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© 2003 American Society for Clinical Oncology Update on Late Relapse of Germ Cell Tumor: A Clinical and Molecular Analysis
From the Divisions of Biostatistics and Hematology/Oncology, Department of Medicine, and Section of Hematology/Oncology, Herman B. Wells Center for Pediatric Research, and Department of Pediatrics, Pathology, Medical and Molecular Genetics, Urology, and Biochemistry/Molecular Biology, Indiana University Medical Center, Indianapolis, IN; and Department of Molecular Genetics, Ohio State University, Columbus, OH. Address reprint requests to Lawrence H. Einhorn, MD, Indiana Cancer Pavilion, RT 473, 535 Barnhill Dr, Indianapolis, IN 46202-5289; email: leinhorn{at}iupui.edu.
Purpose: Analysis of patients with late relapse (LR) of germ cell tumor (GCT) with reports on clinical characteristics, outcomes, and molecular and cytogenetic features. Patients and Methods: Eighty-three patients evaluated at Indiana University from 1993 through 2000 for relapse of GCT more than 2 years from initial therapy were reviewed. Available specimens were investigated for expression of the transcription regulator FoxD3 and apurinic/apyrimidinic endonuclease and the presence of chromosome 12 abnormalities. Results: Median interval from initial presentation to LR was 85 months. Forty-three of 49 LR patients who underwent surgery were rendered disease free (NED), and 20 (46.5%) remain continuously NED. Thirty-two patients received chemotherapy, but only six (18.8%) obtained a complete remission. Five of these patients remain continuously NED after chemotherapy alone, including three who were chemotherapy naïve. Eighteen of these 32 patients were successfully rendered NED by postchemotherapy surgery, and 12 remain continuously NED. Two patients continue on observation with no treatment for their LR. Overall, 69 of the 81 treated patients (85.2%) ultimately achieved an NED state, and 38 (46.9%) remain continuously NED with median follow-up from LR therapy of 24.5 months (range, 1 to 83 months), whereas nine other patients are currently NED after therapy for subsequent relapses. Because of the small numbers of specimens tested, we were unable to draw any definitive conclusions from the molecular and cytogenetic analyses. Conclusion: GCT patients require lifetime follow-up. At the time of LR, surgical resection alone remains our preferred therapy.
ALTHOUGH GERM cell tumor (GCT) is rare, it is the most common malignancy to strike males aged 15 to 35 years. With modern cisplatin-based chemotherapy and/or appropriate surgery, early-stage testicular cancer has a cure rate of 95% to 100%, whereas advanced disease has a remarkable 70% cure rate.1 However, up to 10% of patients who achieve a disease-free status with initial chemotherapy will relapse.2,3 The vast majority of such relapses occur within 2 years from initiation of therapy—a so-called early relapse.2 Second-line cisplatin-based therapies or high-dose chemotherapy with stem cell support are curative in 24%–54% and 57% of cases, respectively.4–6 A smaller minority of patients will relapse more than 2 years from initial therapy—a so-called late relapse (LR). The largest series of LR was published by Baniel et al.7 That study reviewed 81 patients evaluated or treated for a LR of GCT at Indiana University from 1979 to 1992 and reported clinical characteristics and therapeutic outcomes. The results demonstrated that LR of GCT behaves clinically different from GCT at initial presentation or at early relapse. The conclusions of the study were as follows: incidence of LR was 2% to 3%; retroperitoneum and lungs were the primary sites of relapse; alphafetoprotein (AFP) was the predominant marker elevated; LR GCT was chemosensitive but rarely cured by chemotherapy alone; surgical resection is the definitive therapy; and LR patients rendered disease free remain at risk for subsequent early and late relapses. A more recent, smaller report by Gerl et al8 corroborates these clinical findings. Although the clinical characteristics of GCT in LR have been described, the molecular biology that determines its unique clinical behavior, namely, the long latency from initial treatment to recurrence and cisplatin resistance, has not been studied. We have considered three potentially important