A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice.

BACKGROUND: Adult guidelines recommend BEP (bleomycin, etoposide, cisplatin) for all ovarian germ cell tumours, causing debilitating toxicities in young patients who will survive long term. Paediatricians successfully reduce toxicities by using lower bleomycin doses and substituting carboplatin for cisplatin, while testicular and paediatric immature teratomas (ITs) are safely managed with surgery alone. AIM: The aim was to determine whether reduced-toxicity treatment could rationally be extended to patients older than 18 years. METHODS: Multicentre cohort study was carried out in four large UK cancer centres over 12 years. RESULTS: One hundred thirty-eight patients were enrolled. Overall survival was 93%, and event-free survival (EFS) was 72%. Neoadjuvant/adjuvant chemotherapy (82% BEP) caused 27 potentially chronic toxicities, and one patient subsequently died from acute lymphoblastic leukaemia. There was no difference in histology, stage or grade in patients ≤/>18 years, and EFS was not different in these age groups (≤18:28% and >18:28%; log-rank P = 0.96). Histological subtype powerfully predicted EFS (log-rank P = 4.9 × 10-7). Neoadjuvant/adjuvant chemotherapy reduced future relapse/progression in dysgerminoma (n = 37, chemo:0% vs. no chemo:20%), yolk sac tumour (n = 23, 26.3% vs.75%) and mixed germ cell tumour (n = 32, 40%vs.70%) but not in IT (n = 42, 33% vs.15%). Additionally, we observed no radiological responses to chemotherapy in ITs, pathological IT grade did not predict EFS (univariate hazard ratio 0.82, 95% confidence interval: 0.57-1.19, P = 0.94) and there were no deaths in this subtype. CONCLUSION: Survival was excellent but chemotherapy toxicities were severe, implying significant overtreatment. Our data support the extension of reduced-toxicity, paediatric regimens to adults. Our practice-changing findings that IT was chemotherapy resistant and pathological grade uninformative strongly endorse exclusive surgical management of ovarian ITs at all ages.

A randomized phase III study of 72 h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3).

BACKGROUND: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary toxicity often necessitates drug cessation and death occurs in 1%-2% of patients. A continuous infusion of bleomycin might reduce lung toxicity when compared with the conventional weekly boluses given as part of standard BEP chemotherapy. PATIENTS AND METHODS: A phase 3 trial was conducted based on 212 men with IGCCCG good prognosis metastatic germ cell tumours with 1 : 1 randomization. They were stratified for age, smoking history and renal function. Patients received either conventional BEP with weekly bleomycin (30 000 units/week i.v. bolus) or as a 90 000 unit infusion on day 1 over 72 h. The primary endpoint was CT assessed lung toxicity, secondary endpoints included progression-free survival (PFS), changes in lung function testing and quality of life. Repeated measures mixed effects model was used to analyse the data. RESULTS: CT assessed lung toxicity for the infusional and conventional arm patients were respectively 80% versus 62% at the end of treatment and 54% versus 51% at 1-year post-treatment. There was no significant difference between the two arms for CT assessed lung toxicity (estimated regression coefficient = 1.4, 95% CI: -0.36, 3.16). Older patients had higher toxicity (coefficient = 4.81, 95% CI: 3.04, 6.58). Lung toxicity increased after 1 cycle and peaked at end of treatment (P ≤ 0.002) and then declined. Lung function testing did not predict for subsequent lung damage. The median follow-up was 2.5 years. Two-year PFS rate (infusional: 93%, conventional: 94%; hazard ratio =0.91, 95% CI: 0.33, 2.52) was similar. Cough (P = 0.002) but not shortness of breath (P ≥ 0.09) was associated with bleomycin toxicity. CONCLUSIONS: Infusional bleomycin has no advantage over standard administration. It supports abandoning routine pulmonary function testing, instead the presence of cough should be sought and the early use of CT scanning of the chest to evaluate potential lung toxicity is preferred.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. MATERIALS AND METHODS: This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. RESULTS: Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. CONCLUSIONS: Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

The efficacy of tacrolimus and sirolimus in heavily pre-treated unresectable thymic malignancies.

