with primary mediastinal nonsemino- containing regimens displayed alterations Hematologic Disorders matous germ cell tumors was affected in chromosome 5 or 7 in a high proportion by a hematologic disorder, whereas no of patients (60%–90%). In contrast, leu- Associated With Primary cases were seen among 334 patients kemias associated with mediastinal germ Mediastinal Nonsemino- with other extragonadal germ cell tu- cell tumors appeared to have no consis- matous Germ Cell Tumors mors. The hematologic disorder had a tent cytogenetic abnormalities (3). How- statistically significant impact on prog- ever, the typical marker chromosome abnormality of testicular cancer, isochro- Jo¨rg T. Hartmann, Craig R. Nichols, nosis, with none of the 17 reported pa- tients surviving for more than 2 years. mosome i(12p), had been identified Jean-P. Droz, Alan Horwich, Arthur [J Natl Cancer Inst 2000;92:54–61] within leukemic blasts in some cases, in- Gerl, Sophie D. Fossa, Jo¨rg Beyer, dicating a biologic relationship between Jo¨rg Pont, Karim Fizazi, Lawrence testicular cancer and in other Hematologic neoplasias associated cases. Other cytogenetic findings in leu- Einhorn, Lothar Kanz, Carsten with extragonadal germ cell tumors rep- kemic blasts, such as evidence of XXY or Bokemeyer resent one of the most intriguing and bio- trisomy 21 karyotypes, may be related to logically distinctive aspects of male germ Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021 the rare but documented association of cell cancers. Since the association was Background. The association between mediastinal germ cell tumor and Klinefel- first recognized in 1985, a small number primary germ cell tumors of the medi- ter’s syndrome or Down syndrome of cases have been reported (1,2). Patients (13,14). astinum (the space between the lung affected with hematologic malignancies The clinical course of the hematologic pleura that contains the heart and presented with a germ cell tumor located neoplasia in patients with germ cell tu- other chest viscera) and hematologic in the mediastinum, each with a nonsemi- mors tends to be very aggressive, and a malignancies has been described by nomatous histology. Teratocarcinoma and substantial proportion of these patients retrospective analysis of patients endodermal sinus tumors had been noted die before treatment. Patients have either treated at individual clinical centers. in the majority of patients. The largest se- not responded to antileukemic treatment To better characterize the risk of he- ries, with 16 patients, reported a median or attained only brief remissions. A sub- matologic disorders in patients with ex- time interval of 6 months (range, 0–122 group of patients with isolated thrombo- tragonadal germ cell tumors and to de- months) from the diagnosis of mediastinal cytosis/ disorders appears to have scribe the clinical and biologic features germ cell tumor to the occurrence of a a more favorable prognosis (4,5). of the disorders, we studied an unse- hematologic disorder (3). Approximately Only limited data are available regard- lected population in a large, interna- one third of patients presented with both ing the frequency, clinical behavior, and tional, multicenter database. Methods. disorders simultaneously. Most often, biology of hematologic neoplasias in pa- Six hundred thirty-five patients treated the megakaryocytic lineage of hematopoi- tients with primary mediastinal germ cell at 11 centers in the United States and esis was involved in the hematologic ma- tumors. This investigation adds informa- Europe from 1975 through 1996 were lignancy, resulting in acute megakaryo- tion from a large database containing in- evaluated retrospectively. Results. A blastic leukemia, myelodysplasia with formation on patients with extragonadal hematologic disorder was observed in abnormal megakaryocytes, or idiopathic/ germ cell tumors from 11 European and 17 patients with germ cell tumors. All essential thrombocytosis. Other hemato- American cancer centers. The patients cases developed among the 287 patients logic diagnoses included acute lympho- were treated during a recent time period with primary mediastinal nonsemino- cytic or other when cisplatin-based chemotherapy regi- matous germ cell tumors, giving an in- (AML) and, in rare cases, malignant his- mens were generally available. cidence rate in this group of 2.0% (95% tiocytosis or systemic mastocytosis (3–7). confidence interval [CI] = 1.1%–3.1%) Hematologic disorders associated with per year over a median follow-up time primary mediastinal germ cell tumors Affiliations of authors: J. T. Hartmann, L. Kanz, of 3 years. The risk of developing he- have to be distinguished from therapy- C. Bokemeyer, Tuebingen University Medical Cen- matologic disorders was statistically related secondary leukemia. ter II, Germany; C. R. Nichols, Oregon Health Sci- significantly increased in patients with associated with the use of alkylating ences University, Portland; J.-P. Droz, Centre Le´on- primary mediastinal nonseminomatous agents usually occur after an average in- Berard, Groupe d’Etude des Tumeurs Uro-geniales, germ cell tumors in comparison with terval of 5–7 years, often preceded by a Lyon, France; A. Horwich, The Royal Marsden Hos- pital, Sutton, U.K.; A. Gerl, Klinikum Gro␤hadern, the age-matched general population preleukemic period of myelodysplasia Munich, Germany; S. D. Fossa, The Norwegian Ra- (standardized incidence ratio = 250; and frequently progressing to AML, dium Hospital, Oslo, Norway; J. Beyer, Virchow 95% CI = 140–405). The median time French–American–British classification Klinikum, Berlin, Germany; J. Pont, Kaiser-Franz- to onset of hematologic neoplasia was 6 (FAB) subtypes M1 or M2 (8). Topo- Josef Spital, Vienna, Austria; K. Fizazi, Institut Gus- months (range, 0–47 months), and the isomerase II inhibitor-related secondary tave-Roussy, Villejuif, France; L. Einhorn, Indiana median survival after diagnosis of the leukemias are generally diagnosed 2–3 University, Indianapolis. hematologic disorder was 5 months years after chemotherapy and most com- Correspondence to: Carsten Bokemeyer, M.D., Department of /Oncology/Immunology, (range, 0–16 months) (two-sided monly exhibit FAB M4 or M5 phenotype. UKL-University Medical Center II, Eberhard-Karls- P<.0001, comparing survival from the Whereas the latter type of leukemias is University, Otfried-Mueller-Str. 10, 72076 Tuebin- time of diagnosis of the germ cell tumor frequently associated with translocations gen, Germany (e-mail: carsten.bokemeyer@med. of patients with and without hemato- of the long arm of chromosome 11 uni-tuebingen.de). logic disorders). Conclusion.Inour (11q23) (9–12), the leukemias follow- See “Notes” following “References.” study, approximately one in 17 patients ing treatment with alkylating agent- © Oxford University Press

