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Open access

Boju Pan, Anqi Wang, Junyi Pang, Yuhan Zhang, Ming Cui, Jian Sun, and Zhiyong Liang

Introduction

PD-L1 is associated with prognosis and immunotherapeutic response in patients with malignancies. In previous studies, PD-L1 expression was detected in many endocrine tumors. However, the PD-L1 expression status in parathyroid tumors is unknown.

Methods

We included 26 parathyroid carcinoma and 37 adenoma samples, as well as the corresponding patient information. PD-L1 was stained using the FDA-approved PD-L1 IHC 22C3 pharmDx and Ventana PD-L1 (SP263) assays, and staining was assessed by the estimated percentages of positive tumor cells and immune cells, respectively.

Results

We classified the PD-L1 expression in the parathyroid tumors into four groups: (0) <1%, (1) 1–4%, (2) 5–9% and (3) ≥10% positive. With the SP263 clone, 37 (carcinoma:adenoma = 18:19) samples scored 0, 13 (carcinoma:adenoma = 4:9) scored 1, 7 (carcinoma:adenoma = 1:6) scored 2 and 6 (carcinoma:adenoma = 3:3) scored 3. However, in the series of cases using the 22C3 clone, 45 (carcinoma:adenoma = 20:25) samples scored 0, 10 (carcinoma: adenoma = 3:7) scored 1, 5 (carcinoma:adenoma = 1:4) scored 2, and 3 (carcinoma:adenoma = 2:1) scored 3. Concerning tumor-infiltrating immune cells, 57 samples were negative and six were positive with SP263, and 59 were negative and four were positive with 22C3. Moreover, PD-L1 expression was negatively correlated with the Ki-67 index and mitotic rate in parathyroid tumors depending on the different clones. However, the results indicated only moderate consistency between the SP263 and 22C3 clones in parathyroid tumors.

Conclusion

We found deficient PD-L1 expression in the majority of parathyroid tumors. However, the PD-L1 expression score in parathyroid tumors depended greatly on the antibody clone used.

Open access

Sofia S Pereira, Tiago Morais, Madalena M Costa, Mariana P Monteiro, and Duarte Pignatelli

Malignant adrenocortical tumors (ACTs) are rare and highly aggressive; conversely, benign tumors are common and frequently found incidentally (the so-called incidentalomas). Currently, the use of molecular markers in the diagnosis of ACTs is still controversial. The aim of this study was to analyze the molecular profile of different ACTs with the purpose of identifying markers useful for differentiating between these tumors. The ACTs that were studied (n=31) included nonfunctioning adenomas (ACAn)/incidentalomas (n=13), functioning adenomas with Cushing's syndrome (ACAc) (n=7), and carcinomas (n=11); normal adrenal glands (n=12) were used as controls. For each sample, the percentage area stained for the markers StAR, IGF2, IGF1R, p53, MDM2, p21, p27, cyclin D1, Ki-67, β-catenin, and E-cadherin was quantified using a morphometric computerized tool. IGF2, p27, cyclin D1, and Ki-67 were the markers for which the percentage of stained area was significantly higher in carcinoma samples than in adenoma samples. Ki-67 and p27 were the markers that exhibited the highest discriminative power for differential diagnosis between carcinomas and all type of adenomas, while IGF2 and StAR were only found to be useful for differentiating between carcinomas and ACAn and between carcinomas and ACAc respectively. The usefulness of Ki-67 has been recognized before in the differential diagnosis of malignant tumors. The additional use of p27 as an elective marker to distinguish benign ACTs from malignant ACTs should be considered.

Open access

Flávia O Valentim, Bárbara P Coelho, Hélio A Miot, Caroline Y Hayashi, Danilo T A Jaune, Cristiano C Oliveira, Mariângela E A Marques, José Vicente Tagliarini, Emanuel C Castilho, Paula Soares, and Gláucia M F S Mazeto

Background

Computerized image analysis seems to represent a promising diagnostic possibility for thyroid tumors. Our aim was to evaluate the discriminatory diagnostic efficiency of computerized image analysis of cell nuclei from histological materials of follicular tumors.

Methods

We studied paraffin-embedded materials from 42 follicular adenomas (FA), 47 follicular variants of papillary carcinomas (FVPC) and 20 follicular carcinomas (FC) by the software ImageJ. Based on the nuclear morphometry and chromatin texture, the samples were classified as FA, FC or FVPC using the Classification and Regression Trees method.

Results

We observed high diagnostic sensitivity and specificity rates (FVPC: 89.4% and 100%; FC: 95.0% and 92.1%; FA: 90.5 and 95.5%, respectively). When the tumors were compared by pairs (FC vs FA, FVPC vs FA), 100% of the cases were classified correctly.

