Prognostic factors in seminomas with special respect to HCG: results of a prospective multicenter study. Seminoma Study Group

OBJECTIVE: In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas. METHODS: Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test. RESULTS: The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result. CONCLUSIONS: We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum.     

Metastasis of germ cell tumors of the testis]

The development of metastases from germ cell tumours of the testis is studied in terms of its histopathological, ontogenetic, anatomical and evolutive aspects. The treatment of non-seminomatous germ cell tumours and pure seminomas is analysed separately. The prognostic factors defined by the risk of failure of treatment are described and the medical and surgical strategies or combinations of both modalities are proposed for each stage of these cancers. The major points and novelties include: the usual histological polymorphism of these tumours. The markers include alpha-foetoprotein and HCG. Combination chemotherapy, essentially the EBP sequence, is the treatment for non-seminomatous germ cell tumours. In the case of failure, toxic sequences can be used followed by autologous bone marrow transplantation. In the case of persistent lesions (lung, mediastinum, liver, retroperitoneum), salvage surgery may be useful. Metastatic seminomas are treated by radiotherapy and/or chemotherapy, depending on their stage.     

Improved Management of Abdominal Undescended Testicular Tumors with Bulky Confluent Retroperitoneal Nodal Metastases

Purpose

Germ cell tumors of the abdominal undescended testis associated with confluent bulky retroperitoneal metastases are challenging problems. We report the results of neoadjuvant cisplatin based chemotherapy after diagnosis of germ cell tumors by fine needle aspiration cytology of the abdominal testicular mass. After chemotherapy all patients underwent abdominal orchiectomy with retroperitoneal lymph node dissection for residual nonseminomatous germ cell tumors or radiotherapy for pure seminomas.

Materials and Methods

Between 1980 and 1991, 57 of 425 patients (13.4 percent) with germ cell tumors of the testicle had malignancy in an undescended testis, while 39 (68.4 percent) had tumor in an abdominal testis with confluent bulky metastasis. Metastatic evaluation included tumor marker studies, chest x-ray and computerized tomography of the abdomen. Among the tumors 29 (74.4 percent) were large volume seminomas (stages IIc, III and IV) and 10 (25.6 percent) were large volume nonseminomas. All 39 patients received 3 cycles of induction chemotherapy, and orchiectomy was deferred until its completion (14 received vinblastine, actinomycin D and bleomycin-6, and 25 received bleomycin, etoposide and cisplatin). After evaluation of response, the testis was excised. Overall followup was 2 to 12 years (median 4.6).

Results

Of 29 seminomas 14 (48.3 percent) showed a complete and 11 (37.9 percent) showed a partial response. The latter tumors were treated subsequently with radiotherapy. Four patients with progressive disease died, for an actuarial survival rate of 86 percent. Of the 10 patients with nonseminomatous germ cell tumor 2 (20 percent) had a complete response and 4 had a partial response. All patients with a partial response underwent retroperitoneal lymph node dissection. Overall, 4 patients with progression and 2 with a partial response died, for an actuarial survival rate of 39 percent. Of 39 post-chemotherapy orchiectomy specimens 24 (61.5 percent) showed viable tumor cells. Furthermore, 16 of 39 patients (41 percent) had additional ilioinguinal metastases requiring adjuvant radiotherapy or surgery.

Conclusions

Surgical removal of the primary tumor in an undescended testis with bulky metastasis is difficult. We believe that initial chemotherapy followed by 1-stage surgical removal of the primary and residual metastasis is a favorable option to improve compliance and decrease the incidence of loss to followup. Atypically altered ilioinguinal metastases may necessitate a change in radiotherapy ports and/or retroperitoneal lymph node dissection boundaries.The significantly poorer survival with nonseminomatous germ cell tumor could be due to the fact that 50 percent of the lesions were stage IV at presentation. However, multivariate analysis showed only tumor histology to be the significant parameter and not initial stage at presentation.     

