hematologic malignancies associated with germ cell tumors

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10.1586/EHM.12.24 427 ISSN 1747-4086 © 2012 Expert Reviews Ltd www.expert-reviews.com Review Overview of germ cell tumors Germ cell tumors (GCTs) account for 2% of all cancers and are among the most common malignancies in men between 15 and 45 years of age, with the majority of them in the gonads and 2–5% at extragonadal sites. GCTs are classi- fied as seminomatous GCTs (SGCTs) and non- seminomatous GCTs (NSGCTs) [1] . The latter includes embryonal carcinoma (EC), teratoma, teratocarcinoma, yolk-sac tumors and chorio- carcinoma. In addition, ovarian GCTs are called dysgerminomas or dermoid cysts, while the GCTs of cranial origin are germinomas. It is believed that GCTs originate from transformed primordial germ cells (PGCs) or gonocytes. The incidence of GCTs in young white males has doubled since 1975, it is currently close to seven per 100,000 in the USA (SEER Cancer Statistics). The incidence in white males is five- fold higher than that of black males. Brothers of GCT patients have a tenfold increased risk. The risk in monozygotic and paternal twins is 75- and 35-fold, respectively [2] . These data indicate that both environment and genetics contribute to GCT formation. Most patients with primary extragonadal GCTs lack gonadal tumors. Features of extragonadal GCTs include occurring in the midline with the anterior medi- astinum and retroperitoneum as the major sites, and a strong association of primary mediastinal NSGCTs with hematologic malignancies [3–5] . Development of gonadal GCTs The development of germ cell lineage including PGC specification, proliferation, migration and gonadal colonization is tightly regulated by an array of genetic and epigenetic mechanisms [6] . The germ cell niche is critical to germ cell differentiation within the gonads, and disruption of the niche can result in blocked gonocyte maturation and testicular dysgenesis syndrome (TDS) [7] . TDS can present as undescended testes, sterility, hypospadias and, in extreme cases, GCTs. The best example of TDS-related GCT development in humans is 46,XY disorders of sexual development. Some Guang-Quan Zhao* 1,2 and Jonathan E Dowell 2 1 Center for Comprehensive Cancer Care, 4117 Veterans Memorial Drive, Mount Vernon, IL 62864, USA 2 Division of Hematology and Oncology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA *Author for correspondence: Tel.: +1 618 244 6500 [email protected] Germ cell tumor (GCT)-associated hematologic malignancies present a unique challenge to hematologists and hematopathologists. As most GCTs are of gonadal origin, only a small percentage occur at extragonadal sites in the midline. Extragonadal GCTs are believed to originate from the ectopic primordial germ cells that fail to migrate to the urogenital ridge during development. An overactive KIT pathway and overexpression of genes on chromosome 12p are strongly implicated in GCT development. Approximately 54% of extragonadal GCTs are located in the anterior mediastinum. This is disproportionally high among the midline structures, presumably due to a favorable microenvironment for GCT development in the developing thymus. The mediastinal nonseminomatous GCTs have two unique features. First, they are often refractory to current treatment modality with the worst prognosis among GCTs of all sites. Second, they have a tendency to give rise to secondary hematologic neoplasia. The outcome is grave for patients with GCT-associated hematologic malignancies. As standard chemotherapy used to treat their bone marrow-derived counterparts has been ineffective, the best treatment modality to achieve long-term survival is allogeneic hematopoietic stem cell or cord blood transplant for a very limited number of cases. Hematologic malignancies associated with germ cell tumors Expert Rev. Hematol. 5(4), 427–437 (2012) KEYWORDS: chromosome 12p • germ cell tumor • KIT • leukemia • lymphoma • stem cell transplant • Y chromosome For reprint orders, please contact [email protected]

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Page 1: Hematologic malignancies associated with germ cell tumors

10.1586/EHM.12.24 427ISSN 1747-4086© 2012 Expert Reviews Ltdwww.expert-reviews.com

Review

Overview of germ cell tumorsGerm cell tumors (GCTs) account for 2% of all cancers and are among the most common malignancies in men between 15 and 45 years of age, with the majority of them in the gonads and 2–5% at extragonadal sites. GCTs are classi-fied as seminomatous GCTs (SGCTs) and non-seminomatous GCTs (NSGCTs) [1]. The latter includes embryonal carcinoma (EC), teratoma, teratocarcinoma, yolk-sac tumors and chorio -carcinoma. In addition, ovarian GCTs are called dysgerminomas or dermoid cysts, while the GCTs of cranial origin are germinomas. It is believed that GCTs originate from transformed primordial germ cells (PGCs) or gonocytes.

