- Email: [email protected]
Causes of testicular cancer
THE LANCET
COMMENTARY
3
J Kingdom
4
Scanning electron micrograph of microvascular cast from (A) normal placenta at 32 weeks’ gestation showing mature intermediate and terminal villi (⫻1000 reduced by half) and (B) of abnormal, elongated, unbranched capillary cast (⫻2350 reduced by half) from case of IUGR at 30 weeks delivered with absent end-diastolic flow velocity in the umbilical artery
angiogenesis but also to determine the extent to which maternofetal well-being is dependent on the quality of placental angiogenesis. The molecular regulation of villous development and placental angiogenesis must involve the interaction of the cellular components of the placenta (trophoblast, stromal cells, and endothelium) and the local oxygen gradients established both within each villus and between the cellular compartments. The human placenta is richly endowed with angiogenic growth factors and their receptors.7 Vascular endothelial growth factor (VEGF), which is critical for angiogenesis, controls trophoblast function8 and stimulates vascular changes in the placenta. Hypoxia upregulates VEGF and downregulates placental growth factor (PlGF), which shares 53% sequence homology with VEGF.7 Recent studies show that the intensity of immunostaining for VEGF9 and PlGF7 in severe IUGR placenta was no different from that in normal placenta, supporting the notion that the placenta was not hypoxic at delivery. Immunocytochemistry is nonquantitative. Relatively quantitative immunoblot analysis confirmed the lack of change in VEGF levels in severe IUGR.7 In pre-eclampsia, however, levels of PlGF were decreased and those of VEGF increased.7 This may indicate that in pre-eclampsia the intervillous space and anchoring villi (source of invading extravillous trophoblast) remain hypoxic and this may prevent the secondary wave of trophoblast invasion required for successful placentation. Molecular confirmation of Kingdom and Kaufmann’s work requires a systematic study of VEGF and PlGF expression with appropriate sampling strategies to reflect changes in the whole placenta. The groups to be studied should include what Kingdom and Kaufmann have termed “preplacental hypoxia”, as in pregnancy at high altitude and maternal anaemia, “uteroplacental hypoxia”, as in pre-eclampsia, and “postplancental hypoxia”, as in severe IUGR with absent end-diastolic flow velocity in the umbilical arteries.
*Asif Ahmed, Mark D Kilby Reproductive Physiopathology Group, Department of Obstetrics and Gynaecology, University of Birmingham, Birmingham B15 2TG, UK 1
2
Genbacev O, Joslin R, Damsky CH, Pollitti BM, Fischer SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion invitro and models the placental defects that occur in pre-eclampsia. J Clin Invest 1996; 97: 540–50. Krebs C, Macara LM, Leiser R, Bowman AWF, Greer IA, Kingdom JCP. Intrauterine growth restriction and absent diastolic flow
Vol 350 • September 20, 1997
5
6
7 8
9
velocity in umbilical artery is associated with maldevelopment of the terminal placental villous tree. Am J Obstet Gynecol 1996; 175: 1534–42. Macara L, Kingdom JCP, Kaufman P, et al. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996; 17: 37–48. Panigel M, Myers RE. Histological and ultrastructural changes in Rhesus monkey placenta following interruption of the fetal placental circulations by fetectomy or interplacental umbilical ligation. Acta Anatomica 1972; 81: 481–506. Pardi G, Cetin I, Marconi AM, et al. Venous drainage of the human uterus: respiratory gases studies in normal and growth retarded pregnancies. Am J Obstet Gynecol 1992; 166: 699–706. Burton GJ, Reshetnikova OS, Milovanov AP, Teleshova OV. Sterelogical evaluation of vascular adaptations in human placental villi to differing forms of hypoxic stress. Placenta 1996; 17: 49–55. Ahmed A. Heparin-binding angiogenic growth factors in pregnancy. Trophoblast Res 1997; 10: 215–58. Ahmed A, Dunk C, Kniss D, Wilkes M. Role of VEGF receptor-1 (Flt1) in mediating calcium-dependent nitric oxide release and limiting DNA synthesis in human trophoblast cells. Lab Invest 1997; 76: 779–91. Lyall F,Young A, Boswell F, Kingdom JCP, Greer IA. Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction does not support placental hypoxia at delivery. Placenta 1977; 18: 269–76.
