Testiculargermcelltumour (TGCT), the most common cancer affecting young men, has a strong heritable basis as evidenced by the 4-8 fold increased risk of TGCT seen in brothers of TGCT patients [,]. High heritability and observation of multiplex TGCT families have long fuelled anticipation that there may exist a ‘major’ TGCT-susceptibility gene suitable for clinical testing, analogous to BRCA1/BRCA2 in breast cancer. Early genetic linkage studies however proved unfruitful but were very much limited in power by the modest size and low frequency of multiplex TGCT families .
Testiculargermcelltumour (TGCT) is the most common cancer in men aged 15-45 years, with over 18,000 new cases diagnosed annually in Europe 1,2 . The incidence of TGCT has approximately doubled over the last four decades in Western Europe 3 , which implicates environmental or lifestyle factors as risk determinants. However to date no exogenous associations have been robustly validated 4 . Family and twin studies support a strong genetic basis to TGCT susceptibility 5,6 , with brothers of cases having an eight-fold increased risk of TGCT 7 . Direct evidence for inherited genetic susceptibility to TGCT has come from recent genome-wide association studies (GWAS), which have identified a number of independent loci influencing TGCT risk 8-17 . The associations identified by GWAS have provided novel insights into the development of TGCT, highlighting the role of genes involved in KIT/KITLG signalling, telomerase function, microtubule assembly and DNA damage repair 18 .
The characteristic morphology and the immunohisto- chemical profile confirmed the diagnosis of papillary renal cell cancer. Papillary renal cell cancer is differentiated from other subtypes of renal cell cancer by using CK7 and AMACR immunohistochemical markers . Most papil- lary renal cell carcinomas are positive for CK7, whereas clear cell renal cell cancer shows either negative or only a focal or expression pattern . A panel of immunohisto- chemical markers, including CD10, RCC, and vimentin, has been proposed for the identification of renal origin of a metastatic tumour [12,14]. Identification of the most common chromosomal aberrations in papillary renal cell cancer (trisomy of chromosome 7 and 17 as well as loss of Y chromosome ) were not necessary in our case due to convincing histological and immunohistochemical features.
RAS/RAF/MEK/ERK, PI3K/AKT, and STAT3, we did not observe perturbation of ERK or STAT3 signalling in response to silencing IGF1R in TGCT cell lines. Cell lines demonstrating high phospho-AKT in response to IGF1 stimulation, which subsequently decreased upon IGF1R silencing, were the most sensitive to chemical IGF1R inhibition and silencing. In contrast, the two least sensitive cell lines either had very low phospho-AKT levels (in cell line 2102, levels were undetectable) or did not alter phospho-AKT when IGF1R was downregu- lated (TCAM2). In addition, the GCT27 cell line, which had little active IGF1R, nonetheless exhibited decreased AKT signalling when IGF1R expression was reduced and was moderately sensitive to the IGF1R inhibitor, as well as demonstrating an intermediate proliferative response to shRNA-mediated silencing. Therefore, AKT signalling appears to be a key response to IGF1R activa- tion in TGCT cells. This is consistent with data for rhab- domyosarcomas, where sensitivity to IGF1R inhibitors was reversed by constitutively active AKT and, con- versely, progression of in vivo tumour models was asso- ciated with AKT reactivation .
Of the four new loci, the functional mechanism at 16p13.13 is most tangible, with expression of GSPT1 (G1- TO S-PHASE TRANSITION 1) found to be upregulated in risk allele carriers. GSPT1 is a proto-oncogene essential for the G1-to-S phase cell cycle transition and regulates mammalian cell growth 38,39 . Perhaps not surprisingly, GSPT1 has been shown to be upregulated in multiple tumour types, including cancers of the stomach, prostate and breast 40 42 . Furthermore, inherited variants in GSPT1 have been reported to confer elevated risk of gastric cancer 41 . As the sample size of available RNA-seq expression data we used is relatively modest (n ¼ 150), the analysis of this effect in a larger data set would be of signiﬁcant interest. GSPT1 is also cited as a potential target for anticancer therapy 40 , due to its role regulating cell cycle progression, a process effectively targeted for various existing drug classes such as mTOR pathway inhibitors.