54 REPORTS Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 PATIENTS AND METHODS lesions and/or elevation of tumor markers at re- All other statistical analyses were performed with peated controls (15). the use of the SPSS system (SPSS for Windows 8.0 Data Collection software; Microsoft Corp., Redmond, WA) accord- Statistical Analysis ing to the Kaplan–Meier method to calculate sur- We evaluated the medical records of 635 extrago- vival data (18). A multivariate logistic regression nadal germ cell tumor patients treated at 11 cancer including all 287 patients with primary mediastinal centers in the United States and Europe during the The duration of follow-up was calculated on the germ cell tumors was performed to identify patients’ period from 1975 through 1996. The contributing basis of the date of the diagnosis of the extragonadal characteristics predicting the occurrence of leukemia centers, internationally recognized for their experi- germ cell tumor until the date of last contact (if the in association with primary mediastinal germ cell ence in the treatment of germ cell tumors, were as patient was still alive) or the date of death. For all tumor (19). The following categorical variables ;216 ס follows: Indiana University, Indianapolis (n living patients, the current status as of August 1998 were examined: histologic subgroups of the primary time period, 1989 through 1996); Institute Gustave- was verified. Survival calculations in this analysis tumor (yolk sac/teratocarcinoma/other), age group- Roussy, Villejuif, France, Centre Le´on-Berard, were performed both from the diagnosis of the he- ing (ഛ25 years old and ജ26 years old), tumor Lyon, France, and the Groupe d’Etude des Tumeurs matologic disorder and from the evidence of ex- marker concentrations at diagnosis (elevated, yes/ -from these three cen 93 ס Uro-geniales, Lyon (n tragonadal germ cell tumor. To determine the num- ഛ 2 ജ 2 ters; time period, 1975 through 1996); Eberhard- no), size ( 25 cm and 26 cm ) and presence of ber of new cases of leukemia expected in the study Karls-University Medical Center II, Tuebingen, additional metastatic sites (yes/no), medical history group, we used 5-year age group-specific data from (Klinefelter’s syndrome, yes/no), and type of che- time period, 1986 through 1993); Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021 ;13 ס Germany (n the cancer registry of the Federal state of Saarland, motherapy (etoposide, yes/no). Continuous variables ס Hanover University Medical School, Germany (n 88; time period, 1978 through 1995); The Norwe- located in southwest Germany, from 1975 through were age and tumor marker concentrations of LDH, time period, 1996. This cancer registry is a population-based reg- ␤-HCG, and AFP at diagnosis. All reported P values ;48 ס gian Radium Hospital, Oslo (n 1980 through 1995); Klinikum Gro␤hadern, Mu- istry that covers the state of Saarland. The types of were two-sided. time period, 1979 through leukemia reported and included in the calculation ;63 ס nich, Germany (n were lymphoid, myeloid, monocytic, and unclassi- 1996); The Royal Marsden Hospital, Sutton, U.K. (n RESULTS time period, 1979 through 1994); Kaiser- fied/other leukemias. The results were standardized ;65 ס -time on the basis of age and duration of follow-up (pa ;19 ס Franz-Josef Spital, Vienna, Austria (n period, 1975 through 1996); and Virchow-Klinikum, tients’ years of risk) and were expressed with the use In total, 635 patients (median age, 30 time period, 1987 of the standardized incidence ratio (SIR) with the years; range, 14–79 years) were included ;30 ס Berlin, Germany (n through 1994). The reason for referral of patients to associated 95% confidence interval (CI) calculated in the analysis; 341 patients (54%) had a on the assumption of a Poisson distribution (16). each center was the diagnosis of extragonadal germ primary mediastinal tumor, 283 (45%) cell tumor. For data collection, a standardized ques- The SIR was considered statistically significant if tionnaire was sent to each center and completed by the 95% CI did not include the value 1.0. The SIR had a retroperitoneal germ cell tumor, one the responsible co-investigator. All patients’ data was calculated with the use of the SAS system (SAS patient (0.2%) had cervical lymph node were obtained in an anonymous manner; because 6.11 for windows; SAS Institute, Inc., Cary, NC). A involvement, and 10 patients (1.6%) had chart review was done anonymously and retrospec- SAS macro (programmed and available at the Insti- no primary tumor. Of the patients with tively, no institutional approval was necessary at any tute for Medical Information Processing, University mediastinal localization, 287 (84%) had a of the participating institutions. Detailed informa- of Tuebingen) and PROC UNIVARIATE were used tumor of nonseminomatous histology, 51 tion on patients’ characteristics, such as (a) location to calculate the patients’ years at risk, the expected patients (15%) had a seminomatous me- and histology of primary tumor, (b) extent of dis- number of cases for every age group, and the SIR ease, including serum tumor marker concentrations according to the procedure described by Breslow diastinal tumor, and three patients had a of ␤-human chorionic gonadotropin (␤-HCG), ␣-fe- and Day (16). The two patients who presented si- tumor of undetermined histology. toprotein (AFP), and lactate dehydrogenase (LDH), multaneously with both diseases—germ cell tumor Overall, 17 patients with hematologic (c) history of testicular abnormalities, (d) details on and associated leukemia—were not included in the disorders were identified in the whole diagnostic methods, treatment, response to treat- SIR calculation. The rationale for the use of the age dataset of 635 patients. The median age at ment, and follow-up period, and (e) data on second- group-specific data available from the Saarland Can- diagnosis of the germ cell tumor was 23 ary testicular cancer and other secondary cancers, cer Registry was that this procedure considered the years (range, 17–35 years). All of the pa- was acquired. The completed questionnaires were changes in the incidences of leukemias during the checked for plausibility and data consistency at Tu- period of approximately 20 years. Despite some dif- tients with hematologic malignancies had ebingen University Medical Center. When important ferences between the countries included in the the diagnosis of a primary nonseminoma- data were missing, the questionnaires were returned analysis, the incidence rates are comparable. Differ- tous mediastinal germ cell tumor. The his- to the principal investigator at each center. In addi- ences in rates among the participating countries are tologic findings included teratocarcinoma tion, charts of 229 patients (36%) were re-abstracted smaller than those among different cancer registries in 10 patients (59%), endodermal sinus by the principal investigator. For this report, the within single countries, particularly when age- and tumor in four patients (24%), and an un- clinical records of patients who developed a hema- time period-specific data are being considered (17). differentiated germ cell tumor in one pa- tologic malignancy associated with an extragonadal In addition, the proportion of patients developing germ cell tumor were reviewed in detail. All histo- hematologic disorders in the 1st,2nd,and3rd years tient (6%). Two patients (12%) had only a pathologic slides of these cases were reviewed by after diagnosis of extragonadal germ cell tumors was serologic diagnosis based on tumor each center’s hematopathologist. calculated as follows: marker concentrations (elevated serum Tumor response and disease remission were de- fined as follows: Complete remission (CR) was de- fined as a complete disappearance of all clinical, ͑in year 1͒ = radiologic, and biochemical evidence of disease. A partial response with marker normalization (PRm–) No. of new cases was defined as any decrease in tumor size and nor- All patients − (No. of germ cell tumor deaths + No. of new cases) malization of all elevated tumor markers. PR with- 2 out marker normalization (PRm+) was defined as a ͑in years 2 and 3͒ = radiologic response greater than 50% in size but no complete normalization of ␤-HCG and/or AFP and/ No. of new cases or LDH after completion of chemotherapy. Progres- (No. of new germ cell tumor deaths + No. of new cases) sive disease was defined as either an increase in the All patients − + No. still alive with leukemia + No. of prior deaths ͫ 2 ͬ size of residual lesions or the occurrence of new

Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 REPORTS 55 AFP and/or ␤-HCG), with a gross diag- primary tumor. Of the remaining six pa- terized as acute megakaryoblastic leuke- nosis of mediastinal tumor1 (Table 1). tients, four did not achieve a normaliza- mia (FAB M7) in five patients, myelodys- None of the 283 patients with retroperito- tion of any or all of the tumor markers and plasia with abnormal megakaryocyte in neal germ cell tumors and none of the 51 two other patients had a rapid progression five patients, acute undifferentiated leuke- patients with mediastinal seminoma reg- of the hematologic disorder that occurred mia and malignant mastocytosis in two istered in the database developed a hema- simultaneously and, therefore, respon- patients each, and acute myeloblastic leu- tologic disorder. Serum concentrations of siveness to germ cell tumor-related kemia (FAB M2), acute myelomonocytic the tumor markers AFP, ␤-HCG, and therapy was not determined. leukemia (FAB M4), and malignant his- LDH were elevated in 82%, 41%, and The median time from the diagnosis of tiocytosis in one patient each. 47% of the 17 patients, respectively. All the primary mediastinal germ cell tumor Cytogenetic analyses were available of the patients had received cisplatin- to the diagnosis of the hematologic neo- for 13 of 17 patients (Table 2). No con- based combination chemotherapy. One plasia was 6 months (range, 0–47 months) sistent chromosomal abnormality was complete remission and 10 partial remis- (Table 2). Hematologic neoplasms within identified. However, in five (38%) of 13 sions with marker normalization were ob- 1 year of the diagnosis of the germ cell patients, the germ cell tumor marker chro- served, resulting in an overall response tumor occurred in 11 (65%) of the 17 pa-