Causes of testicular cancer Testicular cancer is the commonest malignancy in men aged 15–34, and its incidence is rising.1,2 The risk is increased tenfold among those born with undescended testes.1 A recent cohort study identified 1075 boys treated for cryptorchidism by orchiopexy and/or hormones at Great Ormond Street Hospital for Sick Children, London, from 1951 to 1964.3 From 1971 to June, 1990. 11 boys were diagnosed with testicular tumours (one bilateral), a relative risk of 7·5 when compared with the number expected. Those most at risk were the 120 who had undergone a testicular biopsy (5 cases diagnosed, 0·08 expected, relative risk 67, 95% CI 24–143), leading A J Swerdlow and colleagues3 to speculate about a causal association between the trauma of an open biopsy and the subsequent development of a testicular cancer. The interpretation of statistical association as causal is complex. The association between testicular biopsy and testicular cancer meets two of Bradford Hill’s criteria4—ie, apparent association is specific and the events occurred in the right order (biopsy predates cancer). The strength of the association is questionable, being based on five informative cases. Two of the five cases were bilateral tumours in one individual, and a third had features of dysgenesis. Bilateral tumours are more common in familial cases, and if these are excluded from the analysis the relative risk falls to around 25, with broad confidence intervals. Swerdlow et al could not discern why out of 1075 cases 120 were biopsied, and without this information it is difficult not to view this group as potentially different with an unknown underlying risk of testicular cancer. In a previous study Swerdlow et al5 found no evidence that minor testicular trauma that might occur during sports such as football, horseriding, and cycling, was a risk factor for testicular tumours. Nor is there an increased risk after vasectomy.1 Trauma severe enough to cause testicular atrophy remains a putative risk factor but the evidence is far from conclusive.5 Swerdlow et al3 suggest that the mechanism by which biopsy may cause malignancy is related to the immune 827
THE LANCET
COMMENTARY response it provokes. This has similarities to Greaves’ hypothesis on the aetiology of acute lymphoblastic leukaemia of childhood—namely, an exaggerated cellular response to infection, which leads to clonal expansion of a malignant cell.6 However, in Greaves’ hypothesis the resulting cancer is of the immune system, not of the infected organ. There are several instances of association between chronic inflammation and lymphoma but, except for Marjolin’s ulcer, not with other cancers. There is no evidence that a single incident of trauma can cause cancer, though trauma in patients with cancer may increase the rates of cancer growth and rates of dissemination of disease.7 Other than in skin cancers, where carcinomas are commoner in areas subjected to substantial or repeated trauma, the evidence that trauma contributes substantively to carcinogenesis is weak. The rate of testicular cancer is increasing, as are the rates of cryptorchidism and hypospadias; simultaneously sperm count is declining and male infertility is increasing. These observations have led to speculation about a common aetiology, perhaps related to environmental oestrogen exposure.8 Any such exposure must act within the first weeks or so of gestation to produce such a broad spectrum of effects. Within this context any contribution of biopsy to the overall increase in testicular tumours must be small. A hypothesis of causality should be testable, and this one is. It should be possible to replicate the study elsewhere using a case-control or cohort study design and refocusing the question as “Does testicular tumour increase the risk of testicular tumour?”
