Germ cell tumor associated primitive neuroectodermal tumors.

PURPOSE: This retrospective review was done to assess the prognosis and response in patients presenting with primitive neuroectodermal tumor admixed with germ cell tumor. MATERIALS AND METHODS: Of the 40 patients treated at our institution from 1984 to 1999, 15 had initial stage I and 25 had initial metastatic disease. Median followup after the diagnosis was 25 months (range 4 to 142). RESULTS: Of the 40 patients 15 presented with clinical stage I disease, including 9 treated with retroperitoneal lymph node dissection and 6 who elected surveillance. Seven of the 9 patients had normal lymph nodes and all continuously had no evidence of disease. Two of the 9 patients had lymph nodes involved with teratoma with or without primitive neuroectodermal tumor. Retroperitoneal relapse in 5 of the 6 patients on surveillance was treated with cisplatin based chemotherapy followed by post-chemotherapy retroperitoneal lymph node dissection. Residual primitive neuroectodermal tumor was noted in 4 of the 5 patients and only 3 of 6 are currently without disease at a median followup of 17 months (range 15 to 69). A total of 25 patients presented with metastatic disease, of whom 23 underwent cisplatin based chemotherapy. Only 3 patients achieved complete remission with chemotherapy alone and 2 of the 3 subsequently relapsed. Of the remaining 20 patients 16 underwent post-chemotherapy retroperitoneal lymph node dissection, including 11 with primitive neuroectodermal tumor in the resected specimen. Two of these 11 patients have continuously had no evidence of disease, while an additional 3 currently have no evidence of disease after further therapy. Teratoma was present in the resected specimen in 5 of 16 patients, of whom 2 have continuously had no evidence of disease, while an additional 2 currently have no evidence of disease after further surgical resection. Therefore, 11 of 25 patients who presented with metastatic disease currently have no evidence of disease at a median followup of 19 months (range 2 to 111). CONCLUSIONS: Primitive neuroectodermal tumor in the orchiectomy specimen has adverse prognostic significance. This condition in the retroperitoneum is potentially curable by retroperitoneal lymph node dissection but rarely eradicated by chemotherapy. Therefore, we recommend retroperitoneal lymph node dissection for all clinical stage I cases with primitive neuroectodermal tumor in the orchiectomy specimen. Patients who present with metastatic primitive neuroectodermal tumor should be treated aggressively with surgical resection as an integral part of the therapeutic strategy.

Aortic replacement during post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We reviewed the records of 15 patients with metastatic germ cell cancer who underwent aortic resection and replacement during post-chemotherapy retroperitoneal lymph node dissection to determine the morbidity and the therapeutic benefit. MATERIALS AND METHODS: Between 1970 and 1998, 1,250 patients underwent post-chemotherapy retroperitoneal lymph node dissection. Our retrospective review revealed that 15 patients underwent aortic replacement at that operation. RESULTS: In addition to aortic replacement 11 patients underwent 15 additional procedures, including nephrectomy in 7, vena caval resection in 3, pulmonary resection in 1, small bowel resection in 2, 1 hepatic resection in 1 and L4 vertebrectomy in 1. No patient had necrosis as the only pathological condition. Three patients (20%) had teratoma and 12 (80%) had viable tumor in the retroperitoneal specimen. All 4 patients who underwent post-chemotherapy retroperitoneal lymph node dissection and aortic replacement after induction chemotherapy alone have no evidence of disease. Only 1 of the 11 patients who received salvage chemotherapy with or without previous post-chemotherapy retroperitoneal lymph node dissection have no evidence of disease. Overall 33% of the patients have no evidence of disease. There were no graft related complications. CONCLUSIONS: Aortic resection at post-chemotherapy retroperitoneal lymph node dissection is justified based on therapeutic benefit and morbidity.

Validation of a prediction model and its predictors for the histology of residual masses in nonseminomatous testicular cancer.

