Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo

Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 64% of human breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently, we showed that antagonists of gonadotropin-releasing hormone type II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition, we ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Extensive extranodal metastases of basal-like breast cancer with predominant myoepithelial spindle cell differentiation

A differentiation towards myoepithelial cells has been demonstrated in several types of lesions in the breast. These include multifocal myoepitheliomatosis, the rare mixed tumor or pleomorphic adenoma, adenoid cystic carcinoma, adenomyoepithelioma and myoepithelial carcinoma (malignant myoepithelioma). Myoepithelial carcinoma is the only lesion purely composed of myoepithelial cells. All these tumors are benign and/or of low-grade malignancy, with the exception of malignant myoepithelioma. In contrast to the statement of the current World Health Organization (WHO), recent studies have reported that regional and distant metastases may occur in about 50% of pure myoepithelial carcinomas. The presented case of a breast carcinoma with dominant myoepithelial/spindle cell differentiation in a 58-year-old woman is an excellent example to document the highly aggressive biological behavior of this tumor phenotype. Despite an extensive chemotherapy and radiotherapy, the tumor was rapidly progressive, forming a finally exulcerating local tumor relapse and widespread metastases to the myocardium, lungs, liver, kidneys and skin. Similarities in morphology and biological behavior compared to patients with "triple-negative" (hormone receptor and Her2) monophasic sarcomatoid carcinomas and pure spindle cell sarcomas are discussed.

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.

Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome.

Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.

Androgen receptor status is highly conserved during tumor progression of breast cancer

BACKGROUND With the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences. METHODS AR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined. RESULTS AR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n = 17). CONCLUSIONS Most primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC's is recommended.

The clinical impact of p16 status in fine-needle aspirates of cervical lymph node metastasis of head and neck squamous cell carcinomas

Lymph node involvement is prognostically the most determinant clinical factor for patients with head and neck squamous cell carcinomas (HNSCCs). Ultrasound of the neck and fine-needle aspiration (FNA) cytology is one of the first diagnostic procedures and the most accurate diagnostic staging tool for the neck. Patients with HPV-positive oropharyngeal carcinomas (OPSCC) show a significantly better prognosis when compared with HPV-negative OPSCC. P16 overexpression is accepted as surrogate marker for HPV-positive in OPSCC. These HPV/p16-positive OPSCC are localized either in the palatal tonsils or the base of tongue and frequently present with lymph node metastases. We analyzed the correlation and reliability of p16 expression of the FNA of the lymph node metastasis with the immunohistochemical expression of p16 of the same lymph node metastasis and its corresponding primary tumor, as it could be of importance for determining the localization and different prognosis of the primary tumor. 54 HNSCC patients were evaluated, p16 expression of the primary tumors and their lymph node metastases correlated precisely. In 25 of the 54 HNSCC patients, a FNA of the lymph node metastases was taken before the treatment. The positive cytological and immunohistochemical p16 staining correlated exactly. Of the 17 histologically p16-negative lymph node metastases 15 FNA were p16-negative, whereas two samples were p16-positive. In our view, a cytological p16 analysis of cervical lymph node metastasis can facilitate the correct localization of the primary tumor and discriminate reliably HPV-positive OPSCC from HPV-negative HNSCC with their significantly diverse prognosis.

Radionecrosis or tumor recurrence after radiation of laryngeal and hypopharyngeal carcinomas

OBJECTIVE: To analyze the incidence and diagnostic difficulties of radionecrosis vs tumor recurrence of laryngeal and hypopharyngeal carcinomas. STUDY DESIGN AND SETTING: Retrospective study on 341 patients treated by radiation alone or radiochemotherapy. The clinicopathologic findings, work-up, treatment, and follow-up of 20 patients with symptoms suggestive but negative for tumor recurrence on initial imaging studies and endoscopy were analyzed. RESULTS: The incidence of chondroradionecrosis in 341 irradiated patients was 5%. Ten of 20 patients initially negative for tumor recurrence were treated by total laryngectomy; in all laryngectomy specimens, chondroradionecrosis was present, in six specimens associated with tumor recurrence. Ten patients were treated by tracheotomy and tumor recurrence was detected in one patient during follow-up. CONCLUSION: Chondroradionecrosis is a relatively rare treatment complication. Typical imaging findings suggestive of radionecrosis are often missing. Tumor recurrence may be present beneath an intact mucosa and missed by endoscopy.

