Kenneth M. Grigor

Carcinoma in situ in the testis

Carcinoma in situ (CIS) of the testis is a common precursor of germ-cell tumours in adults and adolescents, with the exception of spermatocytic seminoma. This article reviews existing knowledge on the pathobiology, genetic aspects and epidemiology of CIS, discusses current hypotheses concerning pathogenesis and invasive progression of germ-cell neoplasms and provides guidelines for diagnosis and clinical management of CIS.

Can p53 staining be used to identify patients with aggressive superficial bladder cancer

Approximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life‐threatening muscle‐invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow‐up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow‐up of 10 years. Each of 34 patients that had progressed with ≥ pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801‐positive versus negative group was 2.5, with 95% confidence intervals of 1.05–5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients. Copyright

Some anatomical observations on the human placenta as applied to microvascular surgical practice

The human placenta has many vessels traversing its foetal surface. A variety of sizes is available down to vessels of diameter 1 mm. Selection of a suitable artery can provide a vessel that can be satisfactorily used for microsurgical practice. Where other preparations are not available, the human placenta appears to offer a reasonable, cheap and readily available alternative.

The origin and biology of CIS cells: General discussion

Participants at the 4th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis, representing cell biologists and tumour biologists, met together to discuss the similarities and differences between primordial germ cells (PGCs) of the embryo, and the carcinoma in situ (CIS) stem cell of human testicular germ cell tumours (GCTs). Much has been discovered about PGCs in the last 10 years and we still do not know the exact nature of CIS cells. Knowledge of PGCs comes mainly from mouse experiments and knowledge of CIS comes from the study of human tumours. A mouse model of human GCT would help to investigate the nature of CIS cells. Grafting mouse male genital ridges into mouse fetal testes results in the development of testicular tissue and the formation of teratomatous tumour components. Amplification of PGCs in culture is possible but this results in their transformation into embryonic germ (EG) cells. CIS cells die by apoptosis if they are isolated, and short‐term culture is only possible if the CIS cells are cultured in their normal environment within seminiferous tubules. It may be possible for CIS cells to differentiate in culture although they cannot be maintained in culture as isolated cells. Human CIS cells are likely to be formed as a result of in utero factors rather than agents acting on normal adult testicular germ cells. EG cells stimulate feeder cells by paracrine factors but it is not known if these cells produce autocrine factors.

Special issue on the Impact of endocrine disrupters on reproductive health

This special issue of Reproduction contains articles based on presentations at the 7th Copenhagen Workshop on Endocrine Disrupters, which took place in May 2013. The workshop was the seventh in the series of successful meetings held at Rigshospitalet in Copenhagen since 2000 with the aim of bringing together leading scientists across disciplines to discuss the latest aspects of endocrine disruption with focus on human health, particularly on reproduction. More than 200 scientists from all over the world and from a wide variety of disciplines including endocrinology, basic science, toxicology, reproductive biology, immunology, chemistry, environmental health, and epidemiology gathered for 4 days during the meeting. The papers in this special issue reflect the diversity in the fields of science that contribute to our knowledge on how environmental factors can affect hormone systems and thereby compromise health. Reports on the associations between human exposures and different health outcomes from epidemiological and clinical research are accompanied by reports from studies on experimental animal and laboratory models. One of the sessions at the workshop was dedicated to species differences in endocrine-disrupting effects, including a report of comparative studies that calls for caution in the extrapolation of effects between species (Habert et al. 2014). Comprehensive new data on human exposures to a range of mainly non-persistent chemicals present in our daily environment are also presented (Frederiksen et al. 2014) including a study showing that aniline, to which whole populations are exposed, is a hitherto overlooked

Extra embryonic elements in testicular tumours

Extra embryonic elements in germ cell tumours resemble the trophectoderm or yolk sac endoderm which are the extra embryonic membranes of the developing embryo. True chorionic (trophoblastic) differentiation with syncytiotrophoblast and cytotrophoblast, perhaps with a villous pattern, is rare and is associated with a very poor prognosis and with hCG production. Isolated syncytiotrophoblastic cells also produce hCG but are prognostically less sinister. Yolk sac elements occur in two thirds of non seminomatous germ cell tumours, and affect all age groups. Pure forms of yolk sac tumour (YST) occur but are not common except in infants. They are often associated with AFP production but AFP is not a specific marker for YST. Yolk sac tumours have a similar prognosis to malignant teratoma undifferentiated (MTU: embrvonal carcinoma).

