Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.

Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor.

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

Giant Sertoli cell nodule of the testis: distinction from other Sertoli cell lesions.

The case of a 33-year-old man with a clinically suspected testicular neoplasm is reported here. The radical orchidectomy specimen showed a sharply demarcated, firm, yellow-white 1-cm nodule beneath the tunica albuginea at the upper pole. Microscopical examination showed the encapsulated nodule to be composed of tubules lined by immature Sertoli cells with interspersed spermatogonia and an interwoven network of hyalinised basement membrane having foci of calcification. Immunohistochemical studies verified the fetal phenotype of the Sertoli cells and the non-neoplastic nature of the germ cell component. Except for the large size, the findings were identical to those of a Sertoli cell nodule-a typically microscopic, unencapsulated lesion commonly detected in cryptorchid testes. The term "giant Sertoli cell nodule" is used for this unique, hitherto undescribed lesion and its distinction from other Sertoli cell lesions of the testis is considered here.

Molecular evidence for the independent origin of extra-ovarian papillary serous tumors of low malignant potential.

BACKGROUND: Molecular data suggest that peritoneal tumors in women with advanced-stage ovarian papillary serous adenocarcinoma are monoclonal in origin. Whether the same is true for ovarian tumors of low malignant potential is not known. We compared peritoneal and ovarian tumors from women with advanced-stage ovarian papillary serous tumors of low malignant potential to determine whether the peritoneal tumors arose from the same clone as the ovarian tumors. METHODS: We studied the clonality of 73 peritoneal and ovarian tumors from 18 women with advanced-stage ovarian papillary serous tumors of low malignant potential. Formalin-fixed, paraffin-embedded tumors and representative normal tissues were sectioned and stained with hematoxylin-eosin, representative sections from separate tumors were manually microdissected, genomic DNA was extracted from the microdissected tumors, and the polymerase chain reaction was used to amplify a CAG polymorphic site in the human androgen receptor locus on the X chromosome to determine the inactivation pattern of the X chromosome and the clonality of the tumors. RESULTS: The pattern of X-chromosome inactivation could be determined from the tumors of 13 of 18 patients. Of the 13 patients, seven (54%) had nonrandom inactivation of the X chromosome, and six of the seven had different inactivation patterns in the peritoneal and ovarian tumors. Three of these patients also had different patterns of nonrandom X-chromosome inactivation in tumors from each ovary. The remaining six patients had random patterns of X-chromosome inactivation in the peritoneal and ovarian tumors. CONCLUSIONS: Our data suggest that peritoneal and ovarian tumors of low malignant potential arise independently.

Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation.

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.

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.

Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections.

PURPOSE: We review the long-term outcome of patients with viable nonteratomatous germ cell tumor (NTGCT) in retroperitoneal lymph node dissection (RPLND) specimens after primary or salvage chemotherapy, and the impact of postoperative therapy with two courses of standard-dose cisplatin-based induction chemotherapy. PATIENTS AND METHODS: All patients with viable NTGCT in postchemotherapy RPLND specimens from surgeries performed at Indiana University between July 1975 and March 1991 were retrospectively reviewed. RESULTS: Of 580 postchemotherapy RPLNDs performed, 133 had viable NTGCT in their pathology specimens. Of these 580 postchemotherapy RPLNDs, 417 were performed after primary chemotherapy, and 43 (10%) had viable NTGCT in their pathology specimens. There were 163 RPLNDs performed after salvage chemotherapy and 90 (55%) had viable NTGCT in their pathology specimens. After primary chemotherapy, 34 of 43 had complete resections, and 27 of the 34 received postoperative cisplatin-based chemotherapy. Nineteen of 27 (70%) are continuously disease-free (c-NED). All seven who received no postoperative chemotherapy have relapsed. After salvage chemotherapy, 53 of 90 had complete resections. Of those 53, 25 received postoperative chemotherapy, and nine (36%) are c-NED. Twenty-eight received no postoperative chemotherapy, and 12 (43%) are c-NED. Overall, 43 of 133 patients had incomplete resections, and only four are currently disease-free. There were four postoperative deaths (PODs). CONCLUSION: (1) Incomplete resection of viable NTGCT after primary or salvage chemotherapy portends a very poor prognosis. (2) For patients with complete resection of viable NTGCT following primary chemotherapy, two additional courses of cisplatin-based chemotherapy appear to be safe and effective therapy for reducing the risk of relapse. (3) Additional standard-dose chemotherapy appears to offer no benefit to patients with viable NTGCT in the resected specimen after salvage chemotherapy.