Elective neck dissection for carcinomas of the oral cavity: occult metastases, neck recurrences, and adjuvant treatment of pathologically positive necks

BACKGROUND: Supraomohyoid neck dissection (SOHND) is currently performed in patients with carcinoma of the oral cavity with clinically negative neck. Most investigators consider SOHND as a staging procedure. METHODS: Records of 100 patients with cancer of the oral cavity and clinically negative neck undergoing SOHND were reviewed. The rate and significance of occult metastases are evaluated, the neck recurrences are analyzed and the indication of adjuvant radiation of pN+ necks is discussed. RESULTS: In 34 of 1814 of analyzed lymph nodes, metastatic disease was detected as follows: 30 macrometastases and 4 micrometastases. In 13 of 34 metastases (38%), extracapsular spread was observed. Twenty of 100 patients (20%) had to be upstaged. In 9 of 87 (10%) patients without local recurrence and with a minimal follow-up of 24 months, 5 ipsilateral (4 within the dissection field) and 5 contralateral neck recurrences were observed. Regional recurrence developed in 4% and 35% of patients with pN0 and pN+ necks, respectively. CONCLUSIONS: In 20% of patients with oral cavity tumors and pN0 neck, occult metastases were disclosed. Neck recurrences developed significantly more often in patients with pN+ than in those with pN0 necks. To evaluate the exact indication for an adjuvant treatment of patients with cN0/pN+ necks, prospective studies should be performed.

Heterosis for biomass-related traits in Arabidopsis investigated by quantitative trait loci analysis of the triple testcross design with recombinant inbred lines

Arabidopsis thaliana has emerged as a leading model species in plant genetics and functional genomics including research on the genetic causes of heterosis. We applied a triple testcross (TTC) design and a novel biometrical approach to identify and characterize quantitative trait loci (QTL) for heterosis of five biomass-related traits by (i) estimating the number, genomic positions, and genetic effects of heterotic QTL, (ii) characterizing their mode of gene action, and (iii) testing for presence of epistatic effects by a genomewide scan and marker x marker interactions. In total, 234 recombinant inbred lines (RILs) of Arabidopsis hybrid C24 x Col-0 were crossed to both parental lines and their F1 and analyzed with 110 single-nucleotide polymorphism (SNP) markers. QTL analyses were conducted using linear transformations Z1, Z2, and Z3 calculated from the adjusted entry means of TTC progenies. With Z1, we detected 12 QTL displaying augmented additive effects. With Z2, we mapped six QTL for augmented dominance effects. A one-dimensional genome scan with Z3 revealed two genomic regions with significantly negative dominance x additive epistatic effects. Two-way analyses of variance between marker pairs revealed nine digenic epistatic interactions: six reflecting dominance x dominance effects with variable sign and three reflecting additive x additive effects with positive sign. We conclude that heterosis for biomass-related traits in Arabidopsis has a polygenic basis with overdominance and/or epistasis being presumably the main types of gene action.

Laryngeal and hypopharyngeal carcinomas after (chemo)radiotherapy: a diagnostic dilemma