molecular and cytogenectic factors. First, FoxD3 (formerly known as Genesis) is a transcription regulator and repressor of differentiation that is believed to play a critical role in regulating fundamental decisions of proliferation versus differentiation in normal and malignant embryonic stem cells.9–11 Whether its regulatory function is important in the unique behavior of GCT at LR is not known. Second, potential mechanisms that can account for chemotherapy resistance are numerous and include strategies to enhance the repair of DNA damage such as the base excision repair machinery.12–14 Apurinic/apyrimidinic endonuclease (Ape1) is a multifunctional enzyme of the base excision repair mechanism and has been shown to be overexpressed in a number of malignancies, including GCT.15–19 Beyond its role in DNA repair, Ape1 functions as a regulator of transcription factors via redox pathways, whereby it regulates the expression of genes involved in cell cycling, apoptosis, and cancer promotion.20,21 Whether the expression of Ape1 in GCT at LR contributes to chemotherapy resistance has not been characterized. Finally, essentially all GCT at initial presentation contain abnormalities of chromosome 12 such as the isochromosome 12p [i(12p)] or excess 12p copies.22,23 The exact role that abnormalities of 12p play in GCT pathogenesis remains to be determined. Some studies have suggested that a high copy number of i(12p) is a poor prognostic factor and is associated with a greater possibility of treatment failure.24,25 The extent of 12p abnormalities at LR has not been documented. This study adds to the existing information on the clinical characteristics and outcomes of patients with LR of GCT. In addition, we begin the investigation into possible important molecular and cytogenetic features by reporting the tumor expression of FoxD3 and Ape1 as well as the extent of 12p abnormalities in this unique patient population.
Patients LR of GCT was defined as follows: an initial pathologic diagnosis of seminomatous or nonseminomatous GCT, recurrence of GCT (determined by biopsy, marker elevation without secondary cause, or growth of a previously stable GCT disease site) more than 2 years after beginning successful therapy for an initial GCT presentation, and no clinical evidence of a second primary GCT. Patients who received consultation or treatment for LR of GCT by the Division of Hematology/Oncology or the Department of Urology at Indiana University, Indianapolis, IN, between 1993 and 2000 were included. The Institutional Review Committee for Indiana University approved the study.
Methods Patients rendered disease free by resection of tumor were identified by "no evidence of disease" (NED) plus the most biologically aggressive histologic component in the resected sample (ie, NED-Sarc or NED-GCT). Patients with a residual mass or masses and a normalization of tumor markers after chemotherapy were identified as achieving a "residual mass plus normal markers." Patients with growth or regrowth of disease sites during or within 3 months of the completion of therapy were described as having progressive disease (PD). Complete response (CR) was defined as resolution of all evidence of disease. "Continuously NED" was defined as being without evidence of disease after management for one LR. "Currently NED" was defined as being without evidence of disease after successful treatment for one or more subsequent relapses after the first LR. Those who were alive with active GCT were defined as "alive with disease" (AWD), whereas those who died from their LR were defined as "dead of disease" (DOD). Follow-up intervals were measured from the date of therapy for the first LR to the date of last follow-up or death unless otherwise specified. Expression of FoxD3 was evaluated by immunohistochemical techniques previously described.27 An expression index was calculated as the product of the percentage of cells expressing FoxD3 and the intensity of cellular staining (0–4+). An expression index of 100 or more was considered "high" expression, and an index of less than 100 was considered "low" expression. Expression of Ape1 was evaluated by immunohistochemical techniques previously described, with the exception that a DAKO Universal Staining System (DAKO, Carpinteria, CA) was used to automate the