The incidence of GCTs in young white males has doubled since 1975, it is currently close to seven per 100,000 in the USA (SEER Cancer Statistics). The incidence in white males is five-fold higher than that of black males. Brothers of GCT patients have a tenfold increased risk. The risk in mono zygotic and paternal twins is 75- and 35-fold, respectively [2]. These data

indicate that both environment and genetics contribute to GCT formation. Most patients with primary extra gonadal GCTs lack gonadal tumors. Features of extra gonadal GCTs include occurring in the midline with the anterior medi-astinum and retro peritoneum as the major sites, and a strong association of primary mediastinal NSGCTs with hematologic malignancies [3–5].

Development of gonadal GCTsThe development of germ cell lineage including PGC specification, proliferation, migration and gonadal colonization is tightly regulated by an array of genetic and epigenetic mechanisms [6]. The germ cell niche is critical to germ cell differentiation within the gonads, and disruption of the niche can result in blocked gonocyte maturation and testicular dysgenesis syndrome (TDS) [7]. TDS can present as undescended testes, sterility, hypospadias and, in extreme cases, GCTs. The best example of TDS-related GCT development in humans is 46,XY disorders of sexual development. Some

Guang-Quan Zhao*1,2 and Jonathan E Dowell21Center for Comprehensive Cancer Care, 4117 Veterans Memorial Drive, Mount Vernon, IL 62864, USA 2Division of Hematology and Oncology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA*Author for correspondence: Tel.: +1 618 244 6500 [email protected]

Germ cell tumor (GCT)-associated hematologic malignancies present a unique challenge to hematologists and hematopathologists. As most GCTs are of gonadal origin, only a small percentage occur at extragonadal sites in the midline. Extragonadal GCTs are believed to originate from the ectopic primordial germ cells that fail to migrate to the urogenital ridge during development. An overactive KIT pathway and overexpression of genes on chromosome 12p are strongly implicated in GCT development. Approximately 54% of extragonadal GCTs are located in the anterior mediastinum. This is disproportionally high among the midline structures, presumably due to a favorable microenvironment for GCT development in the developing thymus. The mediastinal nonseminomatous GCTs have two unique features. First, they are often refractory to current treatment modality with the worst prognosis among GCTs of all sites. Second, they have a tendency to give rise to secondary hematologic neoplasia. The outcome is grave for patients with GCT-associated hematologic malignancies. As standard chemotherapy used to treat their bone marrow-derived counterparts has been ineffective, the best treatment modality to achieve long-term survival is allogeneic hematopoietic stem cell or cord blood transplant for a very limited number of cases.

Hematologic malignancies associated with germ cell tumorsExpert Rev. Hematol. 5(4), 427–437 (2012)

Keywords: chromosome 12p • germ cell tumor • KIT • leukemia • lymphoma • stem cell transplant • Y chromosome

Expert Review of Hematology

2012

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4

427

437

© 2012 Expert Reviews Ltd

10.1586/EHM.12.24

1747-4086

1747-4094

Malignancies associated with germ cell tumors

Zhao & Dowell

Expert Rev. Hematol.

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For reprint orders, please contact [email protected]

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of these patients have mutation in the SRY gene, resulting in a lack of Sertoli cells and an altered germ cell niche [8]. Patients with 46,XY disorders of sexual development have an increased incidence of GCTs for which gonadoblastoma (GB) is the precursor lesion [9–11].

As reviewed by Ewen and Koopman, KIT signaling plays key roles in PGC survival, proliferation and migration, as well as gonocyte survival and differentiation [6]. Ectopic KIT ligand (KITLG) expression in germ cells within a disrupted niche was associated with transformation of germ cells, suggesting a critical role of autocrine KIT pathway in GCT formation [12]. In support of this notion, genome-wide scans identified a total of six genes: KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1 as the GCT susceptibility genes with KITLG as the most strongly implicated [13–15]. As proposed and reviewed by Looijenga et al. GCT devel-opment is divided into several phases [1]. Gaining a hyperactive

KIT pathway confers a survival advantage to germ cells and leads to precursor lesions (carcinoma in situ [CIS] or GB). Acquiring chromosome 12p and/or other oncogenes is believed to lead to progression of GCTs. If the transformed PGCs or gonocytes remain committed to germ cell lineage, they form SGCTs later in life. However, if the transformed cells dedifferentiate, they may assume a PGC precursor fate as EC cells which will be the source of NSGCTs.