PURPOSE: We validated a prediction model for histology of residual retroperitoneal masses, either benign or tumor, in patients treated with chemotherapy for metastatic nonseminomatous testicular cancer. MATERIALS AND METHODS: We studied 276 patients treated with chemotherapy before retroperitoneal lymph node dissection at Indiana University Medical Center between 1985 and 1999. A previously developed prediction model was modified to provide predictions for the Indiana population based on 5 predictors. For these predictors, including teratomatous elements in the primary tumor, pre-chemotherapy tumor markers (alpha-fetoprotein and human chorionic gonadotropin), size of the residual mass and reduction in mass size, univariate and multivariate odds ratios were determined. The modified model was evaluated by calculating the concordance statistic and studying model reliability. RESULTS: All odds ratios from univariate and multivariate analyses were in the expected directions. The modified model had good discriminative ability (concordance statistic 0.79). However, the predicted probabilities for benign tissue were generally too high due to the low prevalence of benign tissue (76 of 276 cases or 28%). CONCLUSIONS: This study confirms the predictive ability of formerly identified predictors for the histology of residual retroperitoneal masses in testicular cancer. However, the previously developed prognostic model must be adjusted for the local overall ratio of benign versus tumor histology to provide reliable predictions in the Indiana population.

Cutaneous inflammatory disorder in integrin alphaE (CD103)-deficient mice.

The integrin alpha(E)beta(7) is thought to play an important role in the localization of mucosal, but not of cutaneous T lymphocytes. Thus, it was surprising that 89% of adult alpha(E)(-/-) mice on the 129/Sv x BALB/c background developed inflammatory skin lesions without an apparent infectious etiology. Skin inflammation correlated with alpha(E) deficiency in mice with a mixed 129/Sv x BALB/c background, but not in mice further backcrossed to BALB/c and housed in a second animal facility. These studies suggested that alpha(E) deficiency, in combination with other genetic and/or environmental factors, is involved in lesion development. The lesions were infiltrated by CD4(+) T cells and neutrophils, and associated with increased expression of inflammatory cytokines. Furthermore, skin inflammation resulted from transfer of unfractionated alpha(E)(-/-) splenocytes into scid/scid mice, but not from transfer of wild-type splenocytes, suggesting that the lesions resulted from immune dysregulation. We also studied the role of alpha(E)beta(7) in a murine model of hyperproliferative inflammatory skin disorders that is induced by transfer of minor histocompatibility-mismatched CD4(+)/CD45RB(high) T cells into scid/scid mice under specific environmental conditions. Under housing conditions that were permissive for lesion development, transfer of alpha(E)-deficient CD4(+)/CD45RB(high) T cells significantly exacerbated the cutaneous lesions as compared with lesions observed in mice reconstituted with wild-type donor cells. These experiments suggested that alpha(E)-expressing cells play an important role during the course of cutaneous inflammation. In addition, they suggest that alpha(E)beta(7) deficiency, in combination with other genetic or environmental factors, is a risk factor for inflammatory skin disease.

Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor.

PURPOSE: We evaluated the clinical behavior of clinical stage I pure yolk sac tumor of the testis in adults to determine whether the behavior of this entity is different than that of clinical stage 1 nonseminoma. MATERIALS AND METHODS: We searched the testis cancer database at our institution for adults with clinical stage I pure yolk sac tumor of the testis who underwent retroperitoneal lymph node dissection. We identified 12 such patients and reviewed the database and hospital charts to determine clinical behavior. RESULTS: Disease was pathological stage I in 8 of the 12 patients (66%), including 1 with recurrence after retroperitoneal lymph node dissection. Disease was pathological stage II in 14 patients (33%), including 1 who remains disease-free after electing adjuvant bleomycin, etoposide and cisplatin. Of the 3 patients who elected observation after retroperitoneal lymph node dissection only 1 has had recurrence, while 2 (66%) were cured by retroperitoneal lymph node dissection only. CONCLUSIONS: Contrary to juvenile yolk sac tumor, which has a strong tendency toward hematogenous metastasis, the behavior of clinical stage I adult pure yolk sac tumor is similar to that of all other stage I nonseminomas in adulthood.

Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection.