Background: Major life-threatening complications secondary to cisplatin-based chemotherapy are rare in patients with testiculargermcelltumour (GCT). The incidence of complications increases with dosage of chemotherapy and with a variety of patient-related as well as disease-related conditions. We here report the first case of GCT experiencing as many as four major complications most of which can be explained by the conjunction of several predispositions. Case presentation: A 48 year old patient with testicular seminoma and bulky retroperitoneal and mediastinal metastases underwent cisplatin based chemotherapy. During the third cycle of chemotherapy, he developed thrombosis of the central venous port device, subtotal splenic infarction, and Bleomycin induced pneumonitis (BIP). Three months after completion of therapy, he was struck by thalamic infarction. Genetic testing then revealed heterozygote mutation of Factor V Leiden (FVL). He received full-dose warfarin anticoagulation treatment and steroid treatment for BIP. 18 months thereafter, the patient is still disease-free, oncologically. Neurological symptoms have disappeared, but pulmonary dysfunction persists with a vital capacity of 50%.
Testicular cancer incidence rates show significant heterogeneity between different countries and ethnic groups. The highest rates occur in Caucasian males from Europe and the USA (Waterhouse 1982). Denmark has the highest national incidence rate in the world, 8 men per 100,000 annually (Osterlind 1986). Non-Caucasian populations such as Asians, Africans and Chinese have low rates (Waterhouse 1982). The incidence rate in US Blacks is less than one quarter of that in whites (Brown et al., 1986b) suggesting genetic factors may be relevant in tumour etiology. Enviromental factors may also play a role since Japanese, Chinese and Hispanic immmigrants to the USA have incidence rates intermediate between country of origin and host nation (Menk at a!., 1975; Locke 1980; King and Locke 1980; Spitz at a!., 1986). One possible enviromental factor may be diet. The geographic distribution of fat intake has been found to correlate well with geographic distribution of incidence (Armstrong and Doll 1975). The racial differences may also be explained in part by socio-economic factors; testicular tumours are m ore common in professional and non-manual workers and those living in urban areas (Davies 1981).
In recent studies using the differential display technique, mRNAs from three tumourcell lines, PC-3 (prostate), T24 (bladder) and KCP-4 (head and neck), were amplified and compared with those derived from their acquired cisplatin resistant sublines (Hisano et a l, 1996). Using a total of 15 arbitrary primers in combination with oligo-dT primers, 150 bands differentially displayed between the parental cells and the cisplatin resistant lines were recovered. O f these, 62 hybridized to cellular RNA, as detected by Northern blotting analysis. Twenty-four of the clones were confirmed to be expressed differentially between the sensitive and the resistant cell lines. One of them, the T-plastin gene, which encodes an actin binding protein, was expressed at levels 12-fold higher than the parental bladder tumourcell line, T24. However, this difference was not observed in the other two pairs of cell lines. The transfection of a vector containing full-length T-plastin antisense RNA resulted in decreased T-plastin mRNA expression and increased sensitivity to cisplatin in the resistance T24 subline (T24/DDP10). This subline also showed decreased drug accumulation but transfection with the antisense T-plastin gene resulted in increased drug accumulation. It has therefore been suggested that the overexpression of T-plastin might affect the activity o f the transporter that mediated cisplatin efflux or influx.
Testiculartumour markers are normally measured when a patient presents with a TGCT clinically. In Europe the Testiculartumour markers are measure 1-2 weeks following radical orchidectomy. The testiculartumour markers play an important role in assess- ing response to treatment and follow up. The presence of normal testiculartumour markers prior to orchidectomy does not normally exclude the presence of micrometastatic disease. However, the persistence of testiculartumour markers following post radical in- guinal orchidectomy may occur in patients with hepatic dysfunction, hypogonadotropism and most importantly in metastatic disease. It is also important to note that other malignancies may cause a elevation of testiculartumour markers. Liver, pancreatic, gastric and lung malignancies may cause an elevated AFP level. Pancreatic, liver, gastic, lung, breast, kidney and bladder cancer may cause an elevated b -HCG level.
6 protein-coding RNAs termed microRNAs in GCTs, and discusses potential clinical applications of these markers. Practical aspects that must be considered before such microRNA testing can be incorporated into future routine clinical practice are also highlighted. The ultimate aims of developing circulating microRNA testing alongside conventional tumour marker testing are threefold. Firstly, to rationally reduce or omit the use of CT scans in follow-up for patients whose disease is usually negative for conventional markers (predominantly seminoma subtype) at diagnosis. Secondly, to improve quality of patient survival, through the rational reduction and/or omission of chemotherapy, along with its concomitant late effects, for patients with stage I disease, who are predicted to have excellent outcomes. Thirdly, to improve overall survival for those patients with poor-risk disease, through identification of a robust prognostic signature.