Morphologic observations after percutaneous transluminal balloon angioplasty of early and late aortocoronary saphenous vein bypass grafts.

Clinical and morphologic observations from two patients undergoing percutaneous transluminal angioplasty of stenotic aortocoronary saphenous vein bypass grafts early (3 months) and late (56 months) after graft insertion are described. Each patient had one or more clinically successful graft dilations resulting in an angiographic increase in luminal diameter and a decrease in mean trans-stenotic gradient, and each had restenosis of the graft at the site of previous angioplasty within 2 months of dilation. Both operatively excised grafts had diffuse but variable amounts of intimal fibrous thickening and severe narrowing at the previous angioplasty site. The early graft had no evidence of dilation injury, and the intimal thickening consisted solely of fibrocollagenous tissue free of calcific deposits. In contrast, the late graft had a healing intimal dissection at the angioplasty site, and the intimal thickening consisted of atherosclerotic plaque with calcific deposits. Angiographic and morphologic correlations suggest that the mechanism of saphenous vein angioplasty early (less than or equal to 1 year) after insertion is by graft "stretching," while late (greater than 1 year) after insertion it is by atherosclerotic plaque "fracture" similar to that observed in atherosclerotic coronary arteries subjected to angioplasty procedures.

Germ cell neoplasms of the testis.

Testicular germ cell neoplasia, a disease predominantly of young men, is, for unknown reasons, increasing in incidence. Cryptorchidism, a prior testicular germ cell tumor, a family history of testicular germ cell tumors, and somatosexual ambiguity syndromes remain well-established risk factors. Intratubular germ cell neoplasia of the unclassified type represents the common precursor to the great majority of testicular germ cell tumors, and its identification in testicular biopsies reliably identifies those patients who will often progress to an invasive lesion. Seminoma appears to represent the invasive derivative of intra-tubular germ cell of neoplasia of the unclassified type; problematic variants include seminomas with tubular, granulomatous, and edematous patterns. Spermatocytic seminoma is an essentially nonmetastasizing neoplasm unless complicated by the rare development of a sarcomatous component. Embryonal carcinomas usually occur admixed with other germ cell tumor types. The combination of positivity for placental alkaline phosphatase and negativity for epithelial membrane antigen can assist in the distinction of embryonal carcinomas from somatic carcinomas. The treatment of clinical stage I patients with nonseminomatous germ cell tumor with "surveillance only" may be contraindicated depending on features that include the proportion of embryonal carcinoma and the presence of lymphovascular invasion in the orchiectomy specimen. It is important to be aware that pure, mature teratomas in postpubertal patients may be associated with metastases of teratomatous or nonteratomatous type Yolk sac tumor is characterized by numerous patterns including glandular, myxomatous, sarcomatoid, hepatoid, and parietal variants. Choriocarcinomas classically have a biphasic pattern of syncytiotrophoblast and cytotrophoblast; trophoblastic proliferations lacking a biphasic pattern also occur but are difficult to classify unless this category is broadened. Mixed germ cell tumors, consisting of two or more different elements, are quite common. The polyembryoma is a distinctive, well-organized form of mixed germ cell tumor consisting of embryonal carcinoma and yolk sac tumor.

Rete testis hyperplasia with hyaline globule formation. A lesion simulating yolk sac tumor.

The presence of eosinophilic, hyaline globules in association with epithelial hyperplasia was noted in the rete testis of three patients with germ cell tumors. In the more florid examples, this proliferation formed a solid and microcystic pattern that, in association with the hyaline globules, mimicked a yolk sac tumor component. However, the bland cytologic features of the cells and the conformation to the configuration of the rete testis were keys to its reactive nature. A subsequent review of 48 testicular specimens containing well-defined areas of the rete testis showed hyaline globule formation in the rete testis or tubuli recti in 16 of 27 germ cell tumors, one of five other testicular tumors (four stromal tumors and one plasmacytoma), and none of 16 nonneoplastic cases. Many of the cases that had hyaline globules also showed epithelial hyperplasia. Further analysis demonstrated an incidence of rete testis invasion by neoplasm in cases that had hyaline globules, with or without epithelial hyperplasia, that was significantly higher (p less than 0.01) than that seen in neoplastic cases lacking hyaline globules. We concluded that this pseudoneoplastic reaction developed secondary to invasion of the rete testis by tumor. Immunostains supported the nonneoplastic nature of the proliferative lesions and indicated that the globules represented various proteins that had been absorbed from the lumen of the rete testis by the epithelial-lining cells but not successfully secreted.