Louise Parker Department of Epidemiology, Sir James Spence Institute of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP, UK 1 2
3 4 5 6 7 8
Buetow SA. Epidemiology of testicular cancer. Epidemiol Rev 1995; 17: 433–49. Stone JM, Cruikshank DG, Sandeman T, et al. Trebling of the incidence of testicular cancer in Victoria, Australia (1950–1985). Cancer 1991; 68: 211–19. Swerdlow AJ, Higgins CD, Pike MC. Risk of testicular cancer in cohort of boys with cryptorchidism. BMJ 1997; 314: 1507–11. Hill AB. The environment and disease: association or causation:? Proc R Soc Med 1965; 58: 295–300. Swerdlow AJ, Huttly SA, Smith PG. Is the incidence of testis cancer related to trauma or temperature? Br J Urol 1988; 61: 518–21. Greaves MF. Infant leukaemia: biology, aetiology and treatment. Leukaemia 1996; 10: 372–77. Weiss L. Some effects of mechanical trauma on the development of primary cancers and their metasteses. J Forensic Sci 1990; 35: 614–27. Jensen TK, Toppari S, Keiding N, Skakkebek NE. Do environmental estrogens contribute to the decline in male reproductive health? Clin Chem 1995; 41 (no 12, part 2): 1896–901.
Swimming with the sharks—the MD, MBA The business of medicine in many industrialised countries has been drastically transformed. What was once a highly fragmented industry with little financial oversight has now become a corporate leviathan hungry to cut costs. About 10 years ago, the notion of a physician obtaining a master’s degree in business administration (MBA) would have presupposed someone fleeing the rigours of a clinical practice for a more relaxed business role. Now many physicians are diving headfirst into MBA programmes. The American Medical Association reportedly receives about 20 calls a month from physicians threatening to leave medicine and looking for career advice. The ranks of the American 828
College of Physician Executives swell by about 120 new members each month. In a recent executive MBA programme at the Anderson School at University of California, Los Angeles, 8 out of 72 students were physicians, an overwhelming increase from a decade ago. Reforms in health care have been largely enacted by business-trained professionals without much input from medical professionals. In part, this has occurred because the medical profession has had the most to lose by reforming health care. In the USA the onslaught of corporate medicine run by MBAs touting financial spreadsheets now threatens the income of many physicians. In some cities, physician salaries have decreased by over 30% in the past year. A growing number of physicians have responded to the seismic increase in capitated contracts by adopting the tools of their adversaries. To survive in today’s health-care system, American physicians must not only be a well-trained clinician, but also possess financial expertise and business acumen, skills medical schools and residency programmes have historically not taught. Why does the MD, MBA hold such an attraction beyond the master’s in public health (MPH) or public administration (MPA)? The reason is that it is a headturner. The MBA from a top business school is increasingly associated with financial achievement, which only further enhances the glow of an MD. The dual-degree holder is also credited as an intellectual set apart from other singularly trained professionals. For the physician looking to change careers and leave patient care, the MBA can indicate a commitment to business and differentiation from other job candidates. US business schools have recognised the opportunity to train physicians in business practices. The University of California, Irvine, has established a specialty MBA programme for mid-career healthcare executives and a joint MD, MBA programme for medical students. The University of Pennsylvania Wharton School of Business has long maintained a specific MBA graduate programme in health-care management at its Leonard Davis Institute of Health Economics, which attracts many physicians. Most physicians who obtain MBAs, however, opt for executive MBA programmes. These programmes are usually reserved for those in the middle of their careers who could benefit from business training but lack the time to pursue the degree full time over 2 years. The executive MBA programmes are designed to fulfil all the requirements of a regular MBA programmes but with weekend scheduling, to minimise career disruption. Litigation between patients and their health-care providers will cause competition in health care to evolve from a focus on cost to that of quality. Physicians with business training are better qualified over their businesstrained colleagues to make the best decisions about utilisation of health-care resources. These physicians will undoubtedly play an important role in shaping the healthcare system of the future. Such a task requires people who are “bilingual”, equally versed in speaking the languages of both medicine and business.