Testicular cancer is classified as nonseminoma if, histolog- ically, the tumour contains any component of embryonal carcinoma, yolk sac tumour, choriocarcinoma, or imma- ture teratoma. Patients with histologically pure seminoma but elevated serum AFP or markedly elevated HCG levels may also be considered to have nonseminoma. Patients are considered to have clinical stage I disease after radical orchiectomy when imaging investigations (including CT abdomen and pelvis, chest) and serum tumour markers (i.e., AFP, HCG, LDH) are normal. Pathological stage I disease is similarly defined except that the men have also had a pathologically negative retroperitoneal lymphadenectomy (RPLND). If lymph node metastases are present and com- pletely excised, the patient is considered to have patho- logical stage II (PS II) disease. While most patients with clinical stage I nonseminoma germcelltumour (NSGCT) are cured with orchiectomy, about 20% to 30% will expe- rience recurrence and require additional treatment for cure.
Testiculargermcell tumours (GCT) are an increasingly common group of tumours, particularly in young males. The success of current management strategies is such that the majority of patients can expect to be cured. This success hinges on accurate disease assessment and application of chemotherapy and radiotherapy. Serum markers can be useful surrogate markers of disease activity, but they cannot accurately assess disease bulk or locate sites of tumour spread. For these purposes imaging is invaluable and now plays an integral role not only in assessment of tumour bulk and sites of metastases but also in monitoring response to therapy, surgical planning and accurate assessment of disease at relapse. The primary modality used for imaging patients with these tumours is computed tomography (CT) but plain film radiography, ultrasound and magnetic resonance imaging (MRI) also have roles to play. Positron emission tomography (PET) scanning is now being more widely used but its optimal role has yet to be agreed. This article reviews the literature relating to imaging in testiculargermcell tumours. It covers the role of imaging from diagnosis through staging to post-treatment monitoring and surveillance and evidence for the use of imaging.
side (75.3%) comparable with other studies (Table1).The most common malignant tumour seen was seminoma which is comparable with other studies. The most common benign tumor was leiomyoma in our series which occured in a 23 year old man showed a spindle cell neoplasm with hyalinisation and prominent collagen bands with many thin walled blood vessels which aroused a possibility of solitary fibrous tumour.(SFT). IHC studies showed CD34 negative and SMA positive excluded SFT [7,17.18] . Malignant testicular and paratesticular tumours were less compared to non neoplastic lesions in our study which is comparable to the global statistics. Among the malignant tumors seminoma is the commonest type observed in most studies followed by mixed germcelltumour similar to that seen in various other studies (Table 2). The predominance of mixed germcell tumours among non-seminomatous tumours have also been reported in various studies ,-]14] . Among the mixed non seminomatous germcelltumour , one case of yolk sac tumour with tetratoma and the other was combination tumour of teratoma, embryonal carcinoma and choriocarcinoma which constituted 5% of testicular tumors in our study and it is described with grave prognosis. [19,20] . Of NSGCT ,yolk sac tumour constituted 2 cases followed by tetratoma. Relative frequency of testiculartumour described by different authors show variation may be due to limited number of tumours in each subcategory which can be due the lower incidence of these tumours  – .
The histogenetic classification of Dixon and Moore (1952) had some deficiencies but to a great extent it has been supported by experimental data in mice (Pierce and Abell, 1970).Nevertheless, it was considered to be too complex and was not received favorably by the andrologists and oncologists. Accordingly, the experts of World Health Organization (WHO) were charged to simplify and modify it. The team of WHO experts, led by Mostofi and Serov, proposed a morphologic classification in which they divide testiculargermcell tumors into two main categories: tumors composed of a single cell type and those composed of more than one cell type (Mostofi and Sobin 1977). At the same time a competing classification was proposed by the TesticularTumour Panel and Registry of Great Britain (TTPR) (Pugh 1976). According to the TTPR classifica- tion the germcell tumors were to be divided into three groups: Seminoma (comprising classical seminoma and spermatocytic seminoma), teratoma, and a mixed seminoma-teratoma group. The teratoma group comprised several subcategories, including teratoma differentiated (TD), malignant teratoma intermediate (MTI), malignant teratoma undifferentiated (MTU), malignant teratoma trophoblastic (MTT).