Management of Recurrent Craniopharyngioma

Summary Although histologically benign, craniopharyngioma can regrow either from macroscopic remnants of the tumour left behind at operation, or even after an apparently gross total removal. Recurrence rates vary significantly in the literature, depending on the efficacy of surgical treatment and also on the growth potential of the tumour itself. The main factor influencing tumour regrowth is obviously the extent of surgical resection, as total removal carries a much lesser risk of recurrence compared to subtotal or partial resections (although in such cases radiation therapy can lower this risk significantly). Other factors involved are the duration of follow-up and patient's age at operation, as children tend to relapse more frequently than adults. Even in the “microsurgery” era, characterized by high percentages of total resections, recurrences remain high and continue to represent a major problem of craniopharyngioma treatment. Twenty-seven children and adolescents were operated on for craniopharyngioma at the Department of Neurosurgery, Section of Pediatric Neurosurgery, Catholic University Medical School, Rome, between June 1985 and June 1997. Total tumour resection was achieved in 18 cases, subtotal in 7 and partial 2 instances. One patient died post-operatively. Post-operative neuroradiological investigations confirmed the operative findings, although 3 children with an apparently gross total removal showed a residual non-enhancing calcium fleck adherent to the hypothalamus (which remained stable at the following examinations). Three of the 9 patients with less than total removal underwent post-operative radiation therapy. Out of the 26 surviving patients 6 presented a recurrence of their craniopharyngioma, 2 after an apparently gross total removal and 4 after a subtotal or partial resection (one of them had received radiation therapy). The diagnosis was merely neuroradiological in 5 cases, as only one child presented a clinical picture suggestive of tumour regrowth. Surgery was the first therapeutic option in all cases. Total tumour resection was accomplished in 3 cases, subtotal in 2 and partial in the last one. One child died post-operatively. Four of the 5 survivors received radiation therapy. All the patients are presently alive and stable (mean follow-up: 5.6 yrs). The authors conclude that surgery should be the first therapeutic option in case of recurrent craniopharyngioma and that radiation therapy should also be considered but only as adjuvant therapy.     

DNA ploidy in testicular germ cell neoplasms. Histogenetic and clinical implications.

Flow cytometry was used to determine the DNA ploidy pattern of 148 testicular germ cell neoplasms (seminomas and nonseminomas in pure and mixed histologic phenotypes) and in situ carcinoma (CIS) adjacent to these tumors. The great majority (96.0%) manifested aneuploid DNA contents with minimal intratumoral heterogeneity (2.5%). The mean DNA indices (DI) of CIS (1.7 +/- 0.18), pure seminoma (1.82 +/- 0.55), and the seminoma component of mixed germ cell neoplasms (1.76 +/- 0.13) were statistically similar. The mean DI of nonseminomas pure (1.46 +/- 0.29) or as a component of mixed tumors (1.43 +/- 0.32) was significantly lower (p greater than 0.001) than those of CIS and seminomas. Our data suggest that the similarity between the DNA indices of CIS and seminomas provide evidence that both lesions constitute a temporal evolutionary step in the progression of germ cell tumors and that nonseminomas may subsequently arise from either CIS or seminoma by further loss of chromosomal DNA. These characteristic findings support the nonstochastic theory for germ cell evolution and progression and may be useful in the clinicopathologic evaluation of testicular masses.     

Chemotherapy for poor risk germ cell tumours. An independent evaluation of the POMB/ACE regime

We have evaluated the 7-drug, alternating, high-dose cisplatin regime for germ cell tumours, designated POMB/ACE, in 55 patients with advanced malignant teratomas and 5 patients with bulky metastatic seminomas. All of the latter and 5 of the teratoma patients had relapsed following radiotherapy, chemotherapy or both. The previously untreated teratoma patients included 13 whose tumours were extragonadal. The primary testicular tumour patients comprised 16 with large and 21 with very large volume metastases according to the Medical Research Council criteria. POMB/ACE is effective therapy for poor risk patients with germ cell tumours (including those with the most advanced disease, i.e. hepatic and cerebral metastases) and prolonged treatment after marker normality seems unnecessary. It is a complex regime with significant toxicity and cannot be recommended for the treatment of patients with germ cell tumours who have an excellent prognosis with simpler, shorter and less toxic treatment.     

Intra-abdominal seminomas in persistent müllerian duct syndrome

A young adult with persistent müllerian duct syndrome presented with bilateral Stage III pure seminomas in intra-abdominal testes. Treatment modalities included bilateral orchiectomy, radiotherapy, laminectomy for spinal metastases, and chemotherapy. The literature on this rare condition is reviewed.     

