Percentage Of Embryonal Carcinoma Research Articles

Pathological predictors of metastatic disease in testicular non-seminomatous germ cell tumors: which tumor-node-metastasis staging system?

Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for cancer (AJCC). We investigated pathological predictors of metastatic disease at presentation in 219 non-seminomatous germ cell tumors with reference to both classifications. Age, tumor size, percentage of embryonal carcinoma, lymphovascular invasion, invasion of stromal rete testis, hilar soft tissue, epididymis, spermatic cord, and tunica vaginalis, as well as tumor at spermatic cord margin, were assessed and correlated with clinical stage at presentation. Of the 219 NSGCT cases, 151 (69%) were clinical stage I, 68 (31%) were clinical stage II/III. On univariate analysis, tumor size (P = 0.028), percentage of embryonal carcinoma (P = 0.004), lymphovascular invasion (P = 0.001), stromal rete testis invasion (P = 0.001), hilar soft tissue invasion (P = 0.010), epididymis invasion (P = 0.010), direct spermatic cord invasion (P = 0.001), and tumor at spermatic cord margin ((P = 0.009) were associated with higher clinical stage. On multivariate analysis, lymphovascular invasion (P = 0.003), tumor size (P = 0.005), percentage of embryonal carcinoma (P = 0.005), stromal rete testis invasion (P = 0.008) remained significant. A tumor size of 6 cm and an embryonal carcinoma percentage of 70% were the significant cut-off values. We conclude that in addition to lymphovascular invasion, stromal rete testis invasion, tumor size, and embryonal carcinoma percentage are strong predictors of metastatic disease at presentation and their inclusion should be considered in any future TNM revision. Further, our results support the changes in the AJCC TNM eighth edition as invasion of the epididymis and hilar soft tissue were both univariately significant.

Epidermal growth factor receptor and epididymis invasion as prognostic biomarkers in clinical stage I testicular germ cell tumours

BackgroundInguinal orchiectomy is curative in 70–80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT.MethodsFifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays.ResultsClassical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3–9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations.ConclusionsEpididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT.

Defining a New Prognostic Index for Stage I Nonseminomatous Germ Cell Tumors Using CXCL12 Expression and Proportion of Embryonal Carcinoma.

Up to 50% of patients diagnosed with stage I nonseminomatous germ cell tumors (NSGCTs) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up front. Late toxicities from chemotherapy are increasingly recognized. Based on a potential biologic role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse. Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma), and MIB1 staining for proliferation in formalin-fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCTs. TE08/TE22 trial patients had a 76.4% 2-year relapse-free rate, and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test P = 0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma, and VI defines three prognostic groups that were independently validated. CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy.

Importance of pathology for therapy planning of testicular germ cell tumors

Testicular tumors can be divided into germ cell tumors and sex cord stromal tumors. Malignant testicular germ cell tumors (TGCT) represent about 90-95 % of all testicular tumors and are the most common solid neoplasms in young men aged 20-40 years with an increasing incidence in industrialized countries. Treatment of TGCT is performed by an individual and risk-adapted approach taking primary tumor histology, histopathlogical and molecular prognostic risk factors, tumor stage and for metastasized tumors the response to systemic chemotherapy into consideration. Knowledge of the specific histopathology of the primary tumor and the prognostic factors is of utmost importance for the treating urologist and oncologist in order to avoid undertreatment or overtreatment. Established risk factors which have been validated in retrospective and prospective studies for clinical stage I non-seminomatous TGCT are the presence of vascular invasion and the percentage of embryonal carcinoma. In clinical stage I seminomas tumor size (> 4cm) and presence of rete testis infiltration have been identified as risk factors in retrospective but not in prospective studies. Quantitative histopathology of the primary tumor is also important for the management of small residual masses following chemotherapy: if the masses are ≤ 1cm, postchemotherapy retroperitoneal lymph node dissection is only indicated if the primary tumor contains ≥ 50 % teratoma. Quantitative pathohistology of the resected residual masses is of importance for the decision-making process of a consolidating chemotherapy which is only of benefit if the amount of vital cancer tissue is > 10 %. Resection of residual hepatic and thoracic masses is indispensable. For gonadal stromal tumors knowledge of atypical nuclear forms, increased rate of mitosis and increased growth fractions are important for therapy planning.