James S Kuo Discovery Laboratories Inc, 509 Madison Avenue, 14th Floor, New York, NY 10022, USA
Vol 350 • September 20, 1997
COMMENTARY
3
J Kingdom
4
Scanning electron micrograph of microvascular cast from (A) normal placenta at 32 weeks’ gestation showing mature intermediate and terminal villi (⫻1000 reduced by half) and (B) of abnormal, elongated, unbranched capillary cast (⫻2350 reduced by half) from case of IUGR at 30 weeks delivered with absent end-diastolic flow velocity in the umbilical artery
angiogenesis but also to determine the extent to which maternofetal well-being is dependent on the quality of placental angiogenesis. The molecular regulation of villous development and placental angiogenesis must involve the interaction of the cellular components of the placenta (trophoblast, stromal cells, and endothelium) and the local oxygen gradients established both within each villus and between the cellular compartments. The human placenta is richly endowed with angiogenic growth factors and their receptors.7 Vascular endothelial growth factor (VEGF), which is critical for angiogenesis, controls trophoblast function8 and stimulates vascular changes in the placenta. Hypoxia upregulates VEGF and downregulates placental growth factor (PlGF), which shares 53% sequence homology with VEGF.7 Recent studies show that the intensity of immunostaining for VEGF9 and PlGF7 in severe IUGR placenta was no different from that in normal placenta, supporting the notion that the placenta was not hypoxic at delivery. Immunocytochemistry is nonquantitative. Relatively quantitative immunoblot analysis confirmed the lack of change in VEGF levels in severe IUGR.7 In pre-eclampsia, however, levels of PlGF were decreased and those of VEGF increased.7 This may indicate that in pre-eclampsia the intervillous space and anchoring villi (source of invading extravillous trophoblast) remain hypoxic and this may prevent the secondary wave of trophoblast invasion required for successful placentation. Molecular confirmation of Kingdom and Kaufmann’s work requires a systematic study of VEGF and PlGF expression with appropriate sampling strategies to reflect changes in the whole placenta. The groups to be studied should include what Kingdom and Kaufmann have termed “preplacental hypoxia”, as in pregnancy at high altitude and maternal anaemia, “uteroplacental hypoxia”, as in pre-eclampsia, and “postplancental hypoxia”, as in severe IUGR with absent end-diastolic flow velocity in the umbilical arteries.
*Asif Ahmed, Mark D Kilby Reproductive Physiopathology Group, Department of Obstetrics and Gynaecology, University of Birmingham, Birmingham B15 2TG, UK 1
2
Genbacev O, Joslin R, Damsky CH, Pollitti BM, Fischer SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion invitro and models the placental defects that occur in pre-eclampsia. J Clin Invest 1996; 97: 540–50. Krebs C, Macara LM, Leiser R, Bowman AWF, Greer IA, Kingdom JCP. Intrauterine growth restriction and absent diastolic flow
Vol 350 • September 20, 1997
5
6
7 8
9
velocity in umbilical artery is associated with maldevelopment of the terminal placental villous tree. Am J Obstet Gynecol 1996; 175: 1534–42. Macara L, Kingdom JCP, Kaufman P, et al. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996; 17: 37–48. Panigel M, Myers RE. Histological and ultrastructural changes in Rhesus monkey placenta following interruption of the fetal placental circulations by fetectomy or interplacental umbilical ligation. Acta Anatomica 1972; 81: 481–506. Pardi G, Cetin I, Marconi AM, et al. Venous drainage of the human uterus: respiratory gases studies in normal and growth retarded pregnancies. Am J Obstet Gynecol 1992; 166: 699–706. Burton GJ, Reshetnikova OS, Milovanov AP, Teleshova OV. Sterelogical evaluation of vascular adaptations in human placental villi to differing forms of hypoxic stress. Placenta 1996; 17: 49–55. Ahmed A. Heparin-binding angiogenic growth factors in pregnancy. Trophoblast Res 1997; 10: 215–58. Ahmed A, Dunk C, Kniss D, Wilkes M. Role of VEGF receptor-1 (Flt1) in mediating calcium-dependent nitric oxide release and limiting DNA synthesis in human trophoblast cells. Lab Invest 1997; 76: 779–91. Lyall F,Young A, Boswell F, Kingdom JCP, Greer IA. Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction does not support placental hypoxia at delivery. Placenta 1977; 18: 269–76.