Therapeutic indications for germinal testicular tumors]

The therapeutic indications for germ cell tumours of the testis depend on the histology (pure seminoma: 45%, non-seminomatous germ cell tumour: 55%), the extension and the severity of the prognosis. The well standardised approach to pure seminomas is less clear for non-seminomatous germ cell tumours. Stage I, IIAB pure seminomas (95 to 98% of cases) should be irradiated. The dose and target volume are adapted to prophylactic (I) and curative (II) objectives. Rare seminomas with a large tumour bulk should be treated with chemotherapy. Survival is close to 100%. Stage I non-seminomatous germ cell tumour offers several theoretical possibilities. Radiotherapy is not very popular and chemotherapy appears to be to aggressive, lumboaortic lymph node dissection is being replaced by new imaging modalities and simple follow-up requires a rigorous and disciplined approach. At the Val-de-Grace hospital (France) since 1987, we perform simple orchidectomy in favourable stage I disease: 80% are cured with no other treatment, 20% relapse and are cured by chemotherapy, in the unfavourable stage I cancers (histology, markers) or with uncertain follow-up, limited chemotherapy is performed (3 cycles of EP). Stage II and more advanced non-seminomatous germ cell tumours are divided into moderate forms (IIA, B, III, IVL1) and major forms (IIC, IVL2, L3, H+, CNS+). In the exclusive infradiaphragmatic involvement of moderate forms, some authors propose bilateral lumboaortic lymph node dissection which is invasive surgery with an efficacy declining from 90% (IIA) to 50% (IIB). The majority of teams, particularly Val-de-Grace, administer 3 or 4 courses of BEP followed by assessment (CT scan - markers) and salvage surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunohistochemical and radioimmunological determination of beta-HCG and pregnancy-specific beta 1-protein in seminomas

38 pure and 11 mixed seminomas were studied with the peroxidase-anti-peroxidase method for the presence of chorionic gonadotropin (beta-HCG) and pregnancy-specific beta 1-glycoprotein (SP1). HCG was found in 8 of 49 cases, SP1 in 5 of 49 cases in syncytial and mononuclear giant cells. The 5 pure seminomas with positive tumor markers appear to have no worse prognosis than pure seminomas without HCG or SP1 production. None of the seminomas was found to contain carcinoembryonic antigen or alpha-fetoprotein.     

An immunohistopathological characterisation of mixed non-seminomatous germ cell tumors

Summary Immunohistological techniques were used to characterise inflammatory cell infiltrates in mixed germ cell tumours. The distribution of these infiltrates was much more variable than in pure seminomas but could not be related accurately to any particular tumour type. There were approximately equal numbers of B and T cells in these areas and helper/inducer T cells were more common than suppressor/cytotoxic lymphocytes. Within these areas of inflammatory cells, the subtype composition was similar to that seen in pure seminomas.     

Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1

Pancreaticoduodenal tumors develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN 1) and have a pronounced effect on life expectancy as the principal cause of disease related death. Previous discussion of therapy has focused mainly on syndromes of hormone excess and especially the management of MEN 1 associated Zollinger-Ellison syndrome (ZES). The syndromes of hormone excess, however, may be late features of the endocrinopathy and, when developed, indicate presence of metastases in more than one-third of patients. Recent possibilities for genetic diagnosis have emphasized requirements of prophylactic operation for prevention of malignant development. We recommend screening with biochemical markers and endoscopic ultrasound for early detection, and strong efforts of operative tumor removal before metastases have occurred. Surgery is generally recommended in patients with or without hormonal syndromes in the absence of spread hepatic metastases. Operative procedures include enucleation of tumors in the head of the pancreas, excision of duodenal gastrinomas together with clearance of lymph gland metastases, and as prophylaxis against tumor recurrence combination with distal 80% subtotal pancreatic resection. More extensive surgical tumor reduction is believed to reduce the risks for malignant progression of the pancreaticoduodenal tumors, but this requires further evaluation in MEN 1.     

Remission of hypoglycemia after partial resection of a metastatic islet cell tumor.

The course of a malignant islet cell tumor, producing increased levels of both insulin and glucagon, was studied clinically and in vitro for two years. The patient presented with hypoglycemia, and extensive hepatic metastases were present. Instead of biopsy alone, it was elected to remove the primary in the tail of the pancreas, and subtotal pancreatectomy was performed. There followed a six month interval without hypoglycemia, during which immunoreactive insulin (IRI) decreased (though remaining elevated) and immunoreactive glucagon (IRG) increased markedly. The tumor and a liver metastasis contained elevated IRI and IRG with immunofluorescence for insulin, though typical beta and alpha cells were not present on electron microscopy. A preparation of a monolayer culture of a liver metastasis decreased its IRI production with a similar time course to the clinical improvement, though rapid cell growth continued. Streptozotocin in vitro was markedly cytotoxic. In vivo Streptozotocin caused tumor regression, increase in fasting plasma glucose, decrease in plasma IRI and IRG, and improvement of glucose tolerance. Thus, this case showed elevated IRG in plasma and tumor, improvement in glucoregulation upon excision of the primary, and both in vitro cytotoxicity and clinical improvement with Streptozotocin. It is suggested (1) that cases refractory to therapy directed toward suppression of insulin secretion might benefit from removal of the primary and (2) that further use of cultures of such tumors should be initiated to establish whether they might be useful for predicting in vivo effectiveness of cytotoxic agents.     