PURPOSE OF REVIEW: During recent years, (chemo)radiotherapy has evolved into a primary treatment modality for both early and advanced laryngeal and hypopharyngeal carcinomas. Head and neck surgeons will be concerned more frequently with patients presenting symptoms and signs suggesting recurrent tumor or complications of (chemo)radiotherapy. RECENT FINDINGS: Analysis of histologic characteristics and tumor spread of recurrent carcinomas on whole-organ slices of salvage laryngectomy specimens showed that recurrent laryngeal carcinomas are often present with multiple tumor foci dispersed in different regions; furthermore, they may develop beneath an intact mucosa. Only a few articles analyze the reliability of laryngoscopy and biopsy in detecting recurrences after (chemo)radiotherapy: the number of false negative biopsies is relatively high. The differentiation between radionecrosis and tumor recurrence is difficult by computed tomography scan and magnetic resonance imaging in many cases. Positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging are promising diagnostic modalities to detect or exclude persistent or recurrent disease after (chemo)radiotherapy. SUMMARY: Endoscopy with biopsy, computed tomography scan and conventional magnetic resonance imaging present several deficiencies in diagnosing recurrent disease after (chemo)radiotherapy. New imaging modalities such as positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging show promising results, increasing the diagnostic efficacy.

Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice

BACKGROUND There is an urgent need for preclinical models of prostate cancer; however, clinically relevant patient-derived prostate cancer xenografts (PDXs) are demanding to establish. METHODS Sixty-seven patients who were undergoing palliative transurethral surgery or radical prostatectomy for histologically confirmed, clinically relevant prostate cancer were included in the study. Fresh prostate cancer tissue was identified by frozen analysis in 48 patients. The cancer tissue was transplanted subcutaneously and under the renal capsule of NSG and NOG mice supplemented with human testosterone. All growing PDXs were evaluated by histology and immunohistochemistry. RESULTS Early assessment of the animals at least three months after transplantation included 27/48 (56.3%) eligible PDX cohorts. PDX growth was detected in 10/27 (37%) mouse cohorts. Eight of the ten PDXs were identified as human donor derived lymphomas, including seven Epstein Barr virus (EBV)-positive diffuse large B-cell lymphomas and one EBV-negative peripheral T-cell lymphoma. One sample consisted of benign prostatic tissue, and one sample comprised a benign epithelial cyst. Prostate cancer was not detected in any of the samples. CONCLUSIONS Tumors that arise within the first three months after prostate cancer xenografting may represent patient-derived EBV-positive lymphomas in up to 80% of the early growing PDXs when using triple knockout NSG immunocompromised mice. Therefore, lymphoma should be excluded in prostate cancer xenografts that do not resemble typical prostatic adenocarcinoma. Prostate 9999: XX-XX, 2014. © 2015 Wiley Periodicals, Inc.

Response to neoadjuvant treatment of invasive ductal breast carcinomas including outcome evaluation: MRI analysis by an automatic CAD system in comparison to visual evaluation

BACKGROUND The aim of this study was to evaluate imaging-based response to standardized neoadjuvant chemotherapy (NACT) regimen by dynamic contrast-enhanced magnetic resonance mammography (DCE-MRM), whereas MR images were analyzed by an automatic computer-assisted diagnosis (CAD) system in comparison to visual evaluation. MRI findings were correlated with histopathologic response to NACT and also with the occurrence of metastases in a follow-up analysis. PATIENTS AND METHODS Fifty-four patients with invasive ductal breast carcinomas received two identical MRI examinations (before and after NACT; 1.5T, contrast medium gadoteric acid). Pre-therapeutic images were compared with post-therapeutic examinations by CAD and two blinded human observers, considering morphologic and dynamic MRI parameters as well as tumor size measurements. Imaging-assessed response to NACT was compared with histopathologically verified response. All clinical, histopathologic, and DCE-MRM parameters were correlated with the occurrence of distant metastases. RESULTS Initial and post-initial dynamic parameters significantly changed between pre- and post-therapeutic DCE-MRM. Visually evaluated DCE-MRM revealed sensitivity of 85.7%, specificity of 91.7%, and diagnostic accuracy of 87.0% in evaluating the response to NACT compared to histopathology. CAD analysis led to more false-negative findings (37.0%) compared to visual evaluation (11.1%), resulting in sensitivity of 52.4%, specificity of 100.0%, and diagnostic accuracy of 63.0%. The following dynamic MRI parameters showed significant associations to occurring metastases: Post-initial curve type before NACT (entire lesions, calculated by CAD) and post-initial curve type of the most enhancing tumor parts after NACT (calculated by CAD and manually). CONCLUSIONS In the accurate evaluation of response to neoadjuvant treatment, CAD systems can provide useful additional information due to the high specificity; however, they cannot replace visual imaging evaluation. Besides traditional prognostic factors, contrast medium-induced dynamic MRI parameters reveal significant associations to patient outcome, i.e. occurrence of distant metastases.