mosome i(12p) was found. Other karyo- Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021 tients. Two patients (12%) presented with typic abnormalities included trisomy 8 in .(88.1%–41.3% ס rate of 64.7% (95% CI All of the patients with partial remissions a simultaneous onset of both disorders. two (15%) of 13 patients and the karyo- underwent secondary resection of their The hematologic disorders were charac- type of Klinefelter’s syndrome (XXY) in one patient (8%). Six patients (46%) had normal karyotypes. Table 1. Characteristics of 17 patients with nonseminomatous mediastinal germ cell tumors and Seven (41%) of 17 patients did not re- hematologic disorders* ceive any therapy for their hematologic Characteristic disorder because of its fulminant clinical course. Eight patients with acute nonlym- Median age, y (range) 23 (17–35) phocytic leukemia were treated with com- Anatomic localization of primary tumor Mediastinal 17 (100%) bination chemotherapy based on cytarabi- Retroperitoneal 0 noside/anthracyclines, resulting in only Histology: nonseminomatous GCT 17 (100%) one short remission. Two other patients Teratocarcinoma 10 (59%) underwent allogeneic bone marrow trans- Endodermal sinus tumor 4 (24%) plantation without success: One of them Undifferentiated GCT 1 (6%) had an early relapse, and the other died of Serologic diagnosis only† 2 (12%) treatment-related toxic side effects. Both Elevated serum tumor markers ␣-Fetoprotein 14 (82%) patients with malignant mastocytosis re- Median (range) in ng/mL 5830 (<1 to 64 000) ceived only treatment of their symptoms Human chorionic gonadotropin 7 (41%) with steroids and histamine receptor an- Median (range) in mIU/mL 5 (3–2164) tagonists (data on treatment not shown). Lactate dehydrogenase 8 (47%) Median (range) in IU/L 526 (166–3427) The most common clinical features at Treatment for GCT the diagnosis of the hematologic disorder -organo ,(6 ס PEB 8 (47%) included pancytopenia (n PVB 2 (12%) megaly (i.e., and hepato- -particularly splenomeg ,(5 ס PEI 2 (12%) megaly) (n PVeBV 2 (12%) (4 ס BOP/VIP 1 (6%) aly, or isolated (n CISCA/VB 1 (6%) (Table 3). All patients with acute mega- C-BOP 1 (6%) karyoblastic leukemia presented with Response to treatment for GCT‡ pancytopenia and, in addition, three of CR 1 (6%) five had organomegaly and/or circulating CR 4 (24%) In patients with .(2 ס undifferentiated tumor leukemic blasts (n CRteratoma 5 (29%) CRnecrosis 1 (6%) myelodysplasia with abnormal mega- PRm+/PD 4 (24%) karyocytes, patients presented either with n.e. 2 (12%) pancytopenia or with isolated thrombocy- topenia. The two patients with malignant ;not evaluable because of rapid progression of the hematologic disorder ס .germ cell tumor; n.e ס GCT* -cisplatin, etopo- mastocytosis showed symptoms associ ס cisplatin, vinblastine, bleomycin; PEI ס cisplatin, etoposide, bleomycin; PVB ס PEB ,bleomycin, vincris- ated with increased histamine production ס cisplatin, etoposide, bleomycin, vinblastine; BOP/VIP ס side, ifosfamide; PVeBV -cisplatin, cyclophosphamide, doxorubicin, vinblastine, such as flushing, exanthema, and bron ס tine, cisplatin, etoposide, ifosfamide; CISCA/VB .carboplatin, cisplatin, bleomycin. chospasm ס bleomycin; C-BOP †Patients had a mediastinal mass without histologic diagnosis of the tumor and elevation of tumor marker In the examination of bone marrow as- concentrations ␤-human chorionic gonadotropin and/or ␣-fetoprotein indicating a mediastinal nonsemino- pirates, all of the patients with acute matous GCT. megakaryoblastic leukemia revealed a ‡Evaluation of response based on computed tomography scans and determination of serum tumor marker diffuse infiltration with megakaryocytic achievement of a complete ס complete remission; CRundifferentiated tumor/teratoma/necrosis ס concentrations; CR -partial remission blasts (Table 3). The most common find ס +remission after complete resection of undifferentiated tumor/teratoma/necosis; PRm -progressive disease (8). ing in patients with myelodysplastic syn ס without marker normalization. PD