Precise pathological assessment plays a key role in proper patient management in non–seminoma germ cells tumor

Approximately 30% of stage I nonseminomatous germ cell tumors will have retroperitoneal relapse. The rate for stage I seminomas is 15–20% [1]. Lymphovascular invasion (LVI) in Stage I germ cell tumors is one of the most important risk factors for relapse. Others include histologic type of germ cell tumor and – in mixed tumors – relative proportion of tumor components, especially percentage of embryonal carcinoma. It is worth emphasizing that particular tumor subtypes are inherently associated with LVI – choriocarcinoma being a primary example. However, LVI does not represent a significant risk factor for retroperitoneal relapse in Stage I seminoma cases with literature emphasizing the importance of tumor diameter >4 cm and rete testis invasion [2]. Awareness of factors increasing this risk is necessary for appropriate patient approach. Management of clinical stage I testicular tumor is still a matter of debate and is dependent on many factors as well as institutional preferences. Surveillance, adjuvant chemotherapy or radiotherapy, and retroperitoneal lymph node resection are options depending on tumor histology [3]. Risk–adapted treatment is based on the presence or absence of risk factors. Literature data, especially referring to non–seminoma, report risk–adapted treatment to be equally effective compared with other recognized treatment methods [4]. This is also accepted in seminomas [5]. Yossepowitch et al analyzed 145 patients with testicular germ cell tumors who had undergone radical orchiectomy [6]. Lymphovascular invasion was detected in 38 (26%) men and was significantly correlated with younger age, testicular pain at presentation, elevated pre–orchiectomy serum tumor markers, nonseminoma histology, and advanced clinical stage. In their cohort of men with clinical stage I tumors, testicular pain had a 1.8X–higher likelihood of LVI than those without orchalgia (p = 0.02), and patients with elevated serum tumor markers had an 8.5–fold increased probability of LVI in comparison with those with normal tumor marker levels (p = 0.05). Furthermore in the group of men with nonseminoma histology, the presence of elevated tumor markers at presentation was a strong predictor of LVI on both univariate and multivariate analyses (p = 0.03), controlled for age, pain at presentation, and clinical stage. The relationship between tumor marker levels and LVI has not been extensively studied so far. Authors used widely accepted diagnostic criteria for assessment of LVI. However it is worth emphasizing that in many cases this can be problematic, mostly due to tissue crushing or retraction artifact. Diagnosing LVI in routine H&E (hematoxilin and eosin) sections only can be difficult and the pathologist may seek the assistance of immunohistochemical stains for endothelial markers to validate their observation. Germ cell tumors are aggressive but potentially curable malignancies. Thus, correct diagnosis and comprehensive tumor characteristics enable proper clinical management and treatment. Accounting for appropriate prognostic factors in a particular case is crucial for patients’ prognoses. LVI appears to be such an important factor in germ cell tumors. It is one of the basic elements of a histopathology report of any testicular tumor. However, it is not a usual practice to examine extra sections or deeper levels of paraffin blocks in search of tumor emboli or LVI. Clinical information on factors potentially associated with LVI might initiate such practice among pathologists. Authors suggest that providing pathologists with information on preorchiectomy tumor marker levels and, possibly, testicular pain at presentation may alert them to the likelihood of finding LVI in a testicular tumor specimen. In view of available literature these results are particularly important for non–seminomas, as LVI is a significant risk factor for relapse in these tumors. We are still in need of further studies concerning seminoma cases, where no such correlation has been identified.

Retroperitoneal Lymph Node Dissection with No Adjuvant Chemotherapy in Clinical Stage I Nonseminomatous Germ Cell Tumours: Long-Term Outcome and Analysis of Risk Factors of Recurrence

