H&E and OCT4/CD34 for the assessment of lympho-vascular invasion in seminoma and embryonal carcinoma.

BACKGROUND: Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT), and it is included in the pT stage. However, its detection on hematoxylin and eosin (H&E) slides is very challenging, and previous studies reported fair to moderate inter-observer agreement among dedicated uropathologists. In the present study, we tested H&E and a recently developed in-house double staining for OCT4/CD34 to detect LVI in GCTT. METHODS: Nine authors [5 non-uropathologists and 4 uropathologists] independently evaluated 34 consecutive and retrospectively enrolled cases of GCTT. We assessed the inter-observer agreement (Fleiss's Kappa) with both H&E and OCT4/CD34. Besides, we compared the consensus diagnosis on both H&E and OCT4/CD34-stained sections with the original diagnosis to evaluate the pT re-staging (McNemar test) and identify the sources of disagreement. RESULTS: The inter-observer agreement among uropathologists plus non-uropathologists was fair with both H&E (KF=0.398; p < 0.001) and OCT4/CD34 (KF=0.312; p < 0.001). OCT4/CD34 (KF=0.290; p < 0.001) slightly reduces the inter-observer agreement compared to H&E (KF=0.321; p < 0.001) for non-uropathologists; in contrast, OCT4/CD34 (KF=0.293; p < 0.001) significantly reduces the inter-observer agreement compared to H&E (KF=0.529; p < 0.001) for uropathologists, changing it from moderate to fair. Consensus diagnosis with H&E modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.070), with pT re-staging in 2/34 (5.9 %) cases (p: 0.500). Consensus diagnosis with OCT4/CD34 modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.289), with pT re-staging in 3/34 (8.8 %) cases (p: 0.250). The consensus diagnosis with OCT4/CD34 modified the consensus diagnosis with H&E in 8/34 (23.5 %) cases (p: 0.727), and these findings resulted in pT-restaging in 3/34 (8.8 %) cases (p: 0.500). The sources of disagreement among uropathologists were: H&E [artefactual clefts misinterpreted as LVI in 4/6 (66.7 %) cases and true foci of LVI misinterpreted as clusters of histiocytes within the vessels in 2/6 (33.3 %) cases], OCT4/CD34 [artefactual clefts misinterpreted as LVI in 2/8 (25 %) cases, true LVI misinterpreted as artefactual clefts in 2/8 (25 %) cases or floaters in 4/8 (50 %) cases]. CONCLUSIONS: OCT4/CD34 does not improve the inter-observer agreement for the assessment of LVI in OCT4(+) GCTT. Consensus diagnosis with H&E modifies the LVI status in a significant number of cases, resulting in changes of the pT stage in a relatively small subgroup. Consensus diagnosis with OCT4/CD34 provides little additional benefit since it cannot exclude mimickers of LVI such as floaters and artefactual clefts. These results argue against the adoption of this diagnostic tool for the routine assessment of OCT4(+) GCTT.

Multicentre risk-adapted management for stage I non-seminomatous germ cell tumours.

BACKGROUND: The Spanish Germ Cell Group is composed of 60 centres. Our challenge was to define a surveillance protocol that would be safe and suitable regardless of population size or geographic coverage. METHODS: From January 1994 to January 2004, 589 patients with stage I non-seminomatous germ cell tumours entered a risk-adapted surveillance protocol after orchiectomy. Patients with vascular or local invasion of adjacent structures (231/589; 39%) received two cycles of BE400P (bleomycin 30 U/week, etoposide 100 mg/m2 x4, cisplatinum 25 mg/m2 x4). Other patients (358/589; 61%) were kept on close follow-up (chest X-ray; serum tumour markers: first year every 2 months, second year every 3 months, third year every 4 months; abdominal computed tomography scans at every other outpatient control). The outcomes selected for the study were feasibility, relapse rate and number of patients lost to follow-up and mortality. RESULTS: Median follow-up was 40 months. In the surveillance group, 21 patients were lost to follow-up. In the chemotherapy group, two patients relapsed at 12 and 14.5 months and they are presently free of disease. In the surveillance group, 71 (19%) patients relapsed, of which 55 (71%) relapsed within the first year. Five (1.4%) patients died of their cancer. Factors associated with relapse were embryonal carcinoma and vascular invasion in patients who refused chemotherapy. CONCLUSIONS: Our risk-adapted surveillance protocol provided a low rate of recurrences.