Solitary necrotizing granulomas of the lung: differentiating features and etiology.

The clinical and pathologic features of 86 roentgenographically solitary pulmonary granulomas were reviewed to determine etiology and to provide guidelines for histologic evaluation. Fungal or acid-fast organisms were identified within the tissue in 60 cases (70%) and fragments of a helminth were found in one. The organisms were almost always present in the center of necrotic granulomas, and examination of two blocks containing active granulomas was usually sufficient for their identification. Microbiological cultures were less productive than direct examination of the tissue. In 25 cases an infectious etiology could not be identified: two were diagnosed as hyalinizing granuloma, one as Wegener's granulomatosis, and 22 were not further classified. A prominent overlapping spectrum of histologic features was found between infectious granulomas and Wegener's granulomatosis, suggesting that the latter may represent an abnormal immune response to an infectious agent that is no longer identifiable within the tissue. Caution is urged in diagnosing limited Wegener's granulomatosis and other pulmonary angiitides in patients with roentgenographically solitary granulomas.

Dermoid cyst of the testis: a study of five postpubertal cases, including a pilomatrixoma-like variant, with evidence supporting its separate classification from mature testicular teratoma.

It is controversial if the rare dermoid cyst of the testis should be classified as a variant of mature teratoma or separately. The spectrum of findings is also ill defined, as is the relationship of dermoid cyst to intratubular germ cell neoplasia of the unclassified type (IGCNU). This study therefore reports the findings in five testicular dermoid cysts that occurred in five patients, 17-42 years of age, who presented with testicular masses. Four lesions consisted of a keratin-filled cyst with a thickened wall, whereas one had islands of "shadow" squamous epithelial cells with superimposed calcification and ossification (pilomatrixoma-like variant). Hair was identified grossly in two cases. On microscopic examination, four tumors had hair follicles with sebaceous glands showing a typical, cutaneous-type orientation to an epidermal surface, although no hair shafts were present in two. In addition, the fibrous wall contained smooth muscle bundles (all tumors) and eccrine or apocrine sweat glands (4 tumors). In some cases there were also glands lined by ciliated epithelium (4 tumors, including the pilomatrixoma-like variant), intestinal mucosa (1 tumor), and bone (2 tumors). There was no cytologic atypia or apparent mitotic activity, and no case had IGCNU in the seminiferous tubules. All patients were clinical stage I and were treated by orchiectomy without adjuvant therapy. All were well on follow-up from 1.5 to 9.5 years later. This study supports that dermoid cyst may have noncutaneous teratomatous elements and that an important criterion for its diagnosis is the absence of IGCNU. It also supports that it should be categorized separately from mature testicular teratoma because of the malignant nature of the latter in postpubertal patients. These observations suggest that there are at least two pathways for testicular teratomas in postpubertal patients: the more common being through IGCNU by differentiation from an invasive malignant germ cell tumor and the less common one, taken by dermoid cyst, by direct transformation from a nonmalignant germ cell.

Choriocarcinoma-like lesions in patients with testicular germ cell tumors. Two histologic variants.