process.17,18 The percentage of total tumor cells (nuclei and cytoplasm combined), tumor nuclei, and cytoplasm in a specimen that stained for Ape1 were recorded. Likewise, the intensity of staining for Ape1 in the tumor nuclei and cytoplasm of each sample was scored from 0 to 3, as previously described.15 The mean value for percentage staining and stain intensity for each set (ie, total, nucleus, cytoplasm) was calculated. Values within each set were characterized as "high" if they were above the mean for that set and as "low" if below the mean. The percentage of stromal cells staining for Ape1 in each specimen (nuclear and cytoplasmic staining combined) was also scored and served as a control. Specimens were evaluated for abnormalities of chromosome 12p by fluorescent in situ hybridization (FISH) techniques. For non-paraffin-embedded specimens, the protocol using triple-color FISH analysis of 12p amplification was as previously described.28 For paraffin-embedded specimens, the FISH protocol was a modification of the above and is as follows: FISH analysis was performed on 10-mm sections of tissue affixed to positively charged glass slides. Each slide was baked for 2 hours at 56°C, deparaffinized in xylene (three times, 10 minutes each), and dehydrated in an alcohol series. Tissue pretreatment included exposure to 2x standard saline citrate at 75°C for 10 minutes and proteinase K (14 mg/mL) for 20 minutes. Cellular DNA was denatured in a 70% formamide solution at 75°C for 10 minutes followed by consecutive alcohol washes. Cells were examined on a DMR fluorescence microscope (Leica, Wetzlar, Germany) equipped with appropriate filters for the red, green, and blue colors, and the 100x oil immersion objective was used. The average 12p copy number per cell and the number of i(12p) copies per 20 cells were documented.
Statistical Analysis
From 1993 to 2000, we identified 85 patients with evidence of a LR of GCT. Two patients were excluded because of benign, non-GCT pathology (histoplasmosis-associated granulomatous disease and nodular fasciitis). Thus, the remaining 83 eligible patients were included for analysis.
Patient Characteristics and Management at Initial GCT Diagnosis
Patient Characteristics at LR Median age at LR was 36 years (range, 19 to 55 years), with a median interval to LR of 85 months (range, 25 to 336 months). Patient characteristics at LR are summarized in Table 3  . Notably, 50 patients (60.2%) were symptomatic at the time of LR, whereas 33 patients (39.7%) were asymptomatic and diagnosed at routine follow-up by elevated tumor markers or abnormal radiographic studies. Patients with symptoms at LR had a median interval from initial diagnosis to LR diagnosis of 101 months (range, 26 to 336 months), whereas those without symptoms had a median interval of 66 months (range, 25 to 168 months). AFP was the most commonly elevated tumor marker, and the retroperitoneum and lung were the most commonly involved sites at relapse. Seven patients presented with elevated tumor markers only (six AFP, one hCG) and normal radiographic studies. Six of these patients ultimately manifested measurable disease at a median of 19 months (range, 3 to 32 months) from the time of abnormal tumor marker detection. Regarding LR histology (scored by the most biologically aggressive component), most patients relapsed with GCT; yolk sac tumor was the most common germ cell subtype, being present in 44.6% of GCT specimens. Fourteen patients had pure teratoma and 10 had transformed teratomatous elements (five sarcoma, five adenocarcinoma). Three patients had undetermined pathology (two were diagnosed by marker elevation, one refused biopsy). The majority of patients had disease with good prognosis at LR according to the IGCC classification. Primary therapy for the 83 LR patients was surgery for 49 patients, chemotherapy for 32 patients, and no therapy for two patients.
Primary Surgical Management of LR The outcomes of the 49 patients treated with primary surgery at LR are summarized in Table 4 . Overall, 45 patients in the surgery cohort ultimately were rendered NED. Their current status based on the tumor histology at resection is listed in Table 4. Notably, 64% of those rendered NED-T remain continuously NED, whereas all three patients rendered NED-Sarc had subsequent relapses and are DOD.