Contralateral biopsy in the management of testicular cancer: what we have learned and what we need to improve

There has been ongoing debate whether or not a contralateral testis biopsy should be performed routinely in testicular cancer patients to detect the presence of carcinoma in situ (CIS), which then should be treated to prevent a second overt tumour. At the 8th Copenhagen Workshop on CIS Testis & Germ Cell Cancer (CIS Workshop), held in Denmark in May 2014, preliminary data from two recent retrospective studies in Germany and Denmark were presented (Ruf et al., 2015, Kier et al., 2015). A plenary discussion followed and the main points of discussion are briefly summarized here. Some of the arguments which had already been voiced at the 3rd CIS Workshop (Grigor & Rørth, 1993) were reiterated, but concern raised by false-negative biopsies and new emphasis on the quality of life after treatment have clearly marked the discussion. The concept of taking contralateral testicular biopsies was born in Denmark, where CIS of the testis was first described (Skakkebæk, 1972). The findings confirming the pre-invasive malignant character of CIS (Skakkebæk, 1978) led to the proposal of taking testicular biopsies in patients at risk of testicular cancer and looking for such changes to prevent invasive tumour development. The risk of cancer in the contralateral testicle of patients orchidectomized for germ cell cancer was considered high enough to recommend biopsies as a screening procedure, primarily to avoid metachronous cancer (Berthelsen et al., 1982). This procedure has been standard care in many Danish, German and Austrian centres. In many other countries contralateral biopsies are not routinely performed, mainly because of the successful treatment of the second germ cell cancer, which in general is no longer considered a survival issue. It is a prerequisite for performing a biopsy that CIS always precedes invasive germ cell malignancy, and the assessment of the cohorts of patients who have been biopsied is of fundamental importance for ongoing studies and as the basis of future strategies. Skakkebæk demonstrated that 50 and 70% of patients with CIS developed testicular cancer within 5 and 7 years respectively (Skakkebæk et al., 1981). Thus, it is assumed that all cases of CIS will progress eventually into overt cancer. But we will never know if the incidence of invasive cancer would ever reach 100%, because cases of CIS are now treated before tumour develops. Dr Klaus-Peter Dieckmann suggested during the CIS Workshop’s discussion to look for CIS changes in testicles removed from older men for other reasons, for instance treatment of prostatic cancer, to see if CIS without tumour can be found later in life. Two studies of this kind have been carried out (Giwercman et al., 1991; Linke et al., 2005), but among relatively young men who died suddenly (median age 35 and 33 years, respectively). Both studies found very few cases of unrecognized CIS; 1/399 (0.25%) in the Danish cohort (Giwercman et al., 1991; Olesen et al., 2007) and 6/1388 (0.43%) in the German cohort (Linke et al., 2005). Thus, the number of CIS cases that do not result in tumour development is probably extremely small. However, our case for recommending the screening of all germ cell cancer patients has been weakened by two aspects. First, a relatively large proportion (>1%) of false negative results was found in the retrospective analysis of the Danish screening programme presented at the CIS Workshop (Kier et al., 2015). Secondly, the incidence of metachronous cancer has probably decreased over the last decades owing to the increasing use of systemic, very effective, cisplatin based chemotherapy in the treatment of germ cell malignancies. We have assumed that if a testicular biopsy is proven to be negative for CIS, then the risk of the patient developing testicular cancer is small. However, new and important information indicates that cancer can develop even in testes that have had a previous negative biopsy. This might be caused by a technical or evaluation error, or a too small amount of tissue examined in a single biopsy. Two biopsies from the testis, as initially suggested (Berthelsen & Skakkebæk, 1981), and subsequently implemented at German centres (Dieckmann et al., 2007a), will undoubtedly increase the detection rate of CIS, but it remains to be shown in clinical studies that the rate of metachronous cancers is thereby significantly decreased. The issue is not straightforward; increasing the number of biopsies from a single testis will furthermore increase the complication rate – and it is likely that sporadic

Proceedings of the 5th Copenhagen Workshop on Endocrine Disrupters: Ubiquitous endocrine disrupters and possible human health effects