Conclusion

The computerized image analysis of nuclear features showed to be a useful diagnostic support tool for the histological differentiation between follicular adenomas, follicular variants of papillary carcinomas and follicular carcinomas.

Open access

Olav Inge Håskjold, Henrik Stenestø Foshaug, Therese Benedikte Iversen, Helga Charlotte Kjøren, and Vegard Heimly Brun

Objective

The basis of thyroid nodule diagnostics is ultrasound-guided fine needle biopsy with cytological evaluation (FNC) if ultrasound appearance is not clearly benign. The aim of this study was to investigate the predictive potential of dedicated, expert high-resolution ultrasound, to see if histopathological entities of thyroid nodules can be diagnosed without invasive FNC biopsies.

Design

Prospective case-cohort study.

Methods

187 patients with 221 thyroid nodules were examined with ultrasound and prospectively assigned to the expected histopathological diagnosis: colloid nodule, adenomatoid colloid nodule, follicular adenoma, follicular carcinoma, follicular variant of papillary thyroid carcinoma, papillary thyroid carcinoma, or other thyroid cancer. In 101 of these, we later obtained histopathological reports for comparison.

Results

Overall accuracy for classification into discrete histopathological categories by expert ultrasound was 71.3% and Cohen’s Kappa was 0.62. The sensitivity and specificity for detecting malignancy were 97.3% and 78.1%. The diagnostic accuracy for malignancy was 85.1%. ACR-TIRADS scores for the same nodules had a sensitivity of 97.3%, specificity of 26.6%, and accuracy of 52.5%.

Conclusion

Dedicated expert high-resolution ultrasound without FNC can reliably distinguish benign vs malignant nodules, but also differentiate between several histopathological entities in thyroid nodules. There is potential for a reduction in the number of invasive FNC biopsies and diagnostic operations.

Open access

Irfan Vardarli, Manuel Weber, Frank Weidemann, Dagmar Führer, Ken Herrmann, and Rainer Görges

Objective

The usefulness of routine calcitonin measurement for early detection of medullary thyroid carcinoma (MTC) in patients with nodular thyroid disease (NTD) has been investigated in various studies. Recently, a Cochrane review has been published on this issue, but a meta-analysis is lacking yet. Therefore, we performed this meta-analysis.

Methods

We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of routine calcitonin measurement for detecting MTC in patients with NDT were selected. Statistics were performed by using Stata software, risk of bias was assessed using Review Manager version 5.3.

Results

Seventeen studies, involving 74,407 patients were included in the study. Meta-analysis, using the bivariate random effects model and the hierarchical summary receiver operating characteristic (HSROC) curve revealed the following pooled estimates: sensitivity 0.99 (95% CI, 0.81–1.00), specificity 0.99 (95% CI, 0.97–0.99), positive likelihood ratio (L+) 72.4 (95% CI, 32.3–162.1), and negative likelihood ratio (L−) 0.01 (95% CI, 0.00–0.23). Meta-regression analysis showed that the threshold of basal calcitonin is an independent factor, but in particular performing stimulation test is not an independent factor.

Conclusions

We showed that routine basal serum calcitonin measurement in the management of patients with thyroid nodules is valuable for the detection of MTC. However, the published cut-off values should be considered and, if applicable, the patients monitored in a wait-and-see strategy by experienced physicians to avoid overtreatment.

Open access

Ana Carolina de Jesus Paniza, Thais Biude Mendes, Matheus Duarte Borges Viana, Débora Mota Dias Thomaz, Paula B O Chiappini, Gabriel A Colozza-Gama, Susan Chow Lindsey, Marcos Brasilino de Carvalho, Venâncio Avancini Ferreira Alves, Otavio Curioni, André Uchimura Bastos, and Janete Maria Cerutti

The recent reclassification of a follicular variant of papillary thyroid carcinoma (FVPTC), subset as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), aims to avoid overtreatment of patients with an indolent lesion. The diagnosis of NIFTP has recently been revisited using more rigid criteria. This study presents histological and molecular findings and a long clinical follow-up of 94 FVPTC, 40 cases of follicular adenoma (FTA) and 22 cases of follicular carcinoma (FTC) that were classified before the advent of the NIFTP reclassification. All slides were reviewed using these rigid criteria and analysis of numerous sections of paraffin blocks and reclassified as 7 NIFTPs, 2 EFVPTCs, 29 infiltrative FVPTC (IFVPTCs), 57 invasive EFVPTC (I-EFVPTCs), 39 FTAs and 22 FTCs. Remarkably, EFVPTC and NIFTP patients were all free of disease at the end of follow-up and showed no BRAF mutation. Only one NIFTP sample harbored mutations, an NRAS Q61R. PAX8/PPARG fusion was found in I-EFVPTCs and FTC. Although additional studies are needed to identify a specific molecular profile to aid in the diagnosis of lesions with borderline morphological characteristics, we confirmed that the BRAF V600E mutation is an important tool to exclude the diagnosis of NIFTP. We also show that rigorous histopathological criteria should be strongly followed to avoid missing lesions in which more aggressive behavior is present, mainly via the analysis of capsule or vascular invasion and the presence of papillary structures.