Of the 33 patients rendered NED after the resection of one disease site, 18 (54.5%) remain continuously NED. In contrast, of the 10 patients rendered NED after the resection of two or more disease sites, only two (20%) remain continuously NED. Twenty-three (51.1%) of the 45 patients in the primary surgery cohort who ultimately achieved an NED state went on to have one or more subsequent relapses. Treatment for subsequent relapses involved various combinations of surgery, chemotherapy, and radiation. Eight of these 23 patients were successfully treated and remain currently NED with a median follow-up of 54.5 months (range, 13 to 73 months) from their last therapy. In total, of the 49 patients in the primary surgery cohort, 21 (42.9%) remain continuously NED, eight (16.3%) are currently NED, eight (16.3%) are AWD, and 12 (24.5%) are DOD at a median follow-up of 37 months (range, 1 to 131 months).
Primary Chemotherapeutic Management of LR
Comparing response to primary chemotherapy by prior therapy status, four of the 10 (40%) chemotherapy-naïve patients obtained a CR, whereas the remaining six required postchemotherapy surgery to render them NED-T (three patients), NED-GCT (two patients), and NED-Adeno (one patient). In contrast, only two of the 22 (9.1%) nonchemotherapy-naïve patients who received primary chemotherapy obtained a CR, and 12 required surgery to render them NED-GCT (seven patients), NED-T (three patients), and NED-Sarc (two patients). Of note, two of the three chemotherapy-naïve patients treated with primary surgery at their first LR later obtained a CR when treated with chemotherapy alone at the time of subsequent relapse and remain currently NED at 46 and 82 months, respectively, with no additional treatment. Two patients have received no therapy for their LR. One patient has a rising AFP without radiographic evidence of disease, and one patient with normal markers refuses biopsy or intervention for regrowth of a retroperitoneal mass.
The current status of the total 83 patients at a median follow-up of 29 months (range, 1 to 139 months) may be summarized as follows: 38 (45.8%) patients remain continuously NED, nine (10.8%) are currently NED after subsequent relapse, and 15 (18.1%) and 21 (25.3%) are AWD and DOD, respectively. The current status of patients according to their LR histology is summarized in Table 6
Patients With Marker-Only LR Seven patients had only elevated tumor markers at the time of LR without an identifiable mass. Six had AFP elevation, and one had hCG elevation. Six of these patients ultimately manifested identifiable disease sites during their course at a median interval of 19 months (range, 3 to 32 months) from LR diagnosis. One patient continues to have AFP elevation only at 79+ months from the date of LR and has received no therapy to date. Positron emission tomography (PET) scans were performed in five patients after computed tomography (CT) scans initially failed to reveal sites of disease. Four such PET scans were negative, and one revealed mediastinal disease. Before identifying a disease site, one patient was treated with cisplatin-based chemotherapy with only temporary normalization of AFP followed by a continued rise in AFP. This patient subsequently manifested an iliac mass on a follow-up CT scan and was rendered NED-GCT by surgery. He remains continuously NED 86 months after surgery. Five other patients were treated with surgery only after disease sites were identified by CT scans at follow-up. Three were rendered NED-GCT, and two remain continuously NED at 63 and 89 months, whereas one is AWD after subsequent relapse. The other two patients had a persistently elevated AFP after surgery and are DOD after further therapy failed.
Patients With Retroperitoneal-Only LR
Patients With Multiple Relapses
Molecular and Cytogenetic Analysis
Twenty-six specimens were available for evaluation of Ape1 expression, as summarized in Table 7  . The mean percentage expression within GCT cells was statistically higher than within the normal surrounding stroma (P < .0001, two-sided, two-sample t test). Within the GCT cells, the nucleus had both higher mean percentage (P < .0008, two-sided, two-sample t test) and intensity (P < .0001, two-sided, two-sample t test) of Ape1 staining than the cytoplasm. Only nine of the 26 patients evaluated for Ape1 expression received chemotherapy as initial treatment for their LR. Six of these patients had PD with chemotherapy, and all six had tumor specimens with a high nuclear percentage expression index. Three of these patients are disease free at last follow-up after being surgically rendered NED. The remaining three patients who received primary chemotherapy achieved a residual mass plus normal markers with chemotherapy and remain NED after surgical resection. Two and one of these patients had tumor specimens with high- and low-percentage nuclear Ape1 expression, respectively. There was no identifiable difference in response to chemotherapy or in outcome based on percentage or intensity of cytoplasmic staining (data not shown).