BackgroundThe best management for patients with clinical stage I (CS1) nonseminomatous germ cell tumours (NSGCT) is still under debate. ObjectiveWe evaluated the long-term oncologic outcome of retroperitoneal lymph node dissection (RPLND) in patients with CS1 NSGCTs and reevaluated the traditional predictors of recurrence in a set of patients not undergoing adjuvant treatment. Design, setting, and participantsBetween 1985 and 1995, 322 consecutive CS1 NSGCT patients underwent primary RPLND not followed by adjuvant chemotherapy in a single referral centre. Patients were followed until relapse for a median time of 17 yr. MeasurementsWe estimated the crude cumulative incidence of any recurrence. Categories pN and pT, vascular invasion (VI), percentage of embryonal carcinoma, and presence of teratoma were evaluated as 2-yr recurrence predictors of event in a binary logistic model. Results and limitationsFifty patients had a recurrence (46 in ≤2 yr and only 4 [1.2%] in >2 yr). The 10-yr recurrence incidence was 15.2%. Significant predictors of recurrence at multivariable analysis were pN+, pT >1, and the presence of VI. However, the discriminative ability of the model was modest (Harrell C=0.74); only 9% and 3% of patients had a predicted recurrence probability >30% and >50%, respectively. ConclusionsRPLND alone could prevent recurrence in 85% of patients and minimise late relapses to 1.2%. Most patients could avoid the immediate and late toxicity of chemotherapy. Prognostic parameters combined into the multivariable model appeared of limited use in identifying a subset of patients at high risk of recurrence.

Surgical management of low‐stage nonseminomatous germ cell testicular cancer

The optimal treatment of low-stage nonseminomatous germ cell testicular cancer (NSGCT) is controversial. For clinical stage (CS) I NSGCT, retroperitoneal lymph node dissection (RPLND), two cycles of chemotherapy and surveillance are all accepted treatment options. For CS IIA-B, standard treatments include RPLND (+/- adjuvant chemotherapy) and induction chemotherapy (+/- RPLND). The long-term survival rate is >97% for CS I and 95% for CS IIA-B NSGCT, regardless of the treatment received. The risk of retroperitoneal metastasis varies by clinical stage (25-35% for CS I, 65-85% for CS IIA-B), and the presence of lymphovascular invasion and percentage of embryonal carcinoma in the primary tumour. Patients with elevated serum tumour markers (STMs) and adenopathy of >3 cm are at high risk of having occult systemic disease. Compared with chemotherapy, RPLND is associated with a considerably more favourable long-term morbidity profile and is the most effective method for controlling the retroperitoneum. Surveillance is associated with the lowest risk of long-term complications. As such, we favour surveillance for low-risk CS I, induction chemotherapy for those at high risk of systemic disease (elevated STM, adenopathy >3 cm), and RPLND for all others. Modified template dissections reduce the risk of ejaculatory dysfunction, but might increase the risk of local recurrence. Therefore, we favour a full-bilateral template dissection with nerve-sparing in patients with low-stage NSGCT. The therapeutic efficacy of laparoscopic RPLND is not proven and currently should be considered a staging procedure only. Adjuvant chemotherapy after RPLND is typically restricted to patients with pathological stage N2-3 disease.

Prospective metastatic risk assignment in clinical stage I nonseminomatous germ cell testis cancer: a single institution pilot study ☆

Objective: To gain initial experience with a histopathologic model to assign metastatic risk in patients with clinical stage I nonseminomatous germ cell testis cancer (CSI NSGCTC). Materials and methods: Histopathologic factors were recorded prospectively, and metastatic risk assigned according to the proposed model. In the model tested, percentage of embryonal carcinoma (%EMB) ≥80% and/or vascular invasion (+VI) denoted high (>50%) occult disease risk, while %EMB < 80% plus absence of VI denoted low (≤10%) risk. Risk stratification was correlated with outcome and assessed statistically. Results: There were 54 patients with CSI testis cancer evaluated during the study period. Patients with pure seminoma ( n = 30), Sertoli cell tumor ( n = 1), and Leydig cell tumor ( n = 1) were excluded from analysis. Twenty-two patients had CSI NSGCTC and comprise the pilot study cohort. The median follow-up duration from the time of study entry is 31 months (range, 20–61 months). Utilizing the model tested, a statistically significant higher likelihood of occult disease in the high risk cohort compared to the low risk cohort was observed (67% vs. 0%; Fisher’s exact test, P = 0.005). Conclusions: The results of the present pilot study are encouraging, particularly in the potential of identifying a cohort at low metastatic risk. In the appropriate setting, such a patient might be considered for surveillance alone following orchiectomy. High risk assignment was associated with a positive predictive value (PPV) of 67%. This level of risk is superior to single factor PPV, and if confirmed, could influence clinical decision making. Further experience with this model in an expanded setting is required to establish its reproducibility and predictive value.