Open access

Mieke Van Hemelrijck, Thurkaa Shanmugalingam, Cecilia Bosco, Wahyu Wulaningsih, and Sabine Rohrmann

Background

Despite mounting evidence linking both calcium and IGF1, there is a lack of studies investigating any association between circulating levels of IGF1 and serum calcium.

Methods

Serum calcium, IGF1, and IGF-binding protein 3 (IGFBP3) were measured for 5368 participants in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of IGF1, IGFBP3, and IGF1/IGFBP3 by categories of calcium (lowest 5% (<1.16 mmol/l), mid 90%, and top 5% (≥1.31 mmol/l)). We also performed stratified analyses by sex, age, ethnicity, BMI, serum levels of vitamin D, and bone mineral density (BMD).

Results

Overall, we found that circulating calcium was positively associated with circulating levels of IGF1 and IGFBP3, but not their molar ratio (i.e., geometric mean of IGF1 by increasing calcium categories: 237.63, 246.51, and 264.22 ng/nl; P trend: 0.43; P first vs third category: 0.01). In particular, these associations were observed in women, people aged <60, non-Hispanic whites, those with vitamin D levels above the mean, and those with low BMD. In contrast, there was an inverse association with the molar ratio for those with BMI ≥30 kg/m2.

Conclusion

We found an overall positive association between circulating levels of IGF1 and IGFBP3 and serum calcium. However, stratification by potential effect-modifiers did not support all suggested hypotheses. Our findings provide more insight into the interplay between calcium and IGF1, which in the future can be investigated in larger observational studies allowing for additional stratifications based on a combination of the different effect-modifiers investigated here.

Open access

María J Gómora, Flavia Morales-Vásquez, Enrique Pedernera, Delia Perez-Montiel, Horacio López-Basave, Antonio R Villa, Azucena Hernández-Martínez, Esteban Mena, and Carmen Mendez

The significance of the presence of androgen receptor (AR), estrogen receptor alpha (ER) and progesterone receptor (PR) in ovarian cancer patient survival has been a matter of numerous studies. This study was aimed to describe the expression profile of the three sexual steroid receptors in high-grade serous, endometrioid, mucinous and low-grade serous ovarian carcinoma and its association to the proliferation index in patients with primary ovarian carcinoma diagnosis, before any treatment. Eighty-one samples were obtained from the National Institute of Cancerology in Mexico City and were evaluated for the presence of AR, ER, PR and Ki67 by immunohistochemistry. The four subtypes of ovarian carcinoma displays a specific profile of the eight possible combinations of the steroid receptors with significant differences within the profile and the histological subtypes. High-grade serous carcinoma was characterized by a high frequency of both, triple-negative and AR+ ER− PR+ profiles. Endometrioid carcinoma presented a higher frequency of triple-positive profile. The presence of only AR+ profile was not observed in the endometrioid tumors. The relationship of the receptor profile with the proliferation index in the tumor epithelium shows that the expression of only ER is associated to a reduced proliferation index in endometrioid carcinoma. Steroid hormone receptor expression and co-expression could help characterize ovarian carcinoma.

Open access

Katherine Van Loon, Li Zhang, Jennifer Keiser, Cendy Carrasco, Katherine Glass, Maria-Teresa Ramirez, Sarah Bobiak, Eric K Nakakura, Alan P Venook, Manisha H Shah, and Emily K Bergsland

Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan–Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received 131I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed.

Open access

Deborah Cosentini, Salvatore Grisanti, Alberto Dalla Volta, Marta Laganà, Chiara Fiorentini, Paola Perotti, Sandra Sigala, and Alfredo Berruti

Immunotherapy is widely used in the treatment of different cancer types, including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial cancer. The results of the phase I JAVELIN study failed to demonstrate a substantial activity of the PDL-1 inhibitor Avelumab in advanced adrenocortical carcinoma (ACC). This editorial focus on the possible mechanisms of ACC immunoevasion and suggests strategies to overcome the intrinsic immunotherapy resistance of this disease.