Role of chromosome 12p in GCT developmentAbnormal cytogenetics are frequently found in GCTs; however, only isochromosome 12p, i(12p), has been recognized as a recur-rent abnormality since its discovery in 12 GCTs in 1982 [16]. A larger study revealed i(12p) as a nonrandom chromosomal marker in 80% of GCTs [17]. The remaining 20% of cases often gain a smaller region of 12p [18,19]. There are a number of potentially tumorigenic genes on 12p (Table 1). Downregulation of them is associated with differentiation of GCT cells [18]. However, no single gene of this group has been definitively linked to the pro-gression of GCTs. Nanog is essential in maintaining pluripotency and in PGC development. It is expressed in germ cell CIS, EC and seminomatous GCT, but not in mature teratoma or yolk-sac tumors [20]. GDF3, a member of the TGF-β superfamily, is highly expressed in both mouse and human EC cells and is downregulated upon induced differentiation [21,22]. GDF3 is also expressed in seminomas, the EC components of NSGCTs, and ES cells [22,23]. It can maintain human ES cells in a pluripotent state [23]. Other genes, including Med21, Sox5, DAD-R, BCAT1, KRAS, cyclin D2, Wnt5b, LRP6, ATF7IP, FGF6, FGF23 and Dppa3, may also play a role in GCT development. KRAS and cyclin D2 are well-known promoters of tumorigenesis in general [24,25]. ATF7IP was identified as a GCT susceptibility locus by genome-wide scan [15].

Roles of the Y chromosome in GCT developmentGCTs are predominantly found in young males. Theoretically, this can be attributed to sex chromosomes; either the Y chromosome is part of the etiology or an extra copy of the X chromosome has a protective effect. Indeed, a promising Y chromosome candidate gene, testis specific protein on Y chromosome (TSPY), has been identified. This multicopy gene is mapped within the so-called GB locus on the Y chromosome (GBY). TSPY is highly expressed in germ cell CIS and GB, and it is capable of inducing GB-like structures in the ovaries of transgenic mice [26]. Overexpression of TSPY accelerates cell proliferation by shortening the G(2)/M transition. TSPY bind to cyclin B via a conserved SET/NAP domain and enhances cyclin B1-CDK1 phosphorylation [27]. In addition, TSPY and eEF1A are highly expressed and co-localized in human seminoma cells, and they physically interact via the SET/NAP domain [26,28]. Ectopic TSPY expression in cultured cells upregulates progrowth genes, including those on chromosome 12p13, connecting the Y chromosome with 12p in GCT formation [29]. Thus, the overexpression of TSPY is believed to play a role in germ cell transformation.

Table 1. Selected genes on chromosome 12p that may have a role in germ cell tumor development.

Gene Location Description Function

MED21 12p11.23 Mediator complex subunit 21

RNA pol II regulator

Sox5 12p12.1 SRY-related HMG-box gene 5

Possible oncogene?

DAD-R 12p12.1 Defender against apoptotic cell death

Maintaining cell survival

BCAT1 12p12.1 Branched chain amino-acid transaminase 1

c-myc target, expressed high levels in cancers

KRAS 12p12.1 Kirsten rat sarcoma viral oncogene homolog

Oncogene

Cyclin D2

12p13 Cell cycle regulator Promoting cell growth

FGF6 12p13 FGF6 Promoting cell growth

ATF7IP 12p13.1 ATF7-interacting protein

Regulator of TERT expression

GDF3 12p13.1 Growth and differentiation factor 3

Expressed at high levels in NSGCTs

LRP6 12p13.2 Wnt coreceptor family member

Promoting cell growth

Wnt5B 12p13.3 Member of the Wnt family

Promoting cell growth

FGF23 12p13.3 Fibroblast growth factor 23

Promoting cell growth

Nanog 12p13.31 Nanog homeobox gene

Required for pluripotency and PGC development

Dppa3 12p13.31 Developmental pluripotency associ-ated 3/PGC7/Stella

Expressed in pluripotent cells and PGCs

NSGCT: Nonseminomatous germ cell tumor; PGC: Primordial germ cell.