Testicular cancer: prognostic implications of vascular invasion

In a retrospective study the primary tumors of 33 patients with seminomas and 53 with nonseminomatous germ cell tumors were re-evaluated for vascular invasion. The significance of vascular invasion was analyzed in respect to the appearance of visceral metastases and the effect of adjuvant chemotherapy. Vascular invasion was demonstrated in 27 per cent of the patients with seminomas and 53 per cent with nonseminomatous germ cell testis tumors, while visceral metastases appeared in 9 and 32 per cent, respectively. Without adjuvant chemotherapy all 13 patients with nonseminomatous germ cell testis tumors and vascular invasion had metastases, compared to only 3 of 13 without vascular invasion (p less than 0.0005). Of 9 patients with seminoma and vascular invasion 3 had tumor progression, compared to 1 of 24 without vascular invasion (p greater than 0.05). With adjuvant chemotherapy only 1 of 15 patients (7 per cent) with nonseminomatous germ cell testis tumors and vascular invasion had metastases, compared to 100 per cent of 13 without this treatment. No significant correlation was noted between pT stage versus vascular invasion and pT stage versus tumor progression. The results demonstrate the importance of vascular invasion in the staging of and choice of treatment for early nonseminomatous germ cell testis tumors.     

Proximal subtotal gastrectomy for the treatment of carcinoma of the upper third of the stomach: Its indications based on lymph node metastasis and perigastric lymphatic flow

To clarify the indications for a proximal subtotal gastrectomy in the treatment of carcinoma in the upper third of the stomach based on lymph node metastases, 1055 patients in whom either a D₂ or greater lymph node removal was performed were reviewed. In the patients in which the lesion was confined to the upper stomach and did not invade beyond the muscularis propria of the stomach wall, no metastases to either the lymph nodes above and below the pylorus or the lymph nodes along the greater curvature were observed. A lymphatic flow study revealed a minimal flow to these nodes from the upper stomach in patients without lymph node metastasis, but in cases with lymph node metastases the lymphatic flow changed. The indications for a proximal subtotal gastrectomy for a carcinoma of upper third of the stomach therefore must fulfill the following two conditions: (1) The deepest layer of cancerous invasion does not extend beyond the muscularis propria of the stomach wall, and (2) No macroscopic evidence of lymph node metastasis can be detected during surgery.     

Adenoacanthoma of the pancreas: report of four cases and literature review

Cases of 20 patients with adenoacenthoma of the pancreas with clinicopathologic data, including the four added, are reviewed. The clinical manifestations, sites of metastases, survival and gross pathology appear to be similar to the usual adenocarcinoma of the pancreas. Adenoacanthoma of the pancreas most probably represents squamous metaplasia of an adenocarcinoma or arises from an undifferentiated cell in the pancreatic duct system. The metastases are typically an admixture of both elements but in four cases, pure squamous or adenocarcinoma metastases were encountered. It is suggested that the pancreas should be included as a possible source in those patients with an unknown primary who have a metastasis consisting of either an admixture of squamous and glandular elements or a pure squamous type and in those instances in which a pure squamous and a pure adenocarcinoma are encountered in different metastases.     

Surgical salvage therapy for malignant intrathoracic metastases from nonseminomatous germ cell cancer of testicular origin: analysis of a single-institution experience

BACKGROUND: Cisplatin-based chemotherapy followed by surgical extirpation of residual benign disease represents the usual sequence of curative therapy for metastatic nonseminomatous germ cell cancer of testicular origin. Occasionally, residual disease is malignant in the form of either a persistent nonseminomatous germ cell cancer tumor or degeneration into non-germ cell cancer. We reviewed our institution's experience with patients undergoing salvage operations to remove malignant intrathoracic metastases. METHODS: From 1981 through 2001, 438 patients with nonseminomatous germ cell cancer had operations to remove residual intrathoracic disease after cisplatin-based chemotherapy at Indiana University Hospital. A subset of 134 patients who underwent 186 surgical procedures to remove malignant metastases is the basis of this review. Fifty-nine patients had removal of pulmonary metastases, 49 had removal of mediastinal metastases, and 26 had removal of both pulmonary and mediastinal metastases. Surgical pathology demonstrated 84 patients with persistent nonseminomatous germ cell cancer tumors, 38 with degeneration into non-germ cell cancer, and 12 with both malignant pathologic categories. RESULTS: There were 4 (3.7%) operative deaths. The overall median survival was 5.6 years, with 55 (42.3%) patients alive and well after a mean follow-up of 5.1 years. Seventeen variables were analyzed by using Cox regression. Of these, older age, pulmonary metastases (vs mediastinal metastases), and 4 or more (vs 1) total intrathoracic metastases were significantly (P < or = .01) predictive of inferior long-term survival. CONCLUSIONS: Salvage thoracic surgery to remove malignant metastases from nonseminomatous germ cell cancer tumors of testicular origin can result in long-term survival in select patients. We identified variables that influence survival in this subset.     