Nine men with testicular germ cell tumors developed one of two types of histologically similar cystic lesions that had features of choriocarcinoma. In five cases, these choriocarcinoma-like lesions (CCLL) were felt to represent an unusual proliferation of teratomatous epithelium (teratomatous CCLL); whereas in four cases, the CCLL was felt to represent a nonbiphasic and cystic form of choriocarcinoma similar to the atypical choriocarcinoma described by Mazur et al. except for its cystic nature. Both types usually occurred as focal findings associated with teratomas. Eight of nine patients had received chemotherapy prior to excision of the CCLL. Teratomatous CCLLs often had a lacelike arrangement of atypical epithelium around cysts that contained homogeneous secretion. Mucicarmine stains were positive in four of five cases of teratomatous CCLLs. Cystic atypical choriocarcinoma consisted of stratified mononucleated cells lining cysts containing a coagulum of eosinophilic material. Stains for human chorionic gonadotropin (HCG) were positive in three of four cases of cystic atypical choriocarcinoma, although serum HCG elevations were either negative or just slightly elevated preoperatively. Five patients with a CCLL who were clinically free of disease following surgical excision and who received no additional chemotherapy remained well on follow-up (average, 1.9 years). We encourage the separate recognition of these lesions so that future studies may determine their clinical significance more precisely.

Microcystic Leydig cell tumors mimicking yolk sac tumor: a report of four cases.

We report four cases of Leydig cell tumor of the testis with a microcystic pattern that mimicked yolk sac tumor. The patients ranged in age from 27 to 35 years and, except for one tumor that was discovered incidentally, presented with testicular masses. All tumors were intratesticular, and three were well circumscribed by a rim of fibrous tissue, whereas one showed minor, focal extension into the adjacent testis. The tumors typically had a vaguely lobular architecture subdivided by fibrous bands. Three of the cases had a complex microcystic appearance caused by individually vacuolated cells and coalescent cystic spaces; this pattern accounted for the majority of two tumors. Another case had focal collections of Leydig cells with prominent cytoplasmic vacuoles but lacked the coalescent spaces. The microcyst contents ranged from optically clear to eosinophilic or lightly basophilic, with the latter having the staining qualities of acid mucopolysaccharide. Three tumors had uniform, bland nuclei and low mitotic rates (<1 mitotic figure per 10 high power fields), but one had marked, random nuclear pleomorphism and an average mitotic rate of five mitotic figures per 10 high power fields. By immunohistochemistry, all were diffusely positive for vimentin; two of three were positive for inhibin, and one showed focal positivity for cytokeratin (CAM 5.2). All were negative for alpha-fetoprotein and placentalike alkaline phosphatase and, apart from having microcystic and solid areas, lacked other features typical of yolk sac tumor. Clinical follow-up ranged from 2 months to 2 years with no patient having recurrence or metastasis. The distinction of Leydig cell tumor from yolk sac tumor has important clinical implications because patients with the former usually receive only clinical follow-up, but the latter often requires chemotherapy.

Yolk sac differentiation in germ cell tumors. A morphologic study of 50 cases with emphasis on hepatic, enteric, and parietal yolk sac features.

We assessed 50 germ cell tumors with areas of yolk sac tumor (YST) for a variety of features including histologic patterns; hyaline droplets; syncytiotrophoblastic elements; hepatic, enteric, and parietal yolk sac differentiation; and granulomatous reaction. Of prime interest was the fact that many YSTs formed hepatic-like foci (22%), enteric-like glands (34%), and parietal yolk sac structures (92%). Hepatoid areas were characterized by nests and cords of polygonal, acidophilic cells with prominent nucleoli and intense cytoplasmic staining for alpha-fetoprotein. Enteric differentiation occurred as well-defined glands with a sharp, striated border and relatively bland nuclear features. Ultrastructurally these glands had apical microvilli with associated glycocalyx and long anchoring rootlets. The apical cytoplasm and luminal contents stained for carcinoembryonic antigen. Parietal yolk sac differentiation was characterized by the intercellular accumulation of basement membrane substance as generally thick and longitudinally arranged bands of eosinophilic material. Such material, by electron microscopy, was both intra- and extracellular, and had irregular outlines and inhomogeneous electron density. It contrasted with the strictly intracellular, round, homogeneous, hyaline globules that, we believe, represent visceral yolk sac differentiation. This intercellular material stained positively for laminin, a basement membrane component. Assessment of 22 embryonal carcinomas and 24 germinomas failed to show hepatic, enteric, and parietal yolk sac features, with one possible exception. We believe these features, especially parietal yolk sac differentiation, are helpful in differentiating YSTs from embryonal carcinomas and germinomas.

Trophoblastic tumors of the testis other than classic choriocarcinoma: "monophasic" choriocarcinoma and placental site trophoblastic tumor: a report of two cases.