Causes of testicular cancer Testicular cancer is the commonest malignancy in men aged 15–34, and its incidence is rising.1,2 The risk is increased tenfold among those born with undescended testes.1 A recent cohort study identified 1075 boys treated for cryptorchidism by orchiopexy and/or hormones at Great Ormond Street Hospital for Sick Children, London, from 1951 to 1964.3 From 1971 to June, 1990. 11 boys were diagnosed with testicular tumours (one bilateral), a relative risk of 7·5 when compared with the number expected. Those most at risk were the 120 who had undergone a testicular biopsy (5 cases diagnosed, 0·08 expected, relative risk 67, 95% CI 24–143), leading A J Swerdlow and colleagues3 to speculate about a causal association between the trauma of an open biopsy and the subsequent development of a testicular cancer. The interpretation of statistical association as causal is complex. The association between testicular biopsy and testicular cancer meets two of Bradford Hill’s criteria4—ie, apparent association is specific and the events occurred in the right order (biopsy predates cancer). The strength of the association is questionable, being based on five informative cases. Two of the five cases were bilateral tumours in one individual, and a third had features of dysgenesis. Bilateral tumours are more common in familial cases, and if these are excluded from the analysis the relative risk falls to around 25, with broad confidence intervals. Swerdlow et al could not discern why out of 1075 cases 120 were biopsied, and without this information it is difficult not to view this group as potentially different with an unknown underlying risk of testicular cancer. In a previous study Swerdlow et al5 found no evidence that minor testicular trauma that might occur during sports such as football, horseriding, and cycling, was a risk factor for testicular tumours. Nor is there an increased risk after vasectomy.1 Trauma severe enough to cause testicular atrophy remains a putative risk factor but the evidence is far from conclusive.5 Swerdlow et al3 suggest that the mechanism by which biopsy may cause malignancy is related to the immune 827
THE LANCET
COMMENTARY response it provokes. This has similarities to Greaves’ hypothesis on the aetiology of acute lymphoblastic leukaemia of childhood—namely, an exaggerated cellular response to infection, which leads to clonal expansion of a malignant cell.6 However, in Greaves’ hypothesis the resulting cancer is of the immune system, not of the infected organ. There are several instances of association between chronic inflammation and lymphoma but, except for Marjolin’s ulcer, not with other cancers. There is no evidence that a single incident of trauma can cause cancer, though trauma in patients with cancer may increase the rates of cancer growth and rates of dissemination of disease.7 Other than in skin cancers, where carcinomas are commoner in areas subjected to substantial or repeated trauma, the evidence that trauma contributes substantively to carcinogenesis is weak. The rate of testicular cancer is increasing, as are the rates of cryptorchidism and hypospadias; simultaneously sperm count is declining and male infertility is increasing. These observations have led to speculation about a common aetiology, perhaps related to environmental oestrogen exposure.8 Any such exposure must act within the first weeks or so of gestation to produce such a broad spectrum of effects. Within this context any contribution of biopsy to the overall increase in testicular tumours must be small. A hypothesis of causality should be testable, and this one is. It should be possible to replicate the study elsewhere using a case-control or cohort study design and refocusing the question as “Does testicular tumour increase the risk of testicular tumour?”