56 REPORTS Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 Table 2. Summary of clinicopathologic features of 17 patients with primary mediastinal nonseminomatous germ cell tumor and associated hematologic disorders, all patients died of disease*

Tumor markers Treatment for GCT Interval, mo, Survival after Patient Histology of AFP, HCG, (No. of Response Type of between GCT diagnosis of No. Age, y primary tumor ng/mL mIU/mL cycles) of GCT† associated leukemia Cytogenetics‡ and leukemia leukemia, mo

3 17 Yolk sac 9600 <5 PEI (4) n.e. MDS with abnormal 46, XY, −5q, +17p§ 23 6 megakaryocytes 103 18 n.e. 2960 66 BOP/VIP (5) PD ࿣ n.e. 5 0 143 35 Yolk sac 740 448 C-BOP (6) CR AML M7 46, XY 0 6

257¶ 31 Teratocarcinoma 17 000 4 CISCA/VB CRteratoma AML M2 45–46, XY, −10, −11, 15 0 (4/2) +19q, i(12p), −13, +i(13p), +16p, +19q§

267¶ 23 Teratocarcinoma 64 000 350 PVeBV (4) CRteratoma AUL 47, XXY, i(12p) 47 5 279¶ 23 Teratocarcinoma 310 3 PVB (4) PD AML M7 n.e. 4 1 283¶ 25 Yolk sac 2130 3 PVeBV (4) CR Mast cell 46, XY 35 5

necrosis Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021

285¶ 35 Teratocarcinoma n.e. n.e. PVB (4) CRundifferentiated tumor Mast cell 46, XY 13 16 457 22 Teratocarcinoma 1311 2164 PEI (4) PRm+ AML M7 46, XY 4 14

469 18 Teratocarcinoma 13 690 302 PEB (4) CRteratoma AML M7 n.e. 10 5

475 26 Teratocarcinoma 3210 10 PEB (4) CRteratoma AML M7 n.e. 5 1

530 31 Teratocarcinoma 5830 <5 PEB (4) CRundifferentiated tumor MDS with abnormal 46, XY 3 3 megakaryocytes 536 25 Undifferentiated <1 <5 PEB (4) n.e. MDS with abnormal 47, XY, +8 i(12p) 0 4 GCT megakaryocytes

541 25 Teratocarcinoma 13 590 <5 PEB (4) CRundifferentiated tumor MDS with abnormal 46, XY 10 3 megakaryocytes 567 20 Teratocarcinoma n.e. <5 PEB (4) PD AUL 46, XY, 10 1 t(3;12)(15;21)(15;22)

589 17 n.e. 40 600 25 PEB (4) CRundifferentiated tumor AML M4 49, XY, +8, +13, 68 +i(12p)

623 17 Yolk sac 9235 <5 PEB (4) CRundifferentiated tumorն MDS with abnormal 46, XY, i(12p) 6 5 megakaryocytes