BACKGROUND: Thymomas and thymic carcinomas, although uncommon, constitute a significant proportion of anterior mediastinal tumours. Systemic chemotherapy is the mainstay of treatment for inoperable or recurrent disease, but immunosuppressive therapy may provide an alternative treatment strategy. PATIENTS AND METHODS: We present a series of 18 patients diagnosed with unresectable thymic tumours, of which eight received immunosuppressive therapy following relapse after chemotherapy. RESULTS: Eight individuals were treated with primary immunotherapy after a median of 3.5 lines of chemotherapy (range 2-6 lines), of which 3 had confirmed myasthenia gravis (MG). After 3 months, 2 patients achieved a radiological partial response and 4 had stable disease. The median time to progression measured 6.8 months (CI 1.4-19.3 months). Two of the 4 patients who progressed on tacrolimus and prednisolone received sirolimus. One of these patients has stable disease (SD) at 21 months, and the other has SD at 3 months. CONCLUSIONS: Although previous case reports have related tacrolimus therapy with tumour shrinkage in patients with MG-associated invasive thymomas, these data are the first to demonstrate the efficacy of such immunosuppressive agents in a larger cohort of heavily pre-treated patients with thymic tumours. Our experience adds to the limited anecdotal evidence in the literature, and suggests that immunosuppressive agents represent a valuable additional treatment for thymic tumours.

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour.

BACKGROUND: We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability. METHODS: Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP. RESULTS: Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72-1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1-6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64-100%). CONCLUSION: Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol.

BACKGROUND: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). METHODS: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan-Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. RESULTS: At study entry, the median age was 76 years (inter-quartile range: 70-80 years), the median PSA was 79 ng ml(-1), and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ≥11 g dl(-1) decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25-0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno-thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001). CONCLUSION: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer.

BACKGROUND: The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. METHODS: Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC. RESULTS: Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%-35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien-Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90-4200) ml and 189 (70-420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6-15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy. CONCLUSIONS: Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.

Increased haematopoietic progenitor cells are associated with poor outcome in patients with metastatic renal cancer treated with sunitinib.

BACKGROUND: Haematopoietic progenitor cells (HPCs) are present in blood in metastatic renal cell cancer (mRCC). We investigate their expression in mRCC patients treated with sunitinib and correlate their expression with plasma growth factor levels [insulin-like growth factor (IGF)-1]. METHODS: Circulating HPCs (CD34(+)/CD45(+)) and plasma IGF-1 levels were measured at specific sequential time points (0, 6, 18 and 28 weeks) in 43 untreated mRCC patients receiving sunitinib (50 mg for 28 days followed by 14-day off treatment). Univariate and multivariate analysis assessed the prognostic significance of HPCs and IGF-1. RESULTS: HPCs levels were raised in 40 of 43 (93%) of patients. IGF-1 levels were raised in 9 of 43 patients (21%). Univariate and multivariate analysis revealed that high HPCs before treatment were associated with a significantly shorter overall survival (hazard ratio 3.3, 95% confidence interval 1.23-8.8, P=0.01), which was not the case for IGF-1 levels. Both HPC and IGF-1 levels fell with sunitinib (61% and 14% fall, respectively, P <0.05 for both). A positive correlation between the falls in HPC and IGF-1 occurred (P<0.001). CONCLUSIONS: HPCs are over expressed in the peripheral blood in the majority of patients with mRCC. Higher levels are associated with poor prognosis. A concurrent fall in HPCs and growth factor expression (IGF-1) with sunitinib occurs.

Low-dose induction chemotherapy with Baby-BOP in patients with metastatic germ-cell tumours does not compromise outcome: a single-centre experience.

BACKGROUND: In some institutions advanced metastatic germ-cell tumour (GCT) is treated with low-dose induction chemotherapy in specific settings. There is a lack of published data supporting its use. The data presented here specifically address this issue for the first time. PATIENTS AND METHODS: Twenty patients with metastatic GCT treated were with low-dose induction chemotherapy [Baby-BOP (bBOP)] between 1998 and 2009. We report the toxicity and outcome and compare it with a control group. RESULTS: bBOP was well tolerated with no treatment-related deaths and a lack of chemotherapy-related toxicity. It was associated with a significant fall in tumour markers (median HCG fell from 35 195 to 11 028 IU/l). The first subsequent cycle of standard chemotherapy was administered a median of 9.5 days after initial treatment and was not associated with excess toxicity. The 2-year overall survival of the poor-prognosis patients treated with bBOP was 79.0% [95% confidence interval (CI) 48% to 93%], which is not significantly different from the 2-year overall survival of 80% [95% CI 55% to 92%] of the poor-prognosis patients, who did not receive bBOP. CONCLUSION: Low-dose induction chemotherapy can be given safely in selected individuals and does not adversely affect subsequent chemotherapy or outcome.