This special issue of International Journal of Andrology contains the proceedings of the 5th Copenhagen Workshop on Endocrine Disrupters with the subtitle ‘‘Ubiquitous endocrine disrupters and possible human health effects’’, which took place during 20–22 May 2009. The focus of the meeting was on human health effects of endocrine disrupters present in the environment of our modern daily life with emphasis on reproductive effects but also in relation to emerging evidence of other effects. The workshop was the fifth in the series of successful meetings held at Rigshospitalet in Copenhagen since 2000. The aim of these meetings has from the beginning been to bring together leading scientists with different expertise to discus the latest aspects of endocrine disruption. This 5 meeting in the series once again succeeded in this aim and gathered highly engaged participants from multiple disciplines including basic science, toxicology, reproductive biology, endocrinology, immunology and epidemiology. This mixing of people with different backgrounds not only proved to be beneficial for the sharing of ideas and results but also for opening up for new collaborations across disciplines. This special issue contains papers from nearly all speakers of the meeting resulting in a collection of review papers and original studies representing state of the art within the field of endocrine disrupters and human health. To bring the readers a feeling for the discussions that followed each presentation, we have also included the edited comments from the audience after nearly all of the articles in this volume. All papers accepted for this volume have passed the ordinary peer review process of the Journal. The organization of the workshop was a group effort of many people at the Department of Growth and Reproduction but we would in particular like to thank Tina Tronier, Kathrine Hurtigkarl, Anette M. Pedersen, and Britt M. Christensen for their valuable assistance. We also would like to thank Vivien McGrath (Edinburgh) for excellent editorial assistance. Finally, we gratefully acknowledge the generous support from the Danish Ministry of Environment and the Danish Ministry of Health, which made the workshop and this publication possible.

Proceedings of the 7th Copenhagen Workshop on Testicular Carcinoma in Situ and Germ Cell Cancer, 13–15 October 2010

We are pleased to present to our readers a special issue of the International Journal of Andrology containing the proceedings of the 7th Copenhagen Workshop on Testicular Carcinoma in situ and Germ Cell Cancer, held in Copenhagen, Denmark, between October 13th and 15th, 2010. Thirty years have passed since the 1st Copenhagen Workshop on Carcinoma in situ took place in 1980 and the publication of the first proceedings in the International Journal of Andrology (Skakkebæk et al., 1981). Despite this round anniversary, the topic remains alive, because the aetiology and pathogenesis of testicular cancer are still not yet completely elucidated and more needs to be done to improve early detection of carcinoma in situ. Thus scientists keep returning to Copenhagen and – as was true for all previous workshops – the list of participants who attended the 7th one, read as a virtual who-is-who in the field of the basic aspects of germ cell cancer. Despite focussing on translational and basic aspects, the programme encompassed a broad variety of relevant topics, including a review of the approaches to early diagnosis and late side effects of treatment. Thus both, clinicians and molecular geneticists alike could find something of interest at the meeting; either during plenary lectures or at the excellent poster sessions. Most of the speakers contributed papers for this special issue, which reflects very well the variety of topics, the current state-of-the-art in the field covering the diagnosis and basic aspects of testicular cancer. All papers were subjected to the usual, stringent peer-review process according to the requirements of the International Journal of Andrology. Please note that many papers in this special issue are followed by comments voiced by the audience during the meeting; this will give you a feeling of a lively scientific discussion invoked by each topic during the workshop. In addition to the papers presented, several peer-reviewed studies of various aspects of testicular cancer, which had been accepted for publication in the International Journal of Andrology independently of the meeting, are also included in this issue. We feel that these papers enrich this issue while their authors will benefit from the greater attention of the testis cancer research community. As editors of this special issue, we extend our gratitude to all contributors for their excellent articles. We warmly thank all members of the local Organizing Committee, in particular Kathrine Hurtigkarl, Anne Marie Ottesen, Kristian Almstrup, Anette M. Pedersen, Anne Jørgensen, Kate Ewen, Tina Tronier, Britt de Stricker and Britt Meyer Christensen. We thank also Vivien McGrath (Edinburgh) and Andy Beare (Copenhagen) for editorial assistance. Finally, we gratefully acknowledge financial support from the Lundbeck Foundation, the Global Excellence in Health Award from the Regional Council for the Capital Region of Denmark, and the Danish Cancer Society.