We report two unusual forms of testicular trophoblastic tumor. One was a mixed germ cell tumor in a 19-year-old man that had a predominant component of nodules of cytotrophoblast cells with only rare syncytiotrophoblast cells. These nodules of "monophasic" choriocarcinoma were diffusely positive for human chorionic gonadotropin (hCG), which stained the syncytiotrophoblast cells more intensely; stains for human placental lactogen (HPL) highlighted only the latter cells. The second tumor occurred in a 16-month-old boy. It consisted of a pure proliferation of intermediate trophoblast cells and was identical to the placental site trophoblastic tumor of the uterus. The tumor cells showed diffuse immunoreactivity for HPL and patchy staining for hCG. Despite the occurrence of vascular wall invasion, the patient was alive and well at 8 years follow-up with no treatment other than orchiectomy. These cases show that trophoblastic tumors other than classic choriocarcinoma occur rarely in the testis. The differential diagnosis of the "monophasic" choriocarcinoma included seminoma and the solid variant of yolk sac tumor, but the tumor had larger, more irregular nuclei than those of seminoma and was not associated with distinctive yolk sac tumor patterns. The placental site trophoblastic tumor may be confused with Leydig cell tumor or choriocarcinoma, but awareness of its occurrence in the testis and the immunohistochemical findings should permit its recognition.

The pathology of late recurrence of testicular germ cell tumors.

A total of 91 men had histologically documented late recurrences of testicular germ cell tumors characterized by a complete response to treatment with a subsequent disease-free interval of at least 2 years and no evidence of a second primary lesion. Ninety percent of the patients for whom information was available received chemotherapy shortly after their initial diagnosis of testicular germ cell tumors; most of the other patients were known to have stage I disease initially. Overall, 60% of patients had teratoma in their late recurrences, including 20 patients (22%) in whom teratoma was the only element. Thus, teratoma was the most common type of neoplasm in late recurrences. Excluding teratoma coexisting with other types of neoplasms, yolk sac tumor was the most frequent type of tumor in patients with late recurrence. It occurred in 47% of patients, either alone or with teratoma, another nonteratomatous germ cell tumor type, or a "nongerm cell malignant tumor." Unusual types of yolk sac tumor, including glandular, parietal, clear cell, and pleomorphic patterns, were seen frequently in late recurrences and often raised differential diagnostic problems with "nongerm cell" carcinomas. A smaller number of late recurrences consisted of other types of neoplasms. Twenty percent of patients with late recurrence had a nonteratomatous germ cell tumor other than yolk sac tumor, either alone, with yolk sac tumor, or with a "nongerm cell malignant tumor." Most of these nonteratomatous germ cell tumors other than yolk sac tumor were embryonal carcinoma, although rarely seminoma and choriocarcinoma were encountered. "Nongerm cell malignant tumors," including both sarcomas and carcinomas of various types, occurred in 23% of late-recurrence patients, either alone or with a nonteratomatous germ cell tumor. Late recurrences were seen in many different sites in these patients, including the retroperitoneum, abdomen, pelvis, liver, mediastinum, lung, bone (femur, vertebra, and rib), lymph nodes outside the retroperitoneum and mediastinum (supraclavicular, neck, and axillary regions), scrotum and inguinal regions, adrenal gland, chest wall, and buttocks. Follow-up data were available for 79 of the 91 patients studied. Duration of follow-up ranged from 2 months to 13 years after the patient's first late recurrences; the mean length of follow-up was 4.8 years. Patients whose late recurrences consisted of teratoma only had the most favorable outcomes, with 79% having no evidence of disease at last follow-up. Patients whose late recurrences consisted of pure "nongerm cell malignant tumor" or pure germ cell tumor (yolk sac tumor or other types) had a much worse prognosis: Only 36% to 37% were alive with no evidence of disease. Patients with two different types of nonteratomatous malignancies in their late recurrences had a dismal clinical course: Only 17% with both yolk sac tumor and other nonteratomatous germ cell tumor had no evidence of disease, whereas no patient with both nonteratomatous germ cell tumor and "nongerm cell malignant tumor" was disease free. Late recurrences consisting of teratoma alone often have a favorable outcome, but the prognosis in all other patients is poor. Furthermore, late recurrence is not likely to respond to chemotherapy and is best treated by surgical excision when possible.