PURPOSE: We assess the risk of systemic recurrence after retroperitoneal lymph node dissection for clinical stage I nonseminoma germ cell testis tumor based on predominance of embryonal carcinoma and/or vascular invasion in the orchiectomy specimen. MATERIALS AND METHODS: A total of 292 cases of clinical stage I nonseminoma germ cell testis tumor treated with retroperitoneal lymph node dissection from 1990 to 1995 were identified from the Indiana University database. A minimum of 2 years of followup was required for study entry. Review of the written pathological reports classified tumors as embryonal carcinoma predominant, when it was present at a level greater than any other histology, nonpredominant, when it was present but not as the main histological subtype, and absent. Vascular invasion was categorized as present or absent. RESULTS: Of the 292 cases 226 (77. 4%) were pathological stage I and relapse rate after retroperitoneal lymph node dissection was 10.2%. Vascular invasion and embryonal carcinoma predominance in the orchiectomy specimen were predictors of relapse in this group. None of the 35 pathological stage II cases treated with adjuvant chemotherapy had relapse, whereas relapse occurred in 7 of 31 pathological stage II cases (22.6%) not treated with adjuvant chemotherapy. CONCLUSIONS: Pathological stage I cases with predominant embryonal carcinoma and/or vascular invasion in the orchiectomy specimen have a higher probability of systemic recurrence after retroperitoneal lymph node dissection. Dissection alone still has a major therapeutic impact (77%) in patients with clinical stage I, pathological stage II nonseminoma germ cell testis tumor.

Retroperitoneal lymph node dissection for the management of clinical stage I nonseminoma.

PURPOSE: We review the rationale for the use of retroperitoneal lymph node dissection for clinical stage I nonseminomatous testis cancer. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer.

PURPOSE: To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis. PATIENTS AND METHODS: All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively. RESULTS: Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free. CONCLUSION: Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.

Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice.

The mucosal lymphocyte integrin alpha E(CD103)beta 7 is thought to be important for intraepithelial lymphocyte (IEL) localization or function. We cloned the murine integrin gene encoding alpha E, localized it to chromosome 11, and generated integrin alpha E-deficient mice. In alpha E-/- mice, intestinal and vaginal IEL numbers were reduced, consistent with the known binding of alpha E beta 7 to E-cadherin expressed on epithelial cells. However, it was surprising that lamina propria T lymphocyte numbers were diminished, as E-cadherin is not expressed in the lamina propria. In contrast, peribronchial, intrapulmonary, Peyer's patch, and splenic T lymphocyte numbers were not reduced in alpha E-deficient mice. Thus, alpha E beta 7 was important for generating or maintaining the gut and vaginal T lymphocytes located diffusely within the epithelium or lamina propria but not for generating the gut-associated organized lymphoid tissues. Finally, the impact of alpha E deficiency upon intestinal IEL numbers was greater at 3-4 wk of life than in younger animals, and affected the TCR alpha beta+ CD8+ T cells more than the gamma delta T cells or the TCR alpha beta+ CD4+CD8- population. These findings suggest that alpha E beta 7 is involved in the expansion/recruitment of TCR alpha beta+ CD8+ IEL following microbial colonization. Integrin alpha E-deficient mice will provide an important tool for studying the role of alpha E beta 7 and of alpha E beta 7-expressing mucosal T lymphocytes in vivo.

Advanced testicular cancer: update for urologists.

PURPOSE: Testicular cancer is a model for a curable neoplasm. We review past and present accomplishments in treating testis cancer and emphasize controversial surgical issues of interest to the urologist. MATERIALS AND METHODS: We reviewed early and recent chemotherapy trials of germ cell tumors, stressing random prospective phase III studies. In addition, we address specific and complicated issues that are of particular relevance for the urologist, analyzing recently published articles. RESULTS: Cisplatin combination chemotherapy has dramatically improved the cure rate for patients with germ cell tumors. The indications for post-chemotherapy resection for residual masses are discussed. CONCLUSIONS: The major goal 25 years ago was to develop a successful chemotherapy regimen for disseminated disease, which has now been accomplished with cisplatin combination chemotherapy. Present issues include optimal treatment in patients with poor prognostic characteristics, salvage chemotherapy strategies and indications for post-chemotherapy surgical resection.

Is retroperitoneal lymph node dissection necessary for adult paratesticular rhabdomyosarcoma?

