninvasive lesions, AVPTC histology alone was not associated with worse OS compared to cPTC (P = 0.209). In contrast, among patients who had at least 1 invasive feature, AVPTC histology was independently predictive of worse OS (P < 0.05) {TCV/Columnar hazard ratio [HR] 1.2; [95% confidence interval (CI) 1.1-1.3] and diffuse sclerosing HR 1.3; 95% CI 1.0-1.7]}. All invasive features, except multifocality, were independently associated with worse OS, with metastasis being the most predictive [HR 2.9 (95% CI 2.6-3.2) P < 0.001]. In the absence of invasive features, AVPTC histology has similar OS compared to cPTC. In contrast, diffuse sclerosing and tall cell/columnar variants are associated with worse OS when invasive features are present.

Predicting recurrence of papillary thyroid cancer using the eighth edition of the AJCC/UICC staging system.

The AJCC/UICC classification is widely used for predicting survival in papillary thyroid cancer (PTC), but has not been evaluated as a predictor of recurrence. The hypothesis of this study was that the eighth edition of the AJCC system can be used in this novel way. All patients in the study underwent surgery for PTC at a high-volume endocrine surgery centre in France between 1985 and 2015. The seventh and eighth editions of the AJCC/UICC staging system for PTC were employed to predict recurrence and disease-specific survival using the Kaplan-Meier and log rank tests. Among 4124 patients (79·7 per cent female), median age was 50 (i.q.r. 38-60) years; 3906 patients (94·7 per cent) underwent total thyroidectomy, with lymph node dissection in 2495 (60·5 per cent). The eighth edition of the AJCC/UICC staging system placed 91·8, 7·1, 0·4 and 0·7 per cent of patients in stages I-IV respectively. After reclassifying patients from the seventh to the eighth AJCC/UICC edition, the disease was downstaged in 23·8 per cent. Over a median follow-up of 7 years, 260 patients (6·4 per cent) developed recurrent disease, including 5·2 per cent of patients with stage I, 19·6 per cent with stage II, 59 per cent with stage III and 50 per cent with stage IV disease, according to the eighth edition. The eighth edition was a better predictor of recurrence than the seventh edition. The eighth edition of the AJCC/UICC staging system appears to be a novel tool for predicting PTC recurrence, which is a meaningful outcome for this indolent disease. The eighth edition can be used to risk-stratify patients, keeping in mind that other molecular and pathological predictive factors must be integrated into the assessment of recurrence risk.

MKL1 overexpression predicts poor prognosis in patients with papillary thyroid cancer and promotes nodal metastasis.

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for cervical lymph node metastasis (LNM), which increases the risk of locoregional recurrence and decreases survival probability in some high-risk groups. Hence, there is a pressing requirement for a reliable biomarker to predict LNM in thyroid cancer. In the present study, MKL1 (also known as MRTFA) expression was significantly increased in PTC patients with LNM compared with those without. Further receiver operating characteristic (ROC) analysis showed that MKL1 expression had a diagnostic value in the differentiation of LNM in PTC. Furthermore, Kaplan-Meier analysis revealed that high MKL1 expression was associated with significantly decreased survival in PTC. Additionally, our study indicated that MKL1 promoted the migration and invasion of PTC cells. MKL1 interacted with and recruited Smad3 to the promoter of MMP2 to activate MMP2 transcription upon treatment with TGF-β. Moreover, there was significant correlation between expression of TGF-β, MKL1 and MMP2 in our clinical cohort of specimens from individuals with PTC. Our results suggest that the detection of MKL1 expression could be used to predict cervical LNM and inform post-operative follow-up in individuals with PTC.

Projecting Survival in Papillary Thyroid Cancer: A Comparison of the 7th and 8th Editions of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) Staging Systems in A Contemporary National Patient Cohort

Pontius, Lauren N.; Oyekunle, Taofik; Thomas, Samantha M.; Stang, Michael T. MD; Scheri, Randall P. MD, FACS; Roman, Sanziana A. MD, FACS; Sosa, Julie A. MD, FACS Author Information

Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems.

Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC.

BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer.