Triple isotope (δD, δ17O, δ18O) study on precipitation, drip water and speleothem fluid inclusions for a Western Central European cave (NW Switzerland)

Deuterium (δD) and oxygen (δ18O) isotopes are powerful tracers of the hydrological cycle and have been extensively used for paleoclimate reconstructions as they can provide information on past precipitation, temperature and atmospheric circulation. More recently, the use of δ17O excess derived from precise measurement of δ17O and δ18O gives new and additional insights in tracing the hydrological cycle whereas uncertainties surround this proxy. However, 17O excess could provide additional information on the atmospheric conditions at the moisture source as well as about fractionations associated with transport and site processes. In this paper we trace water stable isotopes (δD,δ17O and δ18O) along their path from precipitation to cave drip water and finally to speleothem fluid inclusions for Milandre cave in northwestern Switzerland. A two year-long daily resolved precipitation isotope record close to the cave site is compared to collected cave drip water (3 months average resolution) and fluid inclusions of modern and Holocene stalagmites. Amount weighted mean δD,δ18O and δ17O are -71.0‰, -9.9‰, -5.2‰ for precipitation, -60.3‰, -8.7‰, -4.6‰ for cave drip water and -61.3‰, -8.3‰, -4.7‰ for recent fluid inclusions respectively. Second order parameters have also been derived in precipitation and drip water and present similar values with 18 per meg for 17O excess whereas d-excess is 1.5‰ more negative in drip water. Furthermore, the atmospheric signal is shifted towards enriched values in the drip water and fluid inclusions (Δ of ~ + 10‰ for δD). The isotopic composition of cave drip water exhibits a weak seasonal signal which is shifted by around 8 - 10 months (groundwater residence time) when compared to the precipitation. Moreover, we carried out the first δ17O measurement in speleothem fluid inclusions, as well as the first comparison of the δ17 O behaviour from the meteoric water to the fluid inclusions entrapment in speleothems. This study on precipitation, drip water and fluid inclusions will be used as a speleothem proxy calibration for Milandre cave in order to reconstruct paleotemperatures and moisture source variations for Western Central Europe.

Implications of intraglandular lymph node metastases in primary carcinomas of the parotid gland

OBJECTIVES/HYPOTHESIS Assess the diagnostic and prognostic relevance of intraglandular lymph node (IGLN) metastases in primary parotid gland carcinomas (PGCs). STUDY DESIGN Retrospective study at a tertiary referral university hospital. METHODS We reviewed the records of 95 patients with primary PGCs, treated at least surgically, between 1997 and 2010. We assessed the clinicopathological associations of IGLN metastases, their prognostic significance, and predictive value in the diagnosis of occult neck lymph node metastases RESULTS Twenty-four (25.26%) patients had IGLN metastases. This feature was significantly more prevalent in patients with advanced pT status (P = .01), pN status (P < .01), and overall stage (P < .001); high-risk carcinomas (P = .01); as well as in patients with treatment failures (P < .01). IGLN involvement was significantly associated with decreased univariate disease-free survival (P < .001). Positive and negative predictive values and accuracy for IGLN involvement in the detection of occult neck lymph node metastases were 63.64%, 90.48%, and 84.91%, respectively. The diagnostic values were generally higher in patients with low-risk subtype of PGCs. CONCLUSIONS IGLN involvement provides prognostic information and is associated with advanced tumoral stage and higher risk of recurrence. This feature could be used as a potential readout to determine whether a neck dissection in clinically negative neck lymph nodes is needed or not. LEVEL OF EVIDENCE 4.