Recurrent seminomas: Clinical features and biologic implications

ObjectivesCertain patients with seminoma and clinically atypical phenotypes—visceral metastases, elevated levels of β human chorionic gonadotropin (βHCG), and/or recurrent disease—have a poor prognosis. The primary goal of this pilot study was to characterize the clinical characteristics and treatment profile of these rare patients. We also wished to test whether these tumors expressed any specific biomarkers that might distinguish them as a unique subtype of seminoma.Materials and methodsWe retrospectively identified 25 patients with a history of seminoma plus visceral metastases, βHCG levels >200 mU/ml, and/or recurrent disease. We reviewed these patients' histories for treatment efficacy and clinical outcome. Tissue samples were available from 6 of those patients, and we studied them for expression of the markers OCT 3/4, PLAP, CD30, TRA-1-60, c-kit, and gp200. We compared our results with the expression of those markers in tissue samples from mixed seminoma/embryonal carcinomas and classic seminomas.ResultsOur analysis suggested that certain chemotherapeutic regimens (such as ifosfamide, paclitaxel, and cisplatin) are efficacious for the treatment of patients with these atypical seminomas. Further, specimens from the atypical seminomas generally had staining profiles that resembled those of classic seminomas and the seminoma components in mixed germ-cell tumors, but the profiles differed from those of the embryonal carcinoma components in the same mixed germ-cell tumors.ConclusionsAlthough these atypical seminomas tend to be resistant to chemotherapy, they may still respond to certain chemotherapeutic regimens. Our pilot immunohistochemical study also suggested that the unique phenotypes associated with these atypical seminomas do not result from any relationship with embryonal carcinomas. More study is needed to confirm these initial findings.     

Choroid plexus papillomas: long-term follow-up results in a surgically treated series

The medical records and histological specimens from 26 patients with choroid plexus papillomas operated on at one institution were reviewed retrospectively. Four patients died perioperatively, and 21 of the remaining 22 patients were followed through March, 1986; the patient lost to follow-up review was last seen 14 years postoperatively. Of the 14 patients who underwent gross total removal of their tumor, one had a recurrence at 11 years postoperatively and two died in the perioperative period. Of the 12 patients who underwent subtotal removal of their tumor, two died in the perioperative period. The two patients who did not have radiation therapy postoperatively are free of apparent disease at 6 and 8 years after their operation. Eight patients underwent radiation therapy after subtotal removal of their tumor; four of these remain alive and well, and four have died of progressive disease. The role of irradiation in the treatment of subtotally resected lesion remains controversial, but this therapy is thought to be indicated for recurrent disease after a surgical excision that is as complete as possible. Histopathologically, the presence of occasional mitotic figures, microscopic infiltration, ependymal differentiation, or mild to moderate atypia was not correlated with likelihood of complete resectability or tendency to recurrence.     

Evaluation of recurrent metastatic brain tumor of lung cancer origin

The authors examined numerous clinical features in 15 patients in whom brain metastases from lung cancer recurred after total or subtotal removal. The incidence of recurrence after initial removal of brain nodules was 46.9% (15 of 32 cases). There was no significant correlation between the incidence of recurrence and the histology of the lung cancer, the site of brain nodules, or age. Recurrent brain nodules were the cause of or contributed to death in 60% of recurrent cases. Recurrence was within 3 months of initial removal of brain nodules in 10 of the 15 patients. Brain metastasis recurred only at the initial site in 11 cases (73.3%). Three patients developed carcinomatous meningitis and one had multiple metastases in addition to recurrence or regrowth at the original site. The primary lung cancer was relatively stable at the time of recurrence of brain nodules in 60% of the patients. Tumor removal and radiotherapy are highly recommended for prevention of early recurrence following initial removal of brain metastases. Removal of metastatic tumor is advised in the event of recurrence after 1 year from initial surgery, since the outcome after second surgery tends to be fair. However, tumor removal and radiotherapy are sometimes capable of inducing recurrence of brain nodules. Therefore, it is hoped that more effective cancer chemotherapy will be developed in the near future.