achievement of a complete remission after complete resection of a residual tumor mass ס complete response; CRundifferentiated tumor/teratoma/necrosis ס Abbreviations are as follows: CR* fetoprotein; HCG-␣ ס progressive disease; n.e., not evaluable; AFP ס partial remission without marker normalization; PD ס +containing undifferentiated tumor/teratoma/necrosis; PRm cisplatin, vinblastine, bleomycin; PVeBV ס cisplatin, etoposide, ifosfamide; PVB ס cisplatin, etoposide, bleomycin; PEI ס germ cell tumor; PEB ס human gonadotropin; GCT-␤ ס acute ס carboplatin, cisplatin, bleomycin; AML ס cisplatin, cyclophosphamide, doxorubicin, vinblastine, bleomycin; C-BOP ס cisplatin, etoposide, bleomycin, vinblastine; CISCA/VB ס acute undifferentiated ס acute myeloblastic leukemia; AUL ס acute myelomonocytic leukemia; AML M2 ס acute megakaryoblastic leukemia; AML M4 ס myeloid leukemia; AML M7 . ס leukemia [see reference (8) for description of morphologic subtypes]. MDS †Reference (15). translocation. Note: losses and gains can involve entire chromosomes or individual chromosome arms ס gain of chromosomal sequences; t ס + ;loss of chromosomal sequences ס −‡ .(long arm ס short arm, q ס p) §Chromosomal loss was heterozygous in each case. ࿣Autopsy result. ¶Previously published in reference (48). նResected tumor contained hematopoietic elements. dromes was an increased number of ab- months) for germ cell tumor patients who size. This difference is highly statistically normal megakaryocytes or an excess of did not develop hematologic neoplasia significant, as indicated by the 95% CI. blast cells. Aspirates of patients with my- (P<.0001) (Fig. 1). The proportion of patients developing elodysplastic syndromes revealed either The proportion of patients developing hematologic disorders was highest in the an increased cellularity or a hypocellular hematologic neoplasia associated with first year (4.8% in the first 12 months) marrow with a marked dysplasia of the mediastinal germ cell tumors of nonsemi- after the diagnosis of mediastinal non- erythrocyte lineage (Table 3). nomatous differentiation after a median seminomatous germ cell tumor, decreas- ing to 1.5% and to 0.6% during the 2nd 63–1 ס All 17 patients died within 2 years af- follow-up of 32 months (95% CI and 3rd years, respectively. No further ס ter diagnosis of their hematologic neopla- months) was 5.9% (17 of 287; 95% CI sia, resulting in a median survival time 3.5%–9.3%), corresponding to an inci- cases of secondary leukemia were ob- served either among the 270 patients with –1.1% ס of 5 months (range, 0–16 months). The dence rate of 2.0% (95% CI median survival from the time of the 3.1%) per year. The SIR among the 287 primary mediastinal nonseminomatous diagnosis of extragonadal germ cell tu- patients with primary mediastinal non- germ cell tumors or among the remaining mors was 14 months (range, 4–52 seminomatous germ cell tumors—during 348 patients with extragonadal germ cell months) for 850 person-years at risk—was 250 (95% tumors during the observation period. In 21.4–8.6 ס months; 95% CI -since only 0.06 cases of the logistic regression model, no particu ,(405–140 ס those who developed hematologic disor- CI ders compared with 51 months (range, de novo leukemia were expected during lar patients’ characteristics—with the ex- -this time period for a population of this ception of mediastinal germ cell tumor lo 106+–0 ס months; 95% CI 178+–0

Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 REPORTS 57 Table 3. Characteristics of hematologic neoplasms in primary mediastinal nonseminomatous germ of cases was described by Nichols et al. cell tumor (3) in 1990 in a report of 16 patients with Diagnosis Clinical features Pathologic features mediastinal germ cell tumors with associ- (No. of patients) (No. of patients) (No. of patients) ated hematologic neoplasia who had been treated at two institutions in the United Myelodysplastic syndrome with Thrombocytopenia (3) Abnormal megakaryocytes (3) abnormal megakaryocytes (5) Increased cellularity (3) States from September 1983 through De- Decreased cellularity (1) cember 1988. From 1976 through 1988, Marked dysplasia (2) the same authors had evaluated 31 con- Mast cell leukemia (2) Flushing (2) Mast cell infiltration secutive patients with primary mediasti- Thrombocytopenia (1) nal germ cell tumors at Indiana Univer- Malignant histiocytosis (1) Splenomegaly Hypercellular marrow sity. Hematologic neoplasms developed Increased megakaryocytes Acute myeloid leukemia (9) in five (16%) of the patients with medi- M2* (1) Circulating blast cells Typical myeloblastic cells astinal germ cell tumors (3). M4* (1) Pancytopenia Typical blast cells Based on our data, hematologic ma- AUL (2) Splenomegaly (1) Undifferentiated blasts (2)