Treatment for poor prognosis NSGCT is typically based on cisplatin-based chemotherapy and surgery (with an unclear sequence); however, due to the rarity of this disease, no level 1 evidence is available from randomised trials. Post-chemotherapy, there is a high rate of residual and often chemorefractory cancer in patients with primary mediastinal non- seminoma [173, 174]. Although not adequately assessed, the lower chemosensitivity of primary mediastinal NSGCT compared with other TGCCs means that primary surgery or early surgery after one to two cycles of chemotherapy in patients with localised disease may be advantageous to the classical sequence used in metastatic NSGCT (i.e. completion of chemotherapy followed by resection of residual masses). No data are available on the role of radiotherapy in primary mediastinal NSGCT. In contrast to other types of poor prognosis NSGCT, the benefit of early chemotherapy intensification for patients with an unfavourable decline in tumour markers is less clear for primary mediastinal NSGCT than for other tumour types . Caution should be exercised with the use of bleomycin (conduct repeated lung function assessment and/or replace with ifosfamide) to limit the risk of pulmonary
Formalin-fixed paraffin-embedded tissue samples were retrospectively collected. The histopathological lesions of interest were analysed to select the area with more than 80% of malignant cells. All cases were reviewed by the same pathologist (AA) and classified according to WHO criteria. Histopathological review of the testis tumour included tumour size, presence or absence of LVI, rete testis invasion, epididymis invasion (EI) and predomi- nant histological subtype. Three sections cut from tissue blocks of 0.1 mm each were mounted on tissue microar- ray (TMA) blocks. TMA block sections 3-μm thick were mounted on REAL ™ Capillary Gap Microscope Slides
The incidence of TGCT has doubled over the last 40 years. This increase is unlikely to be caused by genetic predisposition alone and environmental factors most likely play an important role as well. Although TGCT is an infrequent disease and it is highly curable, it is still important to unravel the environmental risk factors as well as genetic predisposition for TGCT. Early identification of men with increased risk for inherited TGCT might lead to early detection and improved treatment outcome. In the current literature there are no data on the clinical behaviour (or prognosis) of TGCT in patients with familial TGCT. However, clinical observation does not suggest any differences in survival and presently there is no reason to expect that familial TGCT has a different outcome than sporadic TGCT. Thus identifying TGCT in genetically predisposed men at an earlier stage is expected to improve survival similar to sporadic cases. Early detection could theoretically be achieved by ultrasound of the testes, palpation (routine testicular self examination) and/or by measuring tumour markers. Presently, however, there is no proof that men who routinely examine their testes are more likely to detect earlier stage tumours or improve their prospects for survival  and there are no data on possible benefits of clinical surveillance in familial TGCT. Treatment of TGCT may be further optimized using new insights in the oncogenetic pathways involved, possibly reducing the need for toxic chemotherapy and radiotherapy. The unravelling of the genetic pathway of TGCT might result in the opportunity to develop gene therapy. There are some trials in other types of cancer with promising results. The use of genetically modified autologous tumour cells appears to be a valuable approach for cancer therapy. Further studies are required to determine whether effects on immune activation will result in actual clinical benefit for patients .
Methods: Immunohistochemical staining (IHC) against Mediator complex subunit MED15 was conducted on a TGCT cohort containing tumor-free testis ( n = 35), intratubular germcell neoplasia unclassified (IGCNU, n = 14), seminomas (SEM, n = 107) and non-seminomatous germcell tumors (NSGCT, n = 42), further subdivided into embryonic carcinomas (EC, n = 30), yolk sac tumors (YST, n = 5), chorionic carcinomas (CC, n = 5) and teratomas (TER, n = 2). Quantification of MED15 protein expression was performed through IHC followed by semi-quantitative image analysis using the Definiens software.
Sanger sequencing was used for exons 13, 20, 22 and 23. Intron-exon boundaries were included in all analyses. We identified 12 previously reported single nucleotide polymorphisms and two novel single nucleotide variants. No likely deleterious variants were identified; notably no mutations that were predicted to truncate the protein were identified. Conclusions: Taken together with previous studies, the findings reported here suggest a very limited role for either germ-line or somatic DICER1 mutations in the etiology of TGCT.
With this clinical picture, paraneoplastic syndrome was in the top differentials and we sought to rule out common cancers via investigating for tumor markers and imaging. CTs of the chest and abdomen, in addition to renal, abdominal, and testicular ultrasounds were done. Testicular ultrasounds [Figure 2] revealed a well-defined heterogeneous focal mass with cystic changes and micro-calcification in the left testicle. The mass measured 5 cm by 2.7 cm in size. Pan-CT was performed pre- and post-contrast using a triphasic study, and the scan showed multiple retroperitoneal lymph nodes that are most likely related to the testicular tumor, with no suggestion of thoracic or abdominal metastasis.