Spindle cell mural nodules in cystic ovarian mucinous tumors. A clinicopathologic and immunohistochemical study of five cases.

We studied five cystic ovarian mucinous tumors with spindle cell mural nodules to define their histologic and immunohistochemical properties. Three of these mural nodules consisted of carcinomatous nests surrounded by highly pleomorphic polygonal and spindle cells. There were transition zones between the pleomorphic cells and the cell nests. In all three cases, both cell populations coexpressed cytokeratin and vimentin, suggesting a diagnosis of anaplastic carcinoma. A fourth nodule consisted of moderately differentiated adenocarcinoma embedded in prominent, cytologically uniform spindle cells. These cells were histologically distinct from the carcinoma; there were no zones of transition. The carcinoma was strongly positive for cytokeratin but only weakly positive for vimentin; the spindle cells expressed vimentin but not cytokeratin. We diagnosed this lesion as carcinoma with a reactive spindle cell stroma. A fifth mural nodule was composed entirely of interlacing fascicles of uniform spindle cells that were negative for cytokeratin but positive for vimentin, muscle-specific actin, and desmin; these findings support a diagnosis of leiomyoma. Two of the four patients with malignant nodules died of disease; the rest are alive and disease-free after follow-up intervals ranging from 1 to 4 years. This study demonstrates the usefulness of immunohistochemistry in distinguishing variant forms of spindle cell mural nodules in cystic ovarian mucinous tumors. It further suggests that malignant nodules do not necessarily carry a poor prognosis.

Primitive neuroectodermal tumors arising in testicular germ cell neoplasms.

Twenty-nine young men (mean age 29 years) had primitive neuroectodermal tumors (PNETs) arising in germ cell tumors (GCTs). Nine patients had PNETs confined to the testis, eight patients had PNETs in the testis and at metastatic sites, and 12 patients had PNETs identified only at extratesticular sites. Immunohistochemistry was of use in the further classification of these PNETs as neuroblastoma, medulloepithelioma, peripheral neuroepithelioma, or ependymoblastoma. The histologic pattern of PNETs in the testis (neuroblastoma or medulloepithelioma) did not predict which tumors metastasized. PNETs localized to the testis did not affect prognosis. Eight patients with no PNETs outside the testis were free of disease 1 month to 10 years after diagnosis. PNETs in extratesticular sites were an adverse prognostic factor. Nineteen patients with extratesticular PNETs had adequate clinical follow-up. Thirteen are dead of disease from 4 months to 5 1/2 years (mean 26 months) after diagnosis, four are alive with disease 6 months to 2 years after diagnosis, and two have no evidence of disease with short follow-up (6 and 17 months). Mean survival was longer (34 months) for patients whose extratesticular PNET was neuroblastoma than for those with other types of PNETs (13 months). Chemotherapy directed against GCTs was not effective in patients who developed metastatic PNETs of GCT origin. We conclude that extratesticular PNETs in patients with testicular GCTs are usually fatal, but patients with neuroblastomatous metastases may have a more prolonged course.

Nephroblastoma-like tumors in patients with testicular germ cell tumors.

Nephroblastoma-like tumors (NLTs) developed in metastatic sites in nine men with testicular germ cell tumors (GCTs). These tumors had a characteristic "triphasic" admixture of primitive tubular structures, sometimes with a glomeruloid pattern, blastema and stroma. Skeletal muscle differentiation was apparent in two cases. Specific neuroendocrine markers (synaptophysin and chromogranin A) were negative. All patients were treated by surgical excision. Six patients were alive with no evidence of disease from 4 to 12 years after diagnosis of GCT and NLT. One patient was alive with disease 6 years after diagnosis of GCT and 3 years after diagnosis of NLT. One man who also had metastatic primitive neuroectodermal tumor (PNET) had short survival, and one patient died of postoperative infection. We conclude that patients with testicular GCTs in whom NLTs develop in metastatic sites often experience prolonged survival. Surgical excision appears to be adequate treatment for NLT arising in metastatic testicular GCT in most patients. It is important to distinguish NLTs from PNETs in metastatic GCTs because of the more aggressive course and the frequently fatal outcome of the latter.