Twenty-seven of 28 LR tumor specimens tested had abnormalities of 12p, as summarized in Table 8
Statistical Analysis Patients at LR were evaluated for an association between differences in disease extent (number of disease sites and IGCC classification at LR) and the primary LR therapy they received (chemotherapy or surgery). As detailed in Table 9 , there was a statistically significant tendency for patients to receive primary chemotherapy rather than surgery in the setting of multiple disease sites (P = .01,  2 test) and a poor versus good or intermediate IGCC classification (P = .0006, Fisher’s exact test).
Univariate and multivariate analyses were performed to identify significant variables (as described in "Statistical Analysis," in Methods) associated with status at last follow-up (NED v non-NED) and overall survival. As stated previously, because of the relatively small data sets for FoxD3 expression, Ape1 expression, and chromosome 12 abnormalities, these were dropped from this analysis. Only those variables that were at least significant in univariate analysis (alpha = 0.10) are shown in Table 7 . In regard to status at last follow-up, a chemotherapy-naïve state at the time of LR (P = .04; OR = 9.11; 95% confidence interval, 1.1 to 76.7) was the only significant covariate in multivariate analysis for being NED versus non-NED. When variables associated with overall survival were evaluated in univariate analysis, only the presence of symptoms at LR was significant for poorer survival (P = .019; HR = 3.74; 95% confidence interval, 1.25 to 11.34).
Over the last two decades, LR of GCT has been characterized as a distinct and unique clinical entity. Early published case series reported on small numbers of patients, and many remarked on the relative lack of efficacy of chemotherapy alone in the LR setting as well as the poor prognosis of these patients.29–35 In 1995, Baniel et al7 from Indiana University published the first large series of patients with LR. Of the 81 patients included, most experienced LR more than 5 years from their de novo GCT therapy. Eighty-one percent relapsed with GCT, whereas 19% relapsed with pure teratoma. Of the 65 patients treated with primary chemotherapy at LR, 17 (26.2%) had a CR. However, only two of these patients, both chemotherapy naïve, remained continuously NED after chemotherapy alone at 12 and 102 months of follow-up. Of the 16 patients treated with primary surgery at LR, 11 remained NED with no additional therapy at a median follow-up of 14 months (range, 5 to 108 months). Three of these patients had GCT at resection. On the basis of the findings of that study, primary surgical resection was established as the preferred therapy for LR patients at our institution. In addition, the need for lifetime monitoring of GCT patients "cured" from their de novo disease was reinforced. Gerl et al8 subsequently published a series of 25 patients with LR in 1997. The clinical characteristics of these patients closely mirrored those of Baniel’s series. Six of 23 (26.1%) treated patients remained continuously NED at last follow-up after being surgically rendered NED-GCT (four patients) and NED-T (two patients). Only two of 16 (12.5%) patients treated with primary chemotherapy remained continuously NED after chemotherapy alone. Interestingly, in contrast to the Baniel series, both of these patients had received prior chemotherapy. Furthermore, all four patients with GCT who received high-dose chemotherapy for their LR failed to obtain a CR. The observations of this current study are consistent with the results from these prior reports. Patients again tended to relapse more than 5 years from their initial GCT diagnosis, with the median time to relapse being just 7 years. Most patients relapsed either in the retroperitoneum or the lungs and had elevation of AFP. As in the Baniel report, relapse with GCT occurred in a four-to-one ratio with pure teratoma.7 The majority of patients had one anatomic site involved, but over one third of the patients had two or more sites involved. The IGCC classification has not been validated as a prognostic tool for GCT in LR. However, when this classification was implemented in this study, over two thirds of assessable patients had good-risk parameters at LR. Despite this "favorable" category, few LR patients are curable with chemotherapy alone. In contrast to the previous reports, the majority of patients in this study received primary surgery at LR rather than chemotherapy. As a single modality of therapy, surgery was again more effective at producing a durable NED state. In 43 of 49 cases, primary surgery for