Yaron Ehrlich

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor

BACKGROUND The emergence of a primitive neuroectodermal tumor (PNET) within a germ-cell tumor (GCT) is rare. We assess the prognosis and response to treatment. PATIENTS AND METHODS Eighty-one patients were identified. Selected patients were treated with cyclophosphamide 1200 mg/m(2), doxorubicin 75 mg/m(2), and vincristine 2 mg i.v. alternating with ifosfamide 1.8 g/m(2) x 5 days plus etoposide 100 mg/m(2) x 5 days (CAV/IE). Ewings sarcoma (EWS) translocation was assessed using a FISH-based method. RESULTS Median follow-up was 41 months. Seventy-six patients had PNET in the primary tumor or in initial metastasis. Five harbored PNET only at relapse. Twenty-six of 76 underwent primary retroperitoneal lymph node dissection, 13 of whom had retroperitoneal PNET and four are dead of disease (DOD). Fifty of 76 were initially treated with GCT chemotherapy (n = 49) or CAV/IE (n = 1). Twenty-seven of these 50 underwent complete postchemotherapy resection of residual PNET and 17 are DOD. Ten patients received CAV/IE. Eight achieved an objective response, and five are currently alive. One of the 14 specimens examined carried the EWS translocation. CONCLUSIONS PNET of GCT origin is associated with an adverse outcome. For low-volume disease, surgery is the optimal initial therapy. CAV/IE may have a role in patients with unresectable disease.

Primitive neuroectodermal tumors in patients with testicular germ cell tumors usually resemble pediatric-type central nervous system embryonal neoplasms and lack chromosome 22 rearrangements

Primitive neuroectodermal tumors (PNETs) are one of the most frequent types of ‘non-germ cell’ tumor in patients with testicular germ cell tumors and have a guarded prognosis when present in metastatic sites after cisplatin-based chemotherapy. Improved treatments, including targeted therapy, require understanding the biology of these neoplasms. We therefore analyzed the morphologic, immunohistochemical and molecular biologic features of 14 PNETs from 14 patients with concurrent or previous testicular germ cell tumors; 12 tumors were from metastatic sites and 2 were primary in the testis. Using standard light microscopic criteria for central nervous system and peripheral PNETs, we classified nine tumors as medulloepithelioma, three as medulloblastoma/supratentorial PNET, one as neuroblastic tumor with abundant neuropil and true rosettes and one as small cell embryonal tumor/PNET (Ewing sarcoma-like). Immunostains directed against INI1, CD57, S-100 protein, NeuN, WT1, neurofilament, CD99, GFAP, synaptophysin, chromogranin, AE1/AE3 cytokeratin, Fli-1 and collagen IV were performed for each case. INI1 was diffusely and strongly positive in all tumors whereas the other stains, except for cytoplasmic WT1 (which showed substantial reactivity in most tumors), were mostly focal to negative, including CD99 (eight negative, six focal) and Fli-1 (all negative). The most consistently reactive ‘neuroendocrine’ marker was CD57. Each case was also analyzed for chromosome 22 rearrangements using a FISH-based break-apart probe method. Only 1 tumor, classified as medulloepithelioma, was scored positive for chromosome 22 translocation (22% rearranged cells) and the remaining 13 were negative, including the one case that resembled peripheral PNET. We conclude that PNETs derived from testicular germ cell tumors mostly resemble central nervous system PNETs and generally lack the chromosome 22 translocation of peripheral PNETs. Future treatment strategies should take these findings into account.

Serum tumor markers in testicular cancer

Testicular cancer has become a model for a curable neoplasm, where biochemical markers play a critical role. Serum tumor markers are integral in patient management and contributes to the diagnosis, staging, and risk assessment, as well as evaluation of response to therapy and detection of relapse. We review their biochemistry, biology, and clinical use in the setting of localized and metastatic disease. The integration of tumor markers in prognostic models as well as the significance of marker kinetics during chemotherapy is discussed.