Identification of clinical stage A nonseminomatous testis cancer patients at extremely low risk for metastatic disease: a combined approach using quantitive immunohistochemical, histopathologic, and radiologic assessment.

PURPOSE: To evaluate previously determined predictors of metastasis in low-stage testis cancer in a consecutive group of clinical stage A patients. PATIENTS AND METHODS: Ninety-one consecutive clinical stage A nonseminomatous germ cell tumor (NSGCT) patients who underwent primary nerve-sparing retroperitoneal lymph node dissection (NSRPLND) had orchiectomy specimens and computed tomographic (CT) scans evaluated blindly in a quantitative fashion. These scores were then correlated with pathologic stage using previously determined paradigms. RESULTS: Using volume of embryonal carcinoma in the orchiectomy specimen, lymph node diameters in the primary landing zones and MIB-1 staining of the orchiectomy specimen, 41 patients were classified as low risk for metastasis. Forty of these 41 had pathologic stage A disease at RPLND. CONCLUSION: These parameters can identify a low-risk group of patients for metastasis who can be rationally offered surveillance.

Proper staging techniques in testicular cancer patients.

Testicular cancer has become a highly curable neoplasm, and research efforts in the 1990s are focusing on ways to improve staging and treatment so as to limit cost and morbidity. Our group has performed a number of recent studies that help to answer a number of important clinical questions. First, do we need to order computed tomography of the chest (CCT) to stage all newly diagnosed patients? Second, how accurate is contemporary era abdominal CT to stage the retroperitoneum in low-stage nonseminoma patients, and are there techniques that may improve accuracy? Third, can histological primary tumor factors be useful to predict stage in low-stage nonseminoma patients? In a study of 201 testicular cancer patients [117 (58%) NSGCT, 84 (42%) seminoma] who had both CCT and chest X-ray (CXR) in initial staging, CXR alone was found to be sufficient initial chest staging in all seminoma patients and in NSGCT patients who had a negative abdominal (CTA). For low-stage patients without retroperitoneal adenopathy, CCT had unacceptable false-positive rates, which precipitated additional invasive maneuvers. For higher stage NSGCT patients with retroperitoneal disease on initial CTA, CXR alone missed a significant number of occult thoracic metastases and CCT remains indicated. In a study of 57 clinical stage 1 NSGCT all having negative staging CTA followed by surgical staging, third and fourth generation CT had a 67% accuracy in predicting retroperitoneal metastases. This contemporary experience shows a 33% false-negative abdominal CT staging rate. Consideration of any nodes, regardless of size, in the primary echelon retroperitoneal areas as indicative of retroperitoneal metastases may hold promise for improving accuracy of CTA in low-stage NSGCT testis cancer. In a study of 92 clinical stage 1 NSGCT patients, determination of primary tumor vascular invasion (VI) and percentage of tumor composed of embryonal carcinoma component (%EMB) was found to be a useful staging tool. A multivariate model using VI and %EMB was able to predict correct stage in 86% of the study cohort, and a probability table with these two variables was created. Using these histological variables in a neural network artificial intelligence program, an expert correctly predicted stage in 92% of patients. In the 1990s chest staging should be tailored to tumor cell type and retroperitoneal disease status. Staging of the retroperitoneum utilizing abdominal CT remains problematic due to the inability to detect microscopic metastases. Primary tumor histological factors, particularly vascular invasion and quantitation of embryonal carcinoma, are clinically useful staging tools.

Immunohistochemical assessment of tumor proliferation and volume of embryonal carcinoma identify patients with clinical stage A nonseminomatous testicular germ cell tumor at low risk for occult metastasis.