LR rendered patients NED, including 10 patients with more than one disease site. Twenty (40.8%) of these patients remain continuously NED after primary surgery alone, including 11 patients with GCT and four with adenocarcinoma. Patients rendered NED by primary resection of more than one disease site remained continuously NED in 20.0% of cases, whereas those rendered NED by primary resection of only one disease site remained continuously NED in 54.5% of cases. The majority of patients (63.6%) with pure teratoma at disease resection have remained continuously NED after primary surgery alone, and 40.6% of patients with nonteratomatous histology are continuously NED. Primary chemotherapy, as a single modality of therapy for LR, provided poorer results. In fact, just two of 81 treated patients in this study were able to avoid surgical therapy. Only six of the 32 patients treated with primary chemotherapy achieved an NED state with chemotherapy alone, and five remain continuously NED. Notably, four of these six patients were chemotherapy naïve before LR. The chemotherapy-naïve state appears to be an important predictor of chemotherapy response in the LR setting. Only 9.1% (two of 22) of those patients who had received chemotherapy before their LR achieved a CR with chemotherapy, compared with 40% (four of 10) of chemotherapy-naïve patients. Furthermore, in multivariate analysis, a statistically higher percentage of chemotherapy-naïve patients remain NED at their last follow-up. Consistent with Gerl’s findings,8 two patients who had received prior chemotherapy not only achieved a CR but have maintained that state.
As summarized in Table 9 Clearly, all patients with pure teratoma at LR should be treated with surgery alone. In patients with nonteratomatous disease who would require a surgery with unacceptably high morbidity or those who have "surgically unresectable" disease, a reasonable strategy would be to use primary chemotherapy where a response could perhaps facilitate surgical resection or, less likely, produce a CR negating the need for surgery. Whether chemotherapy-naïve patients with nonteratomatous disease at LR should preferentially receive primary chemotherapy cannot be fully answered in this or other studies. As demonstrated in this report, chemotherapy-naïve patients often maintain chemosensitivity in stark contrast to those who have previously received chemotherapy. Three to four courses of cisplatin-based chemotherapy may in fact be more tolerable than surgical resection in many of these patients. Moreover, there was no obvious association between time to LR and the maintenance of chemotherapy sensitivity in chemotherapy-naïve patients to guide the choice of primary surgery versus chemotherapy. For example, the chemotherapy-naïve patient with the shortest interval to LR (26 months) who received primary chemotherapy ultimately died of chemorefractory disease. However, a chemotherapy-naïve patient who had a LR at more than 14 years from his initial disease was treated with two surgeries before being "cured" by chemotherapy alone. He has remained NED for almost 8 years. Thus, at this time, we believe it is reasonable to consider chemotherapy alone, chemotherapy followed by surgery, or surgery alone for chemotherapy-naïve patients. Lifetime follow-up after "cure" of a patient’s de novo presentation of GCT is strongly recommended. Such an extended follow-up is designed for prompt detection of a LR. This study was not able to sufficiently document the specific schedule of each patient’s follow-up at the time of their LR, and thus, these data were not reported. One can postulate that more patients undergoing routine follow-up could be diagnosed in the asymptomatic state with less disease volume and result in a greater likelihood of having resectable disease compared with those receiving no follow-up. The importance of discovering the asymptomatic patient at LR is underscored by their improved overall survival, demonstrated in this study. Such a patient can only be found with lifelong clinical, radiographic, and serologic follow-up. At our institution, follow-up strategies for patients who are NED after therapy for de novo GCT presentation are based on two important observations: All patients are potentially at risk for early and late relapse,7and the risk of early relapse is substantially higher than LR (approximately 10% v 2% to 3%).2,3,7,8 Therefore, no patient should be excluded from follow-up, and follow-up should be more intense during the first 2 years. For the first year of follow-up, patients should receive a history and physical, tumor markers, chest x-ray, and