SURVEILLANCE CAN BE THE STANDARD OF CARE FOR STAGE I NONSEMINOMATOUS TESTICULAR TUMORS AND EVEN HIGH RISK PATIENTS

We investigate the results of a surveillance program for stage I nonseminomatous germ cell tumors to validate a surveillance policy, and furthermore improve it by analyzing diagnostic instruments and identifying prognostic factors for relapse. From 1982 to 1994, 90 patients with stage I nonseminomatous germ cell tumors entered a surveillance protocol after orchiectomy. Patients with relapse were treated with cisplatin based chemotherapy. A statistical analysis of possible prognostic factors for relapse was performed. Relapse occurred in 23 (26%) patients. Disease specific survival was 98.9%, and 1 patient died of tumor. Most relapses were located in retroperitoneal lymph nodes only (78%). Tumor markers were the most important indicators of relapse. However, in 22% of patients with relapse abdominal x-ray of lymphangiographic contrast showed the first sign of relapse. Computerized tomography located all but 1 relapse. Vascular invasion (p = 0.0001), tumor size (p = 0.0341) and presence of immature teratoma (p = 0.0154) were significantly predictive of relapse with the multivariate analysis, percentage embryonal carcinoma only by univariate analysis (p = 0.032). The relapse rate was highest (52%) when vascular invasion was present. With surveillance for stage I nonseminomatous germ cell tumors, excellent treatment results can be achieved that are comparable to primary retroperitoneal lymph node dissection. Tumor markers and computerized tomography are highly reliable for detecting relapse. Lymphangiography is still of staging value. Pathological factors may influence the choice of adjuvant treatment. However, relapse risks of 50% to 60% are maximally achieved with presently available prognostic factors, and so sparing morbidity of adjuvant treatment by a surveillance protocol remains a feasible option even in these patients.

RETROPERITONEAL LYMPH NODE DISSECTION FOR THE MANAGEMENT OF CLINICAL STAGE I NONSEMINOMA

We review the rationale for the use of retroperitoneal lymph node dissection for clinical stage I nonseminomatous testis cancer. The published literature regarding the alternative treatments for clinical stage I nonseminoma was reviewed as well as the personal experience of the authors to define the role of retroperitoneal lymph node dissection. Retroperitoneal lymph node dissection alone is curative in 50% to 75% of patients with pathological stage II disease. The only significant long-term morbidity is a 1% chance of small bowel obstruction. If recurrence develops after retroperitoneal lymph node dissection, it is virtually always curable with cisplatin based chemotherapy. Retroperitoneal lymph node dissection retains a therapeutic and staging capability in these patients. The probability for cure, short and long-term morbidity, and minimal need for long-term followup in these patients indicates that retroperitoneal lymph node dissection continues to be standard therapy for clinical stage I nonseminoma.

MIB-1 Immunohistochemistry in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors Predicts Patients at Low Risk for Metastasis

BACKGROUND The clinical Stage I of nonseminomatous germ cell tumors (NSGCT) is inaccurate in 30% of patients. In previous studies on tumor biologic risk factors, low tumor proliferation rates predicted a group of patients at low risk for occult metastatic disease. The goal of this study was to confirm the immunohistochemical assessment of tumor proliferation using MIB-1 (Ki-67 receptor) in a different patient cohort with different investigators to prove the method's reliability. METHODS Orchiectomy specimens of 78 patients with clinical Stage I NSGCT (50 patients with pathologic Stage I and 28 patients with pathologic Stage II disease, all patients underwent retroperitoneal lymph node dissection) were retrospectively analyzed by histopathologic reevaluation and MIB-1 immunostaining. RESULTS Mean MIB-1 values between the two pathologic stages differed significantly (51.5% MIB-1 positive tumors cells in pathologic Stage I and 75.1% MIB-1 positive tumor cells in pathologic Stage II disease; P = 0.02). Using a 70% cutoff value, pathologic stages were correctly classified in 69% of cases (sensitivity of 86%, specificity of 60%, negative predictive value of 88%, and positive predictive value of 55%). Compared with traditional risk factors such as percentage of embryonal carcinoma and vascular invasion, in multivariate analysis, MIB-1 was the best predictor of patients at low risk for metastasis. CONCLUSIONS This study in a different patient population with different investigators confirmed previous results of MIB-1 staining to predict a group of patients with clinical Stage I NSGCT who were at low risk for metastasis. The method is simple and reproducible to improve risk classification in low stage testicular carcinoma. Using this technique, a group of patients at very low risk for metastasis can be identified. [See editorial counterpoint on pages 1641-5 and reply to counterpoint on page 1646, this issue.] Cancer 1997; 79:1710-6. © 1997 American Cancer Society