Long-term follow-up of testicular cancer patients shows no predisposition to osteoporosis.

UNLABELLED: Most patients with testis cancer are cured with treatment. However, the incidence of osteoporosis after prolonged follow-up is unknown. This study investigates the incidence of osteoporosis in 39 testis cancer patients with follow-up from 5 to 28 years. There was no increased incidence of osteoporosis. These initial data are reassuring but require further investigation. INTRODUCTION: The majority of patients with testis cancer are cured with either a unilateral orchidectomy alone or orchidectomy and chemotherapy. However, the long-term incidence of osteoporosis following treatment for testicular cancer has not been established. METHOD: This was a single-centre cross-sectional study, where bone mineral density (BMD) measurements were performed in male patients who were previously treated for testicular cancer. BMD measurements were made by dual-energy X-ray scanning (DXA) using a HOLOGIC imaging bone densitometer. The World Health Organisation criteria were used to define osteoporosis and osteopenia. Blood samples were taken from each patient at the time of the DXA scan. Statistical analyses were performed in STATA10. RESULTS: Neither orchidectomy alone nor orchidectomy and chemotherapy together predisposed to osteoporosis [p value = 0.4 (95%CI -0.1-0.8) and p value = 0.2 (95%CI -0.2-0.7), respectively]. Analysis also showed no evidence of an association between cases of osteopenia and length of follow-up (assessed by logistic regression). CONCLUSION: This work found no association between treatment for testis cancer and the development of osteoporosis. Screening the whole population of testis cancer survivors for osteoporosis in the long term is not necessary; however, targeting specific patients with risk factors may be warranted.

A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer.

When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7-10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.

The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis.

BACKGROUND: The use of adjuvant carboplatin in the management of stage I seminoma of the testis has been limited by the lack of long-term data. In this study, we address this issue for the first time. PATIENTS AND METHODS: Data on 199 patients treated with single-agent carboplatin for stage I seminoma of the testis were prospectively collected. Overall mortality, deaths from circulatory disease and the incidence of second cancers were compared with expected values derived from the UK general population. RESULTS: The median follow-up for the cohort was 9.0 years (range 0.1-20.1). There has been no excess in overall mortality [standardised mortality ratio (SMR) 0.89; 95% CI 0.36-1.83], death from circulatory diseases (SMR 1.44; 95% CI 0.39-3.69) or the incidence of second nontestis cancers (standardised incidence ratio 0.96; 95% CI 0.26-2.45) in this group of patients. These findings also applied to specific follow-up periods of >5 or 10 years. Specifically, neither haematological nor solid nontestis tumours occurred in excess. There was an increase in the long-term development of contralateral testis cancers. CONCLUSIONS: This study addresses some of the concerns surrounding the long-term safety of single-agent carboplatin. It also helps in planning long-term follow-up for patients receiving this form of treatment.

Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over.

Malignant testicular germ cell tumours in the elderly are extremely rare with anecdotal accounts of their aggressive behaviour. Fifty cases of germ cell tumour, diagnosed at the age of 60 years or above, were pathologically reviewed. The oldest patient was 86 years of age, with 78% of cases presenting in men in their 60s. Forty-one (82%) of the tumours were seminomas with only nine cases (18%) of mixed or non-seminomatous germ cell tumour. However, all non-seminomatous types of tumour were represented in the series. The macroscopic tumour size was significantly larger (median=6 cm, range=2-11 cm) than comparable series in younger men. They were also of higher stage with more frequent vascular invasion and rete testis invasion than is typically seen in a younger population. The tumours were less associated with intratubular germ cell neoplasia than in younger men as it was present in only 47% of assessable cases. We conclude that germ cell tumours, in man aged 60 years or above, present at a later stage than in younger men, and although most are seminomas, non-seminomatous tumours may occur with a wide spectrum of morphology.