Leukemic skin lesions (1) lignancies associated with primary me- Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021 M7* (5) Pancytopenia (5) Abnormal megakaryocytic diastinal germ cell tumors are mainly Circulating blast cells (2) blasts (5) disorders of the megakaryocyte lineage Organomegaly (3) characterized as AML M7 (acute mega- karyoblastic leukemia) and myelo- *Different morphologic subtypes of acute myeloid leukemia (AML) are indicated by the letter M followed acute megakaryoblastic dysplastic syndrome with abnormal ס acute undifferentiated leukemia; AML M7 ס by a numeral according to (8); AUL acute myeloblastic leukemia. Or- megakaryocytes. Several cases of acute ס acute myelomonocytic leukemia; AML M2 ס leukemia; AML M4 ,hepatomegaly and splenomegaly. lymphoblastic leukemia (3–5,38,40 ס ganomegaly 41,45), malignant histiocytosis or sys- temic mastocytosis (6,23,25,33,44), and, rarely, monoblastic, myelomonoblastic, mixed-lineage leukemia and idiopathic or essential thrombocytosis (4,5) have also been described. In addition, a patient with a focus of non-Hodgkin’s in the primary mediastinal tumor has been reported (39). Cytogenetic analysis of bone marrow aspirates revealed the finding of the most common karyotypic abnormality of germ cell tumor—isochromosome i(12p)— in 38% (five of 13) of our patients com- pared with 35% (13 of 37) in a summary of data from the literature. Karyotypes of trisomy 8 (16%) as well as the evi- dence of Klinefelter’s syndrome or XXY (14%) have been observed in some pa- tients. Other cytogenetic findings were reported infrequently. Ladanyi et al. (48) Fig. 1. Kaplan–Meier analysis of overall survival of primary nonseminomatous mediastinal germ cell tumor identified a series of six patients with months [range, 4–52 evidence of germ cell origin of the acute 14 ס median overall survival) (270 ס or without (−) leukemia (n (17 ס with (+) (n -months] versus 51 months [range, 0–178+ months; 95% leukemia. One patient had an isochromo 21.4–8.6 ס months; 95% confidence interval months]; P<.0001). some i(12p) in his germ cell tumor and 106+–0 ס confidence interval in leukemic blasts [which were reported earlier in another patient (24)], a second calization and a nonseminomatous ders and primary mediastinal nonsemino- patient had evidence of i(12p) in leukemic histology of endodermal sinus tumor matous germ cell tumor in 1985 (1,2), cells, and, in a third patient, the leukemic -more than 70 cases have been described cells coexpressed myelomonocytic anti –1.6 ס CI 95% ;5.8 ס [relative risk [RR) -in the literature (1–3,6,20–50). Most re- gens (HAM56 [human anti ;13.5 ס or teratocarcinoma (RR (21.2 ,could be identified ports have included a limited number of gen 56], My4, and My9) and cytokeratin—(35.3–5.2 ס CI 95% that predicted the occurrence of hemato- patients; therefore, the incidence rate of suggesting both myeloid and germ cell logic neoplasia in extragonadal germ cell hematologic neoplasia, risk factors for the differentiation. The clonal relationship tumor. occurrence of the associated neoplasia, between a mediastinal germ cell tumor and the RR compared with the normal and acute myelogenous leukemia was DISCUSSION population could not be determined supported by another case reported by Since the original recognition of the among patients with primary mediastinal Woodruff et al. (43). At presentation, association between hematologic disor- germ cell tumors. The largest collection their patient had a mediastinal tumor con-

58 REPORTS Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 sisting histologically of immature tera- tabase are long-term survivors following mors. They often contain areas of yolk sac toma and yolk sac elements and myelo- cisplatin-based chemotherapy, none of the tumor that have a mesenchyme-like plu- dysplasia on bone marrow examination. patients with an additional hematologic ripotent component. These areas may be Both the cells in the bone marrow and disorder is alive at 5 years after diagnosis the location at which germ cell tumors are the mediastinal tumor had the same (Fig. 1). Our analysis clearly confirms transformed into malignancies typical of karyotype [49,XY, +X,+i(12p),+8]. that the risk for developing hematologic nongerminal tissues—sarcomas, most fre- (Note: + indicates the presence of extra disorder among patients with germ cell quently (52). This suggestion is supported copies of the indicated chromosomal ma- tumors affects only those whose primary by the reported observation by Orazi et al. terial.) In addition, Orazi et al. (49) iden- mediastinal germ cell tumor has a non- (49) that the leukemic cells of mediastinal tified leukemic blasts and erythroblasts seminomatous histology. Based on the germ cell tumors occurred predominantly within the yolk sac component of a me- large database containing patients from in the vascular structures of the mesen- diastinal germ cell tumor associated with 11 centers worldwide, the incidence of chyme-like component. In addition, tera- leukemia. The leukemic cells within the leukemia in patients with mediastinal toma containing all three germ layers with mediastinal tumor expressed CD34 and nonseminomatous germ cell tumors is es- varying degrees of differentiation is de-