PURPOSE: We assess the benefit of retroperitoneal lymph node dissection for adult paratesticular rhabdomyosarcoma. MATERIALS AND METHODS: A total of 19 adults with paratesticular rhabdomyosarcoma who underwent retroperitoneal lymph node dissection between 1980 and 1997 comprise our study population. Postoperative chemotherapy was administered in all patients, including cyclophosphamide, doxorubicin and vincristine with or without consolidation with ifosfamide and etoposide in 17, and vincristine, actinomycin D and cyclophosphamide in 2. Radiation therapy also was administered in 2 patients. Patients were classified into pathological and clinical groups according to the Intergroup Rhabdomyosarcoma Studies. Mean followup was 6.4 years (range 0.5 to 17.6). RESULTS: A total of 17 patients (89%) were disease-free and 2 (1 in pathological group I and 1 in pathological group II) died of disease that recurred outside of the retroperitoneum. Of 16 clinical group I patients 9 were in pathological group II. There were negative nodes in 2 of 3 clinical group II patients. Thus, abdominal computerized tomography correctly staged only 8 of 19 patients (42%). CONCLUSIONS: Retroperitoneal lymph node dissection accurately stages paratesticular rhabdomyosarcoma and eliminates the need for abdominal radiotherapy in patients in pathological group II. Combined modality therapy with retroperitoneal lymph node dissection and postoperative chemotherapy achieves a high cure rate.

Retroperitoneal lymphadenectomy in staging and treatment. The development of nerve-sparing techniques.

Currently, where available and widely practiced, nerve-sparing RPLND offers the least toxic and safest alternative in management of clinical stage I nerve-sparing germ cell tumor. Twenty-six percent to 30% of such cases are found to be node positive and, if no adjuvant chemotherapy is elected, two thirds do not relapse; those who do are uniformly rescued by chemotherapy. The 70% who are node negative have no long-term toxicity and do better in quality of life studies than their surveillance counterparts. Also, risk-benefit and cost-benefit studies support the competitive position, of RPLND vis-à-vis the other options. Nonetheless, it is fair to say there are several options for management of clinical stage I nonseminomatous germ cell tumors that, when well applied, work well. Their choice depends on regional factors related to availability and experience.

Can retroperitoneal lymphadenectomy be omitted in some patients after chemotherapy?

The advances in the therapy of high-volume stage II and stage III testicular cancer have been largely due to the development and success of cisplatin-based chemotherapy. Though patients with low- to moderate-volume stage II disease historically were curable with radical retroperitoneal lymph node dissection, patients with higher volumes of metastatic disease were not curable with surgery alone. The advent of cisplatin-based chemotherapy in the 1970s has allowed many of these patients with higher-volume metastatic disease to be cured. Though chemotherapy clearly plays the major role in the therapy of these patients, surgery after chemotherapy has been complimentary in the overall chance for cure of these patients.

Bilateral testicular tumors: management and outcome in 21 patients.

BACKGROUND: The authors examined the clinical course of patients with bilateral testicular tumors to determine whether the outcome after treatment was different from patients with unilateral tumors. METHODS: Using a computerized data base of 2088 patients with testicular carcinoma at Indiana University, 21 patients (1%) were identified with bilateral testicular carcinoma. A retrospective review of hospital and clinic charts was performed. Sixteen patients with metachronous and 5 patients with synchronous testicular tumors were identified. RESULTS: Treatment was based on clinical stage and was similar to therapy given for unilateral disease. The mean age at presentation of the first testicular tumor was 28.4 years (range, 16-47 years). Approximately 50% of the second primary tumors presented > 5 years after the contralateral tumor. At a mean follow-up of 49.9 months (range, 1-276 months), 18 patients were without evidence of disease, 2 were alive with disease, and 1 patient had died of disease. CONCLUSIONS: The treatment of patients with bilateral germ cell tumors is based on the pathology and clinical stage and should not be different from the traditional management of unilateral testicular carcinoma. Patients with unilateral testicular carcinoma should be informed of the necessity of long term follow-up because contralateral testicular carcinoma may occur as long as 25 years later.

Integration of surgery and systemic therapy: results and principles of integration.

Eight hundred seventy patients with metastatic nonseminomatous germ cell cancer underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for resection of residual disease. Several risk factors for relapse and survival were identified as highly significant (P = .00001), namely, presence of residual cancer in the specimen before salvage chemotherapy programs, tumor marker elevation, need for "re-do" PC-RPLND, or unresectability. Although more than half of the entire group (52.5%) had one or more of these risk factors, 67.5% are long-term survivors following PC-RPLND. The remaining 47.5% were referred after primary chemotherapy, without risk factors. Only 9.8% relapsed and 95.5% survived.