GAMEC--a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours.

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen.

A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours.

BACKGROUND: The outcome of patients with germ-cell tumours (GCTs), who relapse more than once or relapse with a mediastinal primary is poor. We have shown that topoisomerase 1 may be an attractive target in relapsed GCT. We investigated the role of irinotecan, paclitaxel and oxaliplatin (IPO) followed by topotecan-based high-dose therapy in responding patients, in this patient population. PATIENTS AND METHODS: Twenty-eight patients with multiply relapsed gonadal and mediastinal GCT were recruited to this phase 2 study. All patients received IPO chemotherapy and 12 (43%) went on to receive high-dose therapy. The outcome of these patients was assessed using the Kaplan-Meier method with a median progression-free follow-up of 1 year. RESULTS: Twenty patients (71%) responded to the therapy including five complete remissions (18%), 13 (46%) marker-negative partial responses and two (7%) marker-positive partial responses. Nine (32%) patients continue to be progression free, and the median survival for the whole group currently measures 17 months. Out of 12 individuals who received subsequent high-dose therapy consolidation, seven (58%) remain progression free. The commonest grade III/IV toxicity was infection (68%) and there were no IPO-related toxic deaths; there was one death from high-dose therapy. CONCLUSION: Topoisomerase I-based IPO chemotherapy that lacks etoposide is very active in multiply relapsed GCT. This data merit further investigation.

Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding.

The management of androgen independent prostate cancer is increasingly disputed. Diethylstilbestrol and steroids have useful second-line activity in its management. The value of chemotherapy still remains contentious. This paper reports a phase 2 study of two orally active chemotherapy drugs in patients who are absolutely hormone refractory having failed primary androgen blockade and combined oestrogens and corticosteroids. In total, 37 patients who were biochemically castrate with absolute hormone refractory prostate cancer and performance status of 0-3 were enrolled. Therapy consisted of chlorambucil 1 mg kg(-1) given as 6 mg a day until the total dose was reached and lomustine 2 mg kg(-1) given every 56 days (CL56). During this time all hormone therapy was stopped. One patient normalised his PSA with a further two having a greater than 50% decline leading to an objective response rate of 10%. The median time to progression was 3.6 months with an overall survival of 7.1 months. The median survival of this group of patients from first becoming androgen independent was 23.5 months. Eight of 17 (47%) patients who were subsequently re-challenged with hormonal therapy following failure of chemotherapy had a further PSA reduction, three (17%) of which were >50%. The median progression-free interval for the eight patients was 4 months. In conclusion, CL56 has a low objective response rate in the management of absolute hormone refractory prostate cancer. Toxicity was mild. Re-induction of hormone sensitivity following failure of chemotherapy was an unexpected finding that requires further study.

The frequency of intratubular embryonal carcinoma: implications for the pathogenesis of germ cell tumours.

AIMS: To define the frequency and distribution of intratubular embryonal carcinoma (IEC) in an attempt to shed light on the pathogenesis of non-seminomatous germ cell tumours (NSGCTs). Intratubular germ cell neoplasia of unclassified type (IGCNU) is common in NSGCT; however, IEC is rarely described. METHODS AND RESULTS: Sixty-two germ cell tumours were reviewed. Immunochemistry for CD30, placental alkaline phosphatase (PLAP) and c-kit was performed. The distribution, immunohistochemistry and morphology of the intratubular neoplasia were noted. All cases showed widespread IGCNU with PLAP and c-kit staining. CD30 showed strong focal intratubular positivity in 20/31 NSGCTs, 1/29 seminomas and 1/4 mixed seminomas/NSGCTs. In 17 of these cases, the CD30+ tubules were not easily identified as IEC on routine stains. These tubules were scanty in number and c-kit was negative, though some showed patchy PLAP staining. The cells within these tubules differed morphologically from IGCNU. CONCLUSIONS: IEC defined by CD30 positivity is not always easily identified on haematoxylin and eosin staining. We suggest that IEC is a common intermediate step between IGCNU and NSGCTs. The patchy and focal distribution of IEC suggests it may evolve quickly to invasive disease.