rived from a malignant precursor cell, em- Downloaded from https://academic.oup.com/jnci/article/92/1/54/2905786 by guest on 23 September 2021 –3.5% ס other myeloid and erythroid markers, as timated to be 5.9% (95% CI well as p53, which was also overex- 9.3%) and is, therefore, clearly lower than bryonal carcinoma or yolk sac tumor. pressed in the mediastinal germ cell tu- an earlier estimate of 16% based on a These precursor cells are totipotential— mor but has been reported very rarely in nonrepresentative cohort of patients with i.e., they are able to differentiate into dif- acute leukemias. The expression of p53 extragonadal germ cell tumor (3). Thus, ferent nongerminal tissues—and malig- was found in another two of six patients. approximately one in 17 patients will be nant transformation of such cells has been In addition, two of five patients with me- affected by this association. The risk of observed frequently (39). In addition, diastinal germ cell tumor-associated leu- developing a germ cell tumor-related leu- teratocarcinoma cells have been shown to kemias showed an i(12p) isochromosome, kemia was highest during the 1st year af- differentiate along hematopoietic lineages which is usually not observed in leuke- ter the diagnosis of a mediastinal germ in vitro and to form hematopoietic tissue mias (51). In the present series, the re- cell tumor, with 12 (71%) of 17 cases oc- in mosaic mice (53,54). Thus, most re- sected yolk sac tumor specimen of one curring in this time interval in the present ported cases of hematologic disorders patient had a focus of i(12p)-positive series. The proportion of patients devel- have been in mediastinal teratocarcinoma blasts. oping germ cell tumor-related leukemia [(3); current series]. The immunohisto- We observed a short interval between decreased from 4.8% in the first 12 chemical and cytogenetic findings of the diagnosis of germ cell tumor and the months to 1.5% and 0.6% during the 2nd the early progenitor marker CD34, p53 diagnosis of the hematologic disorder. and 3rd years, respectively, after the diag- overexpression, and particularly the evi- The median time was 6 months following nosis of mediastinal nonseminomatous dence of trisomy 8—which was found in the diagnosis of germ cell tumor. It is in- germ cell tumor. However, rare cases of two of our patients—suggest some accor- teresting that 10%–30% of patients ob- late onset of the hematologic disease have dance to other stem cell disorders like served presented with a simultaneous on- been reported. The latest case has been chronic granulocytic leukemia and my- set of both disorders in two investigations described in the literature 102 months af- eloproliferative disorders (e.g., polycythe- [current series; (3)]. ter the diagnosis of mediastinal germ cell mia vera and metaplasia of unknown ori- The hematologic neoplasms associated tumor (3). gin). Trisomy 8 (in combination with with primary mediastinal germ cell tu- No specific clinical or biologic vari- overexpression of p53) has been identi- mors possess a very aggressive clinical able could be identified to predict the sub- fied as being responsible for the acute course; patients either die before treat- sequent occurrence of a leukemia, with transformation of chronic granulocytic ment, do not respond to antileukemic the exception of mediastinal germ cell tu- leukemia (55). This finding is consistent therapy, or achieve only short remissions. mor localization and the histology of en- with the coexistence of differentiated he- Allogeneic bone marrow transplantation dodermal sinus tumor and teratocarci- matopoiesis and foci of acute leukemia may be the only curative strategy, despite noma. It remains unclear why some within the same mediastinal germ cell tu- our experience with two patients who patients with nonseminomatous mediasti- mor and provides evidence for a multistep failed to respond to this treatment. How- nal germ cell tumor develop a hemato- hematologic transformation. The accumu- ever, a subgroup of patients with platelet logic disorder, whereas the majority of lation of blast cells within the tumor disorders seemed to have a slightly better patients are unaffected. Clearly, based on blood vessels supports the hypothesis of a prognosis (4,5). The observed survival re- the cytogenetic findings—i.e., high inci- subsequent population in the bone mar- ported in the literature ranges from 1 dence of i(12p)—and the short time be- row, spleen, or liver, which recapitulates month up to 6 months in accordance with fore their diagnosis, no relationship exists the normal embryonal dissemination of the present series, demonstrating a me- between the treatment of germ cell tumor hematopoietic elements from the embryo- dian survival time of 5 months (range, and the development of leukemia. The cy- nal yolk sac into the hematopoietic sites 0–16 months). togenetic and molecular biologic findings (56). This appears to be the same patho- The development of leukemia in pa- (48,49) imply that the hematologic malig- logic mechanism described in myelofi- tients with nonseminomatous extrago- nancy and the mediastinal germ cell tu- brosis with myeloid metaplasia or, in the nadal germ cell tumors clearly affects the mor arise from a common progenitor cell. case of metastatic carcinoma with marrow prognosis. While approximately 50% of Mediastinal germ cell tumors show differ- involvement, where hematopoietic stem patients with nonseminomatous mediasti- ent clinicopathologic features from go- cells populate the fetal sites of blood pro- nal germ cell cancers registered in our da- nadal and retroperitoneal germ cell tu- duction—spleen and liver—to restore he-

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NOTES

1Elevation of AFP and/or ␤-HCG with evidence of a mediastinal mass is considered specific for the diagnosis of extragonadal nonseminomatous germ cell tumor. Tumor markers allow discrimination be- tween nonseminomatous germ cell tumor (elevation of ␤-HCG and AFP) and other mediastinal tumors, including seminomatous germ cell tumor (no el- evated markers).

Manuscript received May 10, 1999; revised Oc- tober 25, 1999; accepted November 3, 1999.

Journal of the National Cancer Institute, Vol. 92, No. 1, January 5, 2000 REPORTS 61