Louise Parker Department of Epidemiology, Sir James Spence Institute of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP, UK 1 2
3 4 5 6 7 8
Buetow SA. Epidemiology of testicular cancer. Epidemiol Rev 1995; 17: 433–49. Stone JM, Cruikshank DG, Sandeman T, et al. Trebling of the incidence of testicular cancer in Victoria, Australia (1950–1985). Cancer 1991; 68: 211–19. Swerdlow AJ, Higgins CD, Pike MC. Risk of testicular cancer in cohort of boys with cryptorchidism. BMJ 1997; 314: 1507–11. Hill AB. The environment and disease: association or causation:? Proc R Soc Med 1965; 58: 295–300. Swerdlow AJ, Huttly SA, Smith PG. Is the incidence of testis cancer related to trauma or temperature? Br J Urol 1988; 61: 518–21. Greaves MF. Infant leukaemia: biology, aetiology and treatment. Leukaemia 1996; 10: 372–77. Weiss L. Some effects of mechanical trauma on the development of primary cancers and their metasteses. J Forensic Sci 1990; 35: 614–27. Jensen TK, Toppari S, Keiding N, Skakkebek NE. Do environmental estrogens contribute to the decline in male reproductive health? Clin Chem 1995; 41 (no 12, part 2): 1896–901.
Swimming with the sharks—the MD, MBA The business of medicine in many industrialised countries has been drastically transformed. What was once a highly fragmented industry with little financial oversight has now become a corporate leviathan hungry to cut costs. About 10 years ago, the notion of a physician obtaining a master’s degree in business administration (MBA) would have presupposed someone fleeing the rigours of a clinical practice for a more relaxed business role. Now many physicians are diving headfirst into MBA programmes. The American Medical Association reportedly receives about 20 calls a month from physicians threatening to leave medicine and looking for career advice. The ranks of the American 828
College of Physician Executives swell by about 120 new members each month. In a recent executive MBA programme at the Anderson School at University of California, Los Angeles, 8 out of 72 students were physicians, an overwhelming increase from a decade ago. Reforms in health care have been largely enacted by business-trained professionals without much input from medical professionals. In part, this has occurred because the medical profession has had the most to lose by reforming health care. In the USA the onslaught of corporate medicine run by MBAs touting financial spreadsheets now threatens the income of many physicians. In some cities, physician salaries have decreased by over 30% in the past year. A growing number of physicians have responded to the seismic increase in capitated contracts by adopting the tools of their adversaries. To survive in today’s health-care system, American physicians must not only be a well-trained clinician, but also possess financial expertise and business acumen, skills medical schools and residency programmes have historically not taught. Why does the MD, MBA hold such an attraction beyond the master’s in public health (MPH) or public administration (MPA)? The reason is that it is a headturner. The MBA from a top business school is increasingly associated with financial achievement, which only further enhances the glow of an MD. The dual-degree holder is also credited as an intellectual set apart from other singularly trained professionals. For the physician looking to change careers and leave patient care, the MBA can indicate a commitment to business and differentiation from other job candidates. US business schools have recognised the opportunity to train physicians in business practices. The University of California, Irvine, has established a specialty MBA programme for mid-career healthcare executives and a joint MD, MBA programme for medical students. The University of Pennsylvania Wharton School of Business has long maintained a specific MBA graduate programme in health-care management at its Leonard Davis Institute of Health Economics, which attracts many physicians. Most physicians who obtain MBAs, however, opt for executive MBA programmes. These programmes are usually reserved for those in the middle of their careers who could benefit from business training but lack the time to pursue the degree full time over 2 years. The executive MBA programmes are designed to fulfil all the requirements of a regular MBA programmes but with weekend scheduling, to minimise career disruption. Litigation between patients and their health-care providers will cause competition in health care to evolve from a focus on cost to that of quality. Physicians with business training are better qualified over their businesstrained colleagues to make the best decisions about utilisation of health-care resources. These physicians will undoubtedly play an important role in shaping the healthcare system of the future. Such a task requires people who are “bilingual”, equally versed in speaking the languages of both medicine and business.
James S Kuo Discovery Laboratories Inc, 509 Madison Avenue, 14th Floor, New York, NY 10022, USA
Vol 350 • September 20, 1997