Molecular pathogenesis and prognostic factors in testicular tumor

Aim of this review article was to critically analyse the recently described zytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosome i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (Cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromsomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in research for prognosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it also will define new approaches to classification and management of germ cell tumors.

Immunohistochemical Expression of Ki-67 to Predict Lymph Node Involvement in Clinical Stage I Nonseminomatous Germ Cell Tumors

Purpose Primary archival tumor tissues of 89 patients with clinical stage I nonseminomatous germ cell tumors were analyzed for MIB-1 expression and histological parameters such as percentage embryonal carcinoma and presence of vascular invasion to determine the value of these parameters to predict absence or presence of occult lymph node disease. Materials and Methods A monoclonal antibody (MIB-1) developed for application in paraffin-embedded tissues was used to measure immunohistochemical expression of Ki-67 for the overall tumor (total MIB-1) and for each malignant cell type present. In addition, the primary tumors were examined for the presence of vascular invasion and determination of quantitative histology. Univariate and multivariate logistic regression models were used for statistical analysis. Results Univariate analysis neither revealed total MIB-1 score nor MIB-1 score in the highest area of staining of the different cell types to significantly predict pathological stage I or stage II disease. However, the presence of vascular invasion (p <0.001) and the percentage of embryonal carcinoma (p <0.0001) were significant risk factors for occult nodal disease. Multivariate logistic regression analysis revealed the combination of vascular invasion and the percentage of embryonal carcinoma to be the best model to predict pathological stage II correctly (86.5%). Discussion The determination of immunohistochemical MIB-1 expression did not correlate with pathological stage in clinical stage I nonseminomatous germ cell tumors (NSGCT). We were not able to define high risk or low risk groups for occult nodal disease based on MIB-1 staining results. However, percentage of embryonal carcinoma and presence of vascular invasion accurately predicted absence or presence of lymph node metastasis in clinical stage I NSGCT. Our study underlines that a prospective multicenter trial is urgently needed to accurately assess the role of MIB-1 staining in management of clinical stage I NSGCT.

MIB‐1 immunohistochemistry in clinical Stage I nonseminomatous testicular germ cell tumors predicts patients at low risk for metastasis

BACKGROUND The clinical Stage I of nonseminomatous germ cell tumors (NSGCT) is inaccurate in 30% of patients. In previous studies on tumor biologic risk factors, low tumor proliferation rates predicted a group of patients at low risk for occult metastatic disease. The goal of this study was to confirm the immunohistochemical assessment of tumor proliferation using MIB-1 (Ki-67 receptor) in a different patient cohort with different investigators to prove the method's reliability. METHODS Orchiectomy specimens of 78 patients with clinical Stage I NSGCT (50 patients with pathologic Stage I and 28 patients with pathologic Stage II disease, all patients underwent retroperitoneal lymph node dissection) were retrospectively analyzed by histopathologic reevaluation and MIB-1 immunostaining. RESULTS Mean MIB-1 values between the two pathologic stages differed significantly (51.5% MIB-1 positive tumors cells in pathologic Stage I and 75.1% MIB-1 positive tumor cells in pathologic Stage II disease; P = 0.02). Using a 70% cutoff value, pathologic stages were correctly classified in 69% of cases (sensitivity of 86%, specificity of 60%, negative predictive value of 88%, and positive predictive value of 55%). Compared with traditional risk factors such as percentage of embryonal carcinoma and vascular invasion, in multivariate analysis, MIB-1 was the best predictor of patients at low risk for metastasis. CONCLUSIONS This study in a different patient population with different investigators confirmed previous results of MIB-1 staining to predict a group of patients with clinical Stage I NSGCT who were at low risk for metastasis. The method is simple and reproducible to improve risk classification in low stage testicular carcinoma. Using this technique, a group of patients at very low risk for metastasis can be identified. [See editorial counterpoint on pages 1641-5 and reply to counterpoint on page 1646, this issue.] Cancer 1997; 79:1710-6. © 1997 American Cancer Society

