After decades of rigorous investigations of chemotherapeutic cancer therapies, many cancers, including those of the head and neck, remain beyond our clinical ability to control them. From 3% to 5% of all patients initially cured of early-stage head and neck cancer will develop second primary tumors or local recurrences. 1 This phenomenon has been explained by the concept of field cancerization, which argues that certain risk factors such as alcohol and tobacco change the lining of the upper aerodigestive tract into a so-called condemned mucosa. In such a scenario, alcohol may represent the key risk factor for neoplastic transformation in the oral cavity, the oro-and hypopharynx. [2][3][4] An increasing amount of evidence suggests that alcohol intake and smoking play a synergistic role in the neoplastic progress.One of the most important achievements of molecular oncology has been the demonstration that cancer represents a genetic disease that begins with genetic damages in the genome of one cell in the form of point mutations, DNA rearrangement and gene amplification leading to the distortion of the expression and biochemical function of respective gene products. Growth factor receptors of the class I subfamily, which include the epidermal growth factor receptor (EGFR/HER1) and the related proteins HER2, HER3 and HER4, have shown that amplification or overexpression of those receptors, especially well documented for HER2 in patients with breast and ovarian cancers, plays an important role in carcinogenesis and tumor progression. [5][6][7][8] Multivariate survival analysis showed that HER2 amplification or overexpression is more predictive of clinical outcome than all other known prognosticators with the exception of positive lymph nodes. 9,10 These findings have validated the HER2 receptor as a target for therapeutic intervention. Moreover, recent clinical investigations have confirmed the benefit of antagonistic HER2 antibody therapy in breast cancer using herceptin. 11 Minute genetic changes such as point mutations have been found to cause constitutive activation of the HER2/neu kinase activity and to induce neoplastic disorders. 12 Similarly, the 2 amino acid substitutions Gly380Arg and Ala391Glu in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) have been shown to be responsible for 2 forms of human dwarfism, namely, achondroplasia and morbus crouzon. [13][14][15] Other mutations in the FGFR3 gene have been associated with bladder and cervix cancer. 16 The FGFR signaling system is composed of 4 receptor tyrosine kinases (RTKs) and more than 20 known ligands and has been implicated in the regulation of a multitude of both physiologic and pathophysiologic processes, including migration, wound healing, angiogenesis and cancer. 17 More recently, we have identified a single nucleotide polymorphism (SNP) in codon 388 of the FGFR4 gene, which plays a pivotal role in the progression of breast cancer. This SNP is present at a significantly higher rate in breast cancer patients with early relap...
Aims: Primary mediastinal germ cell tumours (PMGCTs) are rare mediastinal neoplasms, and their diagnosis can be challenging, owing to small biopsy samples. The aim of this study was to develop a diagnostic algorithm using immunohistochemical staining, with a focus on novel markers, and molecular analysis of isochromosome 12p [i(12p)]. Methods and results: Paraffin-embedded tissues of 32 mediastinal tumours were analysed with immunohistochemical staining for sal-like transcription factor 4 (SALL4), Lin-28 homologue A (LIN28), octamer-binding transcription factor 3/4 (OCT3/4), D2-40, cluster of differentiation 117 (CD117), sex-determining region Y-box 17, sex-determining region Y-box 2 (SOX2), cluster of differentiation 30, the b-subunit of human chorionic gonadotropin (b-hCG), GATA-binding protein 3 (GATA3), forkhead box protein A2 (FOXA2), glypican-3 (GPC3), a-fetoprotein (AFP), terminal deoxynucleotidyl transferase (TdT), nuclear protein of the testis (NUT), and pan-cytokeratin. Quantitative real-time polymerase chain reaction was performed to investigate the i(12p) status. Fifteen seminomas, seven teratomas, one yolk sac tumour, one choriocarcinoma and seven mixed PMGCTs were diagnosed. Each entity had different immunohistochemical staining patterns, which helped to distinguish them: OCT3/4, D2-40, CD117 and TdT for seminoma; OCT3/4 and SOX2 for embryonal carcinoma; FOXA2, GPC3 and AFP for yolk sac tumour; and b-hCG and GATA3 for choriocarcinoma. Mature teratomas stained positively for pan-cytokeratin in epithelial components and focally for SALL4, SOX2, GATA3, D2-40, and FOXA2. Furthermore, a NUT carcinoma mimicking a PMGCT was diagnosed, showing strong nuclear SOX2 staining and speckled nuclear NUT staining. i(12p) was detected in 24 of 27 PMGCTs (89%). Conclusion: A diagnostic algorithm is of great importance for a reliable diagnosis of PMGCT in, usually small, tissue biopsy samples. Therefore, a combination of three to four antibodies to identify the correct histological subtype is usually necessary, in addition to morphological features. The i(12p) status serves as an additional option to indicate a germ cell origin in selected cases.
Yolk‐sac tumours (YSTs), a germ cell tumour subtype, occur in newborns and infants as well as in young adults of age 14‐44 years. In clinics, adult patients with YSTs face a poor prognosis, as these tumours are often therapy‐resistant and count for many germ cell tumour related deaths. So far, the molecular and (epi)genetic mechanisms that control development of YST are far from being understood. We deciphered the molecular and (epi)genetic mechanisms regulating YST formation by meta‐analysing high‐throughput data of gene and microRNA expression, DNA methylation and mutational burden. We validated our findings by qRT‐PCR and immunohistochemical analyses of paediatric and adult YSTs. On a molecular level, paediatric and adult YSTs were nearly indistinguishable, but were considerably different from embryonal carcinomas, the stem cell precursor of YSTs. We identified FOXA2 as a putative key driver of YST formation, subsequently inducing AFP , GPC3 , APOA1/APOB , ALB and GATA3/4/6 expression. In YSTs, WNT‐, BMP‐ and MAPK signalling‐related genes were up‐regulated, while pluripotency‐ and (primordial) germ cell‐associated genes were down‐regulated. Expression of FOXA2 and related key factors seems to be regulated by DNA methylation, histone methylation / acetylation and microRNAs. Additionally, our results highlight FOXA2 as a promising new biomarker for paediatric and adult YSTs.
Aims Malignant germ cell tumours (GCTs) of the testis are rare neoplasms, but the most common solid malignancies in young men. World Health Organization guidelines divide GCTs into five types, for which numerous immunohistochemical markers allow exact histological subtyping in the majority of cases. In contrast, a germ cell origin is often hard to prove in metastatic GCTs that have developed so‐called somatic malignant transformation. A high percentage, up to 89%, of GCTs are characterised by the appearance of isochromosome 12p [i(12p)]. Fluorescence in‐situ hybridisation has been the most common diagnostic method for the detection of i(12p) so far, but has the disadvantages of being time‐consuming, demanding, and not being a stand‐alone method. The aim of the present study was to establish a quantitative real‐time polymerase chain reaction assay as an independent method for detecting i(12p) and regional amplifications of the short arm of chromosome 12 by using DNA extracted from formalin‐fixed paraffin‐embedded tissue. Methods and results A cut‐off value to distinguish between the presence and absence of i(12p) was established in a control set consisting of 36 tumour‐free samples. In a training set of 149 GCT samples, i(12p) was detectable in 133 tumours (89%), but not in 16 tumours (11%). In a test set containing 27 primary and metastatic GCTs, all 16 tumours with metastatic spread and/or somatic malignant transformation were successfully identified by the detection of i(12p). Conclusion In summary, the qPCR assay presented here can help to identify, further characterise and assign a large proportion of histologically inconclusive malignancies to a GCT origin.
Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan–Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns.
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