Articles 48 www.thelancet.com Vol 374 July 4, 2009 Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study Peter Schmid, Yutaka Nagai, Roshan Agarwal, Barry Hancock, Philip M Savage, Neil J Sebire, Iain Lindsay, Michael Wells, Rosemary A Fisher, Delia Short, Edward S Newlands*, Manfred B Wischnewsky, Michael J Seckl Summary Background Placental-site trophoblastic tumours are a rare form of gestational trophoblastic disease and consequently information about optimum management or prognostic factors is restricted. We aimed to assess the long-term outcome of stage-adapted management by surgery, chemotherapy, or both for patients with the disorder. Methods 35 550 women were registered with gestational trophoblastic disease in the UK (1976–2006), of whom 62 were diagnosed with placental-site trophoblastic tumours and included, retrospectively, in the study. Patients were treated by surgery, chemotherapy, or both. We estimated the probabilities of overall survival and survival without recurrence of disease 5 and 10 years after the date of first treatment, and calculated the association of these endpoints with prognostic factors, including time since antecedent pregnancy, serum concentration of β-human chorionic gonadotropin, and stage of disease, with both univariate and multivariate analyses. Findings Probabilities of overall and recurrence-free survival 10 years after first treatment were 70% (95% CI 54–82) and 73% (54–85), respectively. Patients with stage I disease had a 10-year probability of overall survival of 90% (77–100) and did not benefit from postoperative chemotherapy. By contrast, patients with stage II, III, and IV disease required combined treatment with surgery and chemotherapy; probability of overall survival at 10 years was 52% (3–100) for patients with stage II disease and 49% (26–72) for stage III or IV disease. Outcome for patients who had recurrent or refractory disease was poor: only four (22%) patients achieved long-term survival beyond 60 months. Multivariate analysis showed that the only significant independent predictor of overall and recurrence-free survival was time since antecedent pregnancy. A cutoff point of 48 months since antecedent pregnancy could differentiate between patients’ probability of survival (<48 months) or death (≥48 months) with 93% specificity and 100% sensitivity, and with a positive predictive value of 100% and a negative predictive value of 98%. Interpretation Stage-adapted management with surgery for stage I disease, and combined surgery and chemotherapy for stage II, III, and IV disease could improve the effectiveness of treatment for placental-site trophoblastic tumours. Use of 48 months since antecedent pregnancy as a prognostic indicator of survival could help select patients for risk-adapted treatment. Funding National Commissioning Group. Introduction Gestational trophoblastic disease describes a range of proliferative disorders of the placental trophoblast from premalignant hydatidiform moles (complete and partial) to malignant choriocarcinoma and placental-site trophoblastic tumours. Between 2003, and 2007, five per 100 000 women were diagnosed with gestational trophoblastic disease according to the UK registry from three gestational trophoblastic disease centres. Placental-site trophoblastic tumours were first recog- nised as a distinct entity in 1976, when the term trophoblastic pseudotumour was adopted to characterise the apparently benign nature of the disease. 1 However, after reports of a sometimes aggressive and fatal course, 2,3 the nomenclature was changed to placental-site trophoblastic tumours in 1981, and was subsequently accepted by WHO. 4 Placental-site trophoblastic tumours are slow-growing malignant tumours that most often present with amenorrhoea or irregular vaginal bleeding months or possibly years after a normal delivery, abortion, miscarriage, or hydatidiform mole. 5–8 They are the rarest form of gestational trophoblastic disease and are biologically different from other forms. Often, the tumours secrete a low concentration of β-human chorionic gonadotropin (β-hCG), stain well for human placental lactogen (hPL), grow slowly, metastasise months or years after origination, and are resistant to combination chemotherapy regimens. Therefore, total abdominal hysterectomy is the preferred treatment, provided that the disease is localised to the uterus. 5,6,9 When metastatic disease is present, individual patients can respond to and be cured by chemotherapy, either alone or in combination with surgery. Information about optimum management, long-term outcome, and prognostic factors is restricted because the disorder is so rare. Study results have not shown a clear correlation between serum biomarkers and outcome, but do suggest that stage of disease or time from antecedent pregnancy could be relevant prognostic indicators. 5,6,10 Lancet 2009; 374: 48–55 Published Online June 23, 2009 DOI:10.1016/S0140- 6736(09)60618-8 See Comment page 6 Imperial College London, UK (P Schmid MD, R Agarwal MRCP, Prof M J Seckl FRCP); Charing Cross Gestational Trophoblastic Disease Centre, Imperial College NHS Healthcare Trust, London, UK (P Schmid, Y Nagai MD, R Agarwal, P M Savage FRCP, N J Sebire FRCPath, I Lindsay FRCPath, R A Fisher PhD, D Short, Prof E S Newlands FRCP, Prof M J Seckl); University of the Ryukyus, Okinawa, Japan (Y Nagai); Gestational Trophoblastic Disease Centre, Weston Park Hospital, Sheffield, UK (Prof B Hancock FRCP, Prof M Wells FRCPath); Royal Hallamshire Hospital, Sheffield, UK (Prof M Wells); and University of Bremen, Bremen, Germany (Prof M B Wischnewsky PhD) *Prof E S Newlands died in October, 2006 Correspondence to: Dr Peter Schmid or Prof Michael J Seckl, Department of Medical Oncology, Charing Cross Hospital campus, Imperial College NHS Healthcare Trust and Imperial College London, Fulham Palace Road, London W6 8RF, UK p.schmid@imperial.ac.uk m.seckl@imperial.ac.uk