The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80%. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC. A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining. 496 patients with PTC were included, and 309 (62%) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2mm, p=0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49years, p=0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6%, p=0.004), lymph node metastasis (44 vs. 29.4%, p=0.004) and extra-thyroidal extension (44 vs. 22%, p<0.001). Five-year disease-free survival was 89.6% for BRAF(V600E) positive and 96.3% for negative tumours, p<0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57months for both groups. BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.

Impact of Lymph Node Ratio on Survival in Papillary Thyroid Cancer

In papillary thyroid cancer, the role of lymph node dissection remains controversial, and staging systems consider metastatic lymph nodes as a binary entity. The purpose of this study was to determine a threshold lymph node ratio (LNR) that impacted disease-specific mortality (DSM). We utilized the surveillance, epidemiology, and end results (SEER) database to analyze adult patients who underwent thyroidectomy with lymph node dissection. A LNR (metastatic lymph nodes to total lymph nodes) was calculated after eliminating patients with less than three nodes collected. Kaplan-Meier estimates for DSM were plotted for LNRs and compared by the log rank test. The Cox proportional hazards model was used to evaluate LNR with other known clinical and pathologic determinants of prognosis. A total of 10,955 cases contained data on lymph nodes. Median follow-up time was 25months (range 0-59months), and the mean LNR was 0.28±0.37. After comparing Kaplan-Meier survival estimates and overall DSM rates, we found that a LNR ≥0.42 best divided those with lymph node metastasis based on DSM (p<0.01). Those with a LNR ≥0.42 experienced a DSM rate of 1.72% while those with a LNR <0.42 had a DSM rate of 0.65% (p<0.01). In addition, patients with a LNR ≥0.42 experienced a 77% higher DSM rate compared to those with metastatic lymph nodes as a whole. When considered with other known determinants of prognosis, we found that LNR was strongly associated with DSM (hazard ratio 4.33, 95% confidence interval 1.68-11.18, p<0.01). LNR is a strong determinant of DSM, and a threshold LNR of 0.42 can be used to risk-stratify patients with metastatic lymph nodes.

In Papillary Thyroid Cancer, Preoperative Central Neck Ultrasound Detects Only Macroscopic Surgical Disease, But Negative Findings Predict Excellent Long-Term Regional Control and Survival

Ultrasound (US) of the central neck compartment (CNC) is considered of limited sensitivity for nodal spread in papillary thyroid cancer (PTC); elective neck dissection is commonly advocated even in the absence of sonographic abnormalities. We hypothesized that US is an accurate predictor for long-term disease-free survival, regardless of the use of elective central neck dissection in patients with PTC. A retrospective chart review of 331 consecutive PTC patients treated with total thyroidectomy at M.D. Anderson Cancer Center between 1996 and 2003 was performed. Information retrieved included preoperative sonographic status of the CNC, surgical treatment of the neck, demographics, cancer staging, histopathological variables and use of adjuvant treatment. The endpoints for the study were nodal recurrence and survival. There were 112 males and 219 females with a median age of 44 years (range 11-87). The median follow-up time for the series was 71.5 months (range 12.7-148.7). There were 151 (45.6%) patients with a T1, 58 (17.5%) with a T2, 70 (21.1%) with a T3, and 52 (15.7%) with a T4. Preoperative sonographic abnormalities were present in the CNC in 79 (23.9%) patients. During the surveillance period, 11 (3.2%) patients recurred in the central neck, with an average time for recurrence of 22.8 months. Advanced T stage (T3/T4) and abnormal US were independent prognostic factors for recurrence in the central neck (p=0.013 and p=0.005 respectively). There were 119 (35%) patients with a sonographically negative central compartment who underwent elective central neck dissection; 85 of them (71.4%) were found to be histopathologically N(+) while 34 (28.6%) were pN0. There were no differences in overall survival (p=0.32), disease specific survival (DSS; p=0.49), and recurrence-free survival (p=0.32) between these two groups. Preoperative US of the CNC was an age-independent predictor for overall survival (p<0.001), DSS (p=0.0097), and disease-free survival (p=0.0005) on bivariate Cox regression. US of the central compartment is an age-independent predictor for survival and CNC recurrence-free survival in PTC. Prophylactic neck dissection of the central compartment does not improve long-term disease control, regardless of the histopathological status of the lymph nodes retrieved. Our findings emphasize the ability of US to clinically detect relevant nodal disease and support conservative management of the CNC in the absence of abnormal findings.