MIB-1 immunohistochemistry in clinical Stage I nonseminomatous testicular germ cell tumors predicts patients at low risk for metastasis

The clinical Stage I of nonseminomatous germ cell tumors (NSGCT) is inaccurate in 30% of patients. In previous studies on tumor biologic risk factors, low tumor proliferation rates predicted a group of patients at low risk for occult metastatic disease. The goal of this study was to confirm the immunohistochemical assessment of tumor proliferation using MIB-1 (Ki-67 receptor) in a different patient cohort with different investigators to prove the method's reliability. Orchiectomy specimens of 78 patients with clinical Stage I NSGCT (50 patients with pathologic Stage I and 28 patients with pathologic Stage II disease, all patients underwent retroperitoneal lymph node dissection) were retrospectively analyzed by histopathologic reevaluation and MIB-1 immunostaining. Mean MIB-1 values between the two pathologic stages differed significantly (51.5% MIB-1 positive tumors cells in pathologic Stage I and 75.1% MIB-1 positive tumor cells in pathologic Stage II disease; P = 0.02). Using a 70% cutoff value, pathologic stages were correctly classified in 69% of cases (sensitivity of 86%, specificity of 60%, negative predictive value of 88%, and positive predictive value of 55%). Compared with traditional risk factors such as percentage of embryonal carcinoma and vascular invasion, in multivariate analysis, MIB-1 was the best predictor of patients at low risk for metastasis. This study in a different patient population with different investigators confirmed previous results of MIB-1 staining to predict a group of patients with clinical Stage I NSGCT who were at low risk for metastasis. The method is simple and reproducible to improve risk classification in low stage testicular carcinoma. Using this technique, a group of patients at very low risk for metastasis can be identified. [See editorial counterpoint on pages 1641-5 and reply to counterpoint on page 1646, this issue.]

A Surveillance Study of Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis: 10-Year Followup

Purpose We evaluate the 10-year results of a surveillance study of clinical stage I nonseminomatous germ cell tumors of the testis. Materials and Methods Between 1981 and 1984 we recruited 85 consecutive evaluable patients with nonseminomatous germ cell tumors of the testis and normal post-orchiectomy physical examination, chest x-rays, bipedal lymphangiography, abdominal scans and serum tumor markers. The patients were followed for at least 10 years after orchiectomy alone, which was performed elsewhere in 90 percent of the cases. Results The interval between visits was twice as long as it was scheduled. Relapses occurred in 25 patients (29.4 percent) after a median disease-free interval of 7 months (range 2 to 68). Five patients had further relapses and 3 (3.5 percent) died of cancer. Retroperitoneal relapses (19 percent) occurred later than lung relapses, and they were diagnosed when larger than 5 cm. in 7 patients. The percentage of embryonal carcinoma within the tumor associated with relapse (p = 0.008), T category (p = 0.023), scrotal violation (p = 0.042) and vascular invasion (p = 0.063) had a weak correlation but data on T category and vascular invasion were available for only some patients. Conclusions Surveillance is a difficult type of study and missing data may compromise the therapeutic program based on prognostic factors.

Proliferating Cell Nuclear Antigen Expression to Predict Occult Disease in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors

We analyzed primary tumor tissue from 89 clinical stage I nonseminomatous germ cell testicular tumor patients for proliferating cell nuclear antigen expression and histological features to determine if these elements could distinguish pathological stage I (52 patients) from pathological stage II disease or patients who later had relapse (37). Using a monoclonal antibody (PC10††Dako Corp., Carpinteria, California.) developed for use in archival tissue, nuclear proliferating cell nuclear antigen expression was immunohistochemically measured for the overall tumor (total proliferating cell nuclear antigen) and for each neoplastic cell type present. In addition, the primary tumor was examined for the presence of vascular invasion and determination of the percentage of tumor composed of embryonal carcinoma. Univariate logistic regression analysis revealed higher total (p = 0.0001) and higher embryonal carcinoma proliferating cell nuclear antigen expression (p = 0.0437) to be statistically significant risk factors for occult disease, correctly predicting its presence 73% and 61.5% of the time, respectively. More importantly, the presence of vascular invasion and a higher percentage embryonal carcinoma were highly significant risk factors for occult disease and were truly predictive in 80.4% and 77.2% of the cases, respectively. Multivariate logistic regression analysis revealed a combination of vascular invasion and percentage embryonal carcinoma to be the best model to predict occult disease correctly (85.9%). The addition of total or embryonal carcinoma proliferating cell nuclear antigen expression did not improve the clinical use of the model containing vascular invasion and percentage embryonal carcinoma. Although proliferating cell nuclear antigen expression mirrors the biological behavior of clinical stage I nonseminomatous germ cell testicular tumor to some degree, assessment of vascular invasion and percentage embryonal carcinoma has greater clinical use.

Flow-cytometric and quantitative histologic parameters as prognostic indicators for occult retroperitoneal disease in clinical-stage-I non-seminomatous testicular germ-cell tumors.

Our study was performed to clarify whether the combination of DNA flow-cytometric and quantitative histopathological parameters improves the prediction of occult metastatic disease in clinical stage-I non-seminomatous testicular germ-cell tumors (NSGCT). We used archival paraffin primary-tumor tissue of 67 clinical stage-I NSGCT patients who had undergone retroperitoneal lymph-node dissection (RPLND). According to the RPLND specimens, 24 patients were at pathological stage I and 43 at pathological stage II. Archival blocks were redissected for histological re-evaluation. In addition, 50 microns sections were prepared according to the Hedley technique in order to obtain nuclear suspensions which were processed for flow cytometry (FC). In univariate analysis, the percentage of embryonal carcinoma, the percentage of immature teratoma and vascular invasion were the most accurate predictive histopathological parameters. The percentage of aneuploid cells in S-phase was the best predictive FC parameter. In multivariate analysis, the percentage of embryonal carcinoma and the S-phase fraction of aneuploid cells were the only independent markers for occult metastatic disease. According to this statistical approach, 91.0% of pathological stage-I and stage-II cases were correctly classified. Sensitivity was 95.3% and specificity was 83.3%. Using histopathological criteria alone, only 56.7% NSGCT patients were correctly classified.

Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study.

The Testicular Cancer Intergroup Study (TCIS) was undertaken to evaluate the pathologic findings in early-stage testicular cancer as determined by central pathology review, to compare these findings with the interpretation by the contributing pathologists, and to make correlations with various clinical parameters and outcomes. The prospective study of non-seminomatous germ cell testicular cancer staged surgically involved 459 eligible patients with stage I (node-negative) or stage II (node-positive) disease. Pathologic materials from both the orchiectomy and lymphadenectomy specimens were submitted to a central laboratory for evaluation. Central and local pathologists differed significantly in their identification of certain cellular histologies (primarily yolk sac tumors [YST]) and recognition of invasion into vascular structures. In contrast to our prior findings with local pathologic assessment, venous/lymphatic invasion as determined by central review predicted relapse in both stages. In pathologic stage I disease, the relapse rate was 19.4% (12 of 62 cases) for those with invasion versus 6.0% (10 of 168 cases) for those without invasion. In pathologic stage II disease, the respective relapse rates were 63.5% (40 of 63 cases) and 24.0% (six of 25 cases). Vascular invasion was jointly predictive with nodal stage for risk of relapse. The percentage of embryonal carcinoma (EC) in the primary tumor was predictive of nodal stage and relapse in a univariate, but not a multivariate, analysis. In a large substudy, immunohistochemical staining identified a correlation between stain intensity in YST and serum alpha-fetoprotein (AFP) levels. In a similar fashion human chorionic gonadotropin (HCG) staining reactivity occurred exclusively in patients with syncytiotrophoblasts and correlated with serum levels of beta-HCG. A number of tumor histology correlates with clinical parameters have been identified or confirmed. Careful pathologic scrutiny of the primary testicular tumor, especially for vascular invasion, provides important prognostic information.