Division of Prostatic Anterior Fibromuscular Stroma Reduces Urethral Resistance in an Ex Vivo Human Prostate Model

OBJECTIVES To establish the contribution of the anterior fibromuscular stroma to the urethral resistance in an ex vivo human prostate model. The anterior fibromuscular stroma constitutes the anterior portion of the prostatic surgical capsule. METHODS An intact bladder and prostate were obtained from 10 patients who had undergone cystoprostatectomy. The bladder was filled at a predetermined flow rate through a catheter inserted into the bladder dome. The incoming flow was allowed to drain freely through the urethra. The bladder pressures were recorded after a steady state had been reached. The prostatic anterior fibromuscular stroma was incised longitudinally from the prostatic base to its apex. The bladder pressures were recorded before and after the incision was made and again after suture approximation of the cut edges of the anterior fibromuscular stroma. RESULTS The median patient age was 72 years (range 52-81). The median prostatic volume was 46 cm(3) (range 30-260). A statistically significant decrease in bladder pressure was observed after division of the anterior fibromuscular stroma. The mean pressure decreased from 12.5 cm H(2)O to 10.6 cm H(2)O, with a flow rate of 6 mL/s, and from 16.4 cm H(2)O to 13.7 cm H(2)O, with a flow rate of 12 mL/s (P < .0001). This corresponded to a 15% reduction in bladder pressure. A return to the baseline pressure or greater than baseline was recorded after approximation of the anterior fibromuscular stroma. CONCLUSIONS The anterior fibromuscular stroma plays a significant role in maintaining urethral resistance. Its longitudinal division reduced the bladder pressure an average of 15% across flow rates of 6-12 mL/s.

Advances in the treatment of testicular cancer.

Germ cell tumors (GCT) are relatively uncommon, accounting for only 1% of male malignancies in the United States. It has become an important oncological disease for several reasons. It is the most common malignancy in young men 15-35 years old. GCTs are among a unique numbers of neoplasms where biochemical markers play a critical role. Finally, it is a model of curable cancer. In this review we discuss cancer epidemiology, genetics, and therapeutic principles. Recent advances in the management of stage I GCT and controversies in the management of post chemotherapy residual mass are presented.

Lymphovascular invasion in testicular germ cell tumors: clinicopathological correlates

Introduction We assessed clinical–pathological correlates of lymphovascular invasion in testicular germ–cell tumors. Material and methods Archived pathology specimens from 145 patients treated by radical orchiectomy for testicular germ cell tumors at our institution in 1995–2006 were reanalyzed by a dedicated urologic pathologist, and the corresponding medical records were reviewed. The association of lymphovascular invasion with clinical and pathological parameters was tested using stepwise logistic regression analysis. Results Lymphovascular invasion was identified in 38 (26%) patients and was associated with younger age, testicular pain at presentation, elevated serum tumor markers, nonseminoma histology, and advanced clinical stage. Orchalgia was indicated as the impetus for referral in 67 (46%) patients and characterized as a dull aching sensation, persistent or intermittent in nature. Among the 98 men diagnosed with clinical stage I, those presenting with testicular pain had a 1.8X–higher likelihood of lymphovascular invasion than those without pain (95% CI 1.13–14.9, p = 0.02), and patients with elevated serum tumor markers had an 8.5–fold increased probability of lymphovascular invasion than those presenting with normal tumor markers (CI 1.1–54.2, p = 0.05). Among men with nonseminoma histology, elevated tumor markers was the strongest predictor of lymphovascular invasion in both univariate and multivariate analyses (OR 5.05, 95% CI 1.16–21.8, p = 0.03). Conclusion Providing pathologists with information on pre–orchiectomy tumor marker levels and, possibly, testicular pain at presentation may increase their vigilance in searching for lymphovascular invasion, potentially improving their diagnostic accuracy. Whether it may also translate into improved oncological outcomes needs further evaluation.