Preoperative Lateral Neck Ultrasonography as a Long-term Outcome Predictor in Papillary Thyroid Cancer

To evaluate the long-term outcomes and prognostic value of our sonographically based surgical approach to the lateral neck for recurrences in papillary thyroid cancer (PTC). Retrospective medical chart review. Tertiary cancer institution. The study population comprised 331 consecutive patients primarily treated for papillary thyroid carcinoma (PTC) at a tertiary cancer institution between 1996 and 2003. The lateral neck compartments were surgically addressed only in the presence of abnormalities on ultrasonography (US). Recurrence-free interval and overall, disease-specific, and recurrence-free survival. There were 112 male and 219 female patients, with a median age of 44.7 years (range, 11-87 years). The median follow-up time for the series was 77.9 months (range, 12.7-148.7 months). Preoperative US abnormalities were found in the right neck in 13.3%, in the left neck in 12.3%, and bilaterally in 11.2%; all of these patients underwent a lateral neck dissection at the time of the thyroidectomy. There were 11 recurrences in the series (0.3%), with a median time to presentation of 22.8 months (range, 6.0-55.3 months). Predictors of lateral neck disease-free interval were T stage and distant disease at presentation (P = .01 and P < .001, respectively) and the sonographic status of the ipsilateral and central neck (P = .001 and P < .001). The number of abnormal neck compartments in US correlated with the risk of regional failure (P = .01). The presence of US abnormalities in the lateral neck decreased the 10-year disease-specific survival from 98.3% to 66.9% (P < .001). Preoperative US is an excellent outcome predictor for lateral neck disease-free interval and for disease-specific survival in PTC. Sonographically based surgical approach provides excellent long-term regional control and validates current treatment guidelines.

Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer

Background. Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability. Increased VEGF expression has been associated with poor clinical outcomes in many malignancies. Several recent reports have documented over expression of VEGF in papillary thyroid cancer. We hypothesized that increased expression of VEGF would be associated with either an increased risk of recurrence or a decreased recurrence-free survival in papillary thyroid cancer. Methods. Immunohistochemistry was used to detect VEGF expression in archival paraffin-embedded surgical thyroid specimens from 96 subjects with papillary thyroid cancer. Results. VEGF expression was detected in 98% (94/96) of the samples, predominantly of slight-to-moderate intensity in the majority of malignant cells. However, the specific finding of a diffuse pattern of intense immunostaining for VEGF was detected significantly more often than less intense, patchy immunostaining patterns in subjects with distant metastasis at diagnosis (63% versus 15%, P =.005), local recurrence (58% versus 13%, P =.001), and distant recurrence (83% versus 14%, P =.001). Furthermore, this specific pattern of diffuse, intense VEGF expression was associated with a significantly shorter recurrence-free survival than other staining patterns (P =.007). Conclusions. These data demonstrate that the immunohistochemical pattern of VEGF staining in the initial surgical specimen is strongly associated with the incidence of local and distant metastasis in papillary thyroid cancer. (Surgery 2001;129:552-8.)

Cellular DNA pattern, S-phase frequency and survival in papillary thyroid cancer.

A series of 150 patients with papillary thyroid cancer diagnosed in Iceland during the 30-year period from 1955 through 1984 was retrospectively analyzed. Flow cytometric analysis of archival paraffin-embedded material was used to study the prognostic significance of cellular DNA content and s-phase frequency. DNA-aneuploidy was found in 12% of the tumors. It was significantly more common in the elderly, in moderately and poorly differentiated carcinomas, in males and in tumors with a high proportion of s-phase cells. Multivariate analysis using stepwise Cox's model showed aneuploidy, age at diagnosis, lymph node metastasis and tumor extension beyond the thyroid capsule as independent prognostic factors. The frequency of cells in s-phase was generally low (mean 2.7%). Patients with high s-phase frequency (greater than 2.5%) had less favorable prognosis than patients with low values (less than or equal to 2.5%).