Combined post-chemotherapy retroperitoneal lymph node dissection and resection of chest tumor under the same anesthetic is appropriate based on morbidity and tumor pathology.

PURPOSE: We determine if post-chemotherapy resection of residual retroperitoneal and chest tumor under the same anesthetic is reasonable based on tumor pathology and morbidity, and if the finding of necrosis in the abdomen allows observation of chest tumor. MATERIALS AND METHODS: We retrospectively reviewed 143 post-chemotherapy patients who underwent resection of residual retroperitoneal and chest disease under the same anesthetic. RESULTS: Retroperitoneal pathology was generally predictive of chest pathology. Concordance existed in 77.5% of patients with necrosis, 70% with teratoma and 69% with cancer of the abdomen. However, the correlation was much stronger (86%) in predicting necrosis/fibrosis if cases were categorized as uncomplicated by Indiana University criteria. Although the morbidity of the combined approach is higher than that of standard post-chemotherapy retroperitoneal lymph node dissection, it was acceptable. CONCLUSIONS: The morbidity of post-chemotherapy retroperitoneal lymph node dissection and resection of chest disease under the same anesthetic is acceptable. Retroperitoneal pathology generally predicts chest pathology but this correlation is much stronger if the case is uncomplicated based on our criteria. In an uncomplicated case the discovery of necrosis of the abdomen allows observation of chest tumor.

En bloc nephrectomy in patients undergoing post-chemotherapy retroperitoneal lymph node dissection for nonseminomatous testis cancer: indications, implications and outcomes.

PURPOSE: We review the indications for nephrectomy at post-chemotherapy retroperitoneal lymph node dissection, identify patients at risk for nephrectomy and assess the impact of nephrectomy on outcome. MATERIALS AND METHODS: Using a computerized data base and chart review we retrospectively reviewed the records of 848 patients who underwent retroperitoneal lymph node dissection after chemotherapy. RESULTS: En bloc nephrectomy was performed at retroperitoneal lymph node dissection after chemotherapy in 162 of the 848 patients (19%). The indications for nephrectomy included contiguous involvement of perirenal structures in 73% of the cases, renal vein thrombosis in 6%, a poorly functioning or nonfunctioning renal unit in 5% and a combination of these conditions in 16%. Pathological studies of the hilum revealed cancer in 20% of the cases, teratoma in 49% and fibrosis in 31%. Patients requiring nephrectomy had significantly more advanced disease and larger disease volume at presentation and after chemotherapy. There were no significant differences in perioperative morbidity or mortality compared with patients who did not undergo nephrectomy. Only 3 patients required perioperative dialysis and none required long-term renal support. CONCLUSIONS: These findings support en bloc nephrectomy at post-chemotherapy retroperitoneal lymph node dissection in select patients with large volume perihilar retroperitoneal disease.

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.

Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group.

PURPOSE: We determined the need and sequence of retroperitoneal lymph node dissection and thoracotomy in patients with nonseminomatous testicular cancer, and with residual retroperitoneal and pulmonary masses after chemotherapy. MATERIALS AND METHODS: We studied 159 patients undergoing retroperitoneal lymph node dissection and a thoracotomy following cisplatin based induction chemotherapy for metastatic testicular nonseminomatous germ cell tumor. Several well-known predictors for residual histology (necrosis, mature teratoma and cancer) were evaluated. RESULTS: As expected, necrosis was found more often at retroperitoneal lymph node dissection if the primary tumor was negative for teratoma, the residual mass was small or the decrease in size was great. Contrary, neither residual mass size nor the decrease in size was predictive of the histological status of the residual lung lesion. Histological findings in the retroperitoneum and lung were strongly correlated, such that necrosis at retroperitoneal lymph node dissection was associated with an 89% probability of necrosis in the lung. CONCLUSIONS: Retroperitoneal lymph node dissection should be performed before thoracotomy is considered, since the histological status at dissection is a strong predictor of that at thoracotomy.