BACKGROUND: Thirty percent of patients with clinical Stage A nonseminomatous testicular germ cell tumor (NSGCT) are incorrectly clinically staged. In a previous retrospective study at Indiana University, the combination of tumor proliferation rates by flow cytometry and histopathologic evaluation defined risk groups for occult metastatic disease in these patients with clinical Stage A NSGCT: A new immunohistochemical proliferation marker (MIB-1) was therefore used to assess growth fraction in combination with histopathology in an effort to predict pathologic stage in patients with clinical Stage A NSGCT: METHODS: Primary orchiectomy specimens from 90 consecutive patients with clinical Stage A NSGCT (January 1992-November 1993) who underwent retroperitoneal lymph node dissection at Indiana University were histopathologically evaluated. Formalin fixed, paraffin embedded tissue sections were immunohistochemically stained using a monoclonal antibody against the nuclear proliferation-associated antigen Ki-67 (MIB-1). Satisfactory staining was obtained by using an antigen retrieval method based on microwave oven heating of paraffin sections. RESULTS: MIB-1 immunohistochemical staining showed significant differences in mean values between 65 patients (66.1%) with pathologic Stage A NSGCT and 25 (80.4%) patients with pathologic Stage B NSGCT (P = 0.0032). The negative predictive value for patients with pathologic Stage A disease was 87% using a cut-off of 80% or less MIB-1 positively stained cells. A combined approach, using the absolute volume of embryonal carcinoma per patient (< 2 ml) and MIB-1 immunostaining (< or = 80%) was able to define a group of 30% of all patients who were at extremely low risk for occult metastatic disease. CONCLUSIONS: MIB-1 immunostaining in combination with histopathology aided in defining a low risk group patients with clinical Stage A NSGCT but failed to identify patients at high risk for metastasis. The risk factors need to be tested in a prospective clinical trial to determine if they are potentially useful in assigning therapy to individual patients.

[Non-seminomatous germ cell tumors of the testis. Role of the pathologist in the assessment of prognostic factors based on the specimen of orchiectomy. Proposal of an anatomopathological examination report defined by the Study Group of the Committee of Cancerology of the French Association of Urology]. / Tumeurs germinales non séminomateuses du testicule. Rôle de l'anatomopathologiste dans l'établissement des facteurs du prognostic sur la pièce d'orchidectomie. Proposition d'une fiche d'etude anatomopathologique établie par le Groupe de Travail du Comité de Cancérologie de l'Association Française d'Urologie.

Non-seminomatous germ cell tumors of the testis. Role of the pathologist in the definition of the prognostic factors based on examination of the orchidectomy specimen. Proposal of a pathological examination report form defined by the study Group of the Oncology Committee of the French Urological Association.

Predictive parameters in biologic assessment of low-stage retroperitoneal lymph-node dissection.

In all, 30% of patients felt to have clinical stage A nonseminomatous testis cancer in fact have pathologic stage B disease. Although patients with clinical stage A nonseminoma currently enjoy a very high change for cure, a better assignment of therapy at diagnosis could lead to an overall decrease in the morbidity of treatment. This study analyzed orchiectomy specimens from 102 patients with clinical stage A nonseminomatous testis cancer, all of whom underwent pathologic staging via retroperitoneal lymph-node dissection (RPLND). Various parameters of the orchiectomy specimen were analyzed to determine whether or not clinical staging could be improved on the basis of these factors. Statistical analysis resulted in the following model. If the orchiectomy specimen consisted of 100% embryonal carcinoma the patient was classified as being at high risk for retroperitoneal metastasis. In the absence of this finding the aneuploid cell line as determined by flow cytometry was considered. If the percentage of aneuploid cells in the S phase was less than 29% the patient was felt to be at low risk for retroperitoneal metastasis. If this percentage was greater than 29% the patient was classified as being at high risk. Using this paradigm, 77% of pathologic stage A patients and 91% of pathologic stage B patients were correctly classified. The test efficiency was 82%. This pilot study resulted in an interesting model that should be tested prospectively in consecutive patients to determine whether it is clinically useful.

Linfadenectomía retroperitoneal económica en tumor testicular no seminomatoso etapa clínica A: efectos sobre la eyaculación / Economic retroperitoneal lymphadenectomy in non seminomatous testicular tumors stage A: effects in ejaculation

Se presenta una serie de 10 linfadenectomías retroperitoneales en tumores no seminoma etapa A, en quienes se utiliza una técnica económica. Obtienen conservación de la eyaculación en 9 de los 10 casos