abdominal and pelvic CT scans every 2 months. In the second year, all of these should be completed every 4 months. During the third through fifth years, this evaluation should be done every 6 months, with the exclusion of abdominal and pelvic CT scanning. One exception to this exclusion of CT scans would be in patients undergoing postchemotherapy resection for bulky teratoma. Because teratoma can be slow growing, these patients should receive more-prolonged CT evaluation of the areas where the bulky teratoma was resected. After 5 years, patients should undergo a history and physical, tumor markers, and chest x-ray annually for life. One must also be mindful of the potential late vascular, endocrine, and neurologic effects of cisplatin-based chemotherapy that can manifest during follow-up.36 Finally, initial attempts were made to explore potentially important molecular and cytogenetic characteristics of GCT in LR. We evaluated the expression of FoxD3 and Ape1 as well as the presence of 12p abnormalities in available prospective specimens. One mystery surrounding the behavior of GCT in LR is its unusually long latency from a time of presumed cure to recurrence of disease. Some have hypothesized that the LR of GCT may arise from the malignant dedifferentiation of residual, occult teratoma or from the proliferation of previously occult, dormant GCT that behaves atypically.36–39 Therefore, it is reasonable to investigate the expression of factors in primitive germ cell tissue, like FoxD3, which participate in decisions regarding differentiation and proliferation. Only five patients’ tumors out of the 21 specimens evaluated highly expressed FoxD3. No obvious differences in outcome between high and low expressers occurred, and because of the small sample size, further statistical analysis is impractical. Further study with a larger sample size is required to make more definitive statements. Ape1 is a multifunctional enzyme that participates in the base excision repair pathway wherein alkylation and oxidative DNA damage from endogenous as well as exogenous agents (ie, cisplatin, other cytotoxic agents, and radiation) is repaired.12–14 Overexpression of Ape1 has been documented in many malignancies such as cervical, head and neck, ovarian, prostate, and germ cell cancers.15–19 When Ape1 is overexpressed in GCT cell lines, resistance to bleomycin and radiation therapy has been demonstrated.15 In normal and malignant tissues, Ape1 exhibits both nuclear and cytoplasmic expression.15,16,18 Recent data from Kelley and Robertson (manuscript in preparation) from our institution have shown that increased cytoplasmic Ape1 levels in GCT (non-LR) may be associated with resistance to cisplatin-based chemotherapy and may predict relapse. Data on Ape1 expression in this current study were relatively limited, with only 26 available specimens. Ape1 levels were shown to be increased in GCT at LR, with mean values being higher in the nucleus compared with the cytoplasm. Only nine patients with evaluated specimens received chemotherapy; thus, searching for a differential response to chemotherapy was not statistically practical. Whether elevated Ape1 levels are specifically related to the unique chemotherapy resistance in this disease remains unclear, but one hopes it will be elucidated as our data sets increase. Abnormalities of chromosome 12p appear to be preserved almost uniformally in the LR state either as multiple copies of 12p or as its isochromosome form.22,23 As with de novo GCT, the specific biologic consequences that 12p abnormalities have in the LR setting is unknown. Some data have suggested that the number of i(12p) copies in a de novo GCT may act as a prognostic factor, with more than three copies being associated with tumor progression and treatment failure.24,25 No correlation in chemotherapy response or clinical outcome existed in our small LR sample. Ongoing research at our institution evaluating FoxD3 and Ape1 expression and cytogenetic abnormalities at de novo, early relapse, and LR disease states will better clarify the preliminary data presented here and hopefully illuminate the role these molecular and cytogenetic properties may play in this unique and enigmatic disease.
Supported by grant PO1 CA74295 from the National Cancer Institute, Bethesda, MD, and the Walther Cancer Institute, Indianapolis, IN. Presented in part at the 30th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.
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ABSTRACT
INTRODUCTION
or 35 years of age), interval to LR (
100), and 16 had a low expression index (< 100). Consistent with prior data,