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The role of the X chromosome in GCT development has been an intriguing subject. In normal 46,XX females, one X chromo-some is randomly inactivated in somatic cells during early devel-opment. Thus, all somatic cells have one active X chromosome. On the contrary, both X chromosomes remain active in female PGCs during embryogenesis [30]. In many mammalian species, female PGCs enter the prophase of meiosis I once they reach the urogenital ridge, which should reduce the tumorigenicity of PGCs. The question is whether two active X chromosomes protect PGCs from malignant transformation. This can be addressed by examining the incidence of GCTs in 45,XO Turner syndrome (TS) and 47,XXY Klinefelter’s syndrome (KS) patients. TS patients have an increased risk of GCTs. However, a majority of TS patients with GCTs contain Y chromosomal components in their genome, most frequently SRY, TSPY and DZY3 [31]. As TS patients without Y components do not have a significant increase in GCT risk, there is no indication that two active X chromo-somes in PGCs have a protective effect. The fact that KS patients have an increased incidence of both testicular and extragonodal GCTs further supports the notion that the Y chromosome has a dominant role in GCT development, while two X chromosomes have no protective effect [32].

In order to gain new insight into the pathogenesis of GCTs, the above-mentioned candidate genes should be further investigated with modern state-of-the-art technologies. These include single-nucleotide polymorphism, array comparative genomic hybridiza-tion and other forthcoming advanced molecular platforms in addi-tion to conventional karyotype, FISH, reverse transcription-PCR or immunohistochemistry on tumor cells or tissue samples.

Extragonadal GCT formationIt was proposed more than 70 years ago that extragonadal GCTs are derived from the surviving ectopic PGCs that fail to reach the urogenital ridge during embryogenesis [33]. This has become the prevailing model of extragonadal GCT formation. During normal development, the ectopic PGCs that do not reach the gonadal ridge undergo a Bax-mediated apoptosis as a result of KITLG downregulation, while still in the gut endoderm and in the mesenchyme of the midline [34]. If the ectopic PGCs escape apoptosis due to an abnormality in the PGCs themselves or in the microenvironment, they become the founding population of future GCTs.

It is intuitive that GCTs develop in locations where PGCs are present during embryogenesis. The retroperitoneal GCTs are on the path of PGC migration from the hindgut to genital ridge. The anterior mediastinum and suprasella or pineal gland areas are closely associated with the developing foregut where PGCs can potentially be misguided. Interestingly, the distribution of extragonadal GCTs is not proportional to all structures along the midline. Approximately 54% of adult extragonadal GCTs occur in anterior mediastinum, while 45% are in the retroperitoneal area [35]. On the basis of the PGC migration pattern, the dorsal mesentery is likely to have more ectopic PGCs than other loca-tions; hence, a higher number of GCTs in the retroperitoneal area than in other locations is expected. On the contrary, the anterior

mediastinum has a disproportionally high number of GCTs. The underlying pathophysiology for this phenomenon has not been previously addressed conceptually or experimentally.

During embryogenesis, the thymus is formed as the major structure in the anterior mediastinum. Thymus primordium, derived from foregut pharyngeal endoderm and the ectoderm, acquires lymphoid precursors from fetal liver. It is assumed that thymus primordium can provide a microenvironment for ectopic PGCs to survive for years before they form GCTs. There are several pathways affecting PGC proliferation and survival during embryogenesis [6]. Indeed, these pathways (BMP, Wnt and KIT) are present and functional during thymopoiesis.

Thymic epithelial cells (TECs) express both BMP2 and BMP4, and their signaling is required for thymus organogenesis [36]. Multiple Wnt genes including Wnt4, Wnt7a, Wnt7b, Wnt10a and Wnt10b, are expressed by TECs, while thymocytes demonstrate a developmentally regulated pattern of Fz-receptor expression [37]. Inactivation of Wnt1 and Wnt4 resulted in reduced number of thymocytes [38]. The third pathway is mediated by KITLG/KIT. KITLG expression in the TECs has been documented in both the mouse and human [39,40]. KIT signaling is essential for the thymo-cyte lineage commitment and repertoire formation [41]. Thus, the TEC-derived BMPs, Wnt proteins and KITLG should contribute to the niche for ectopic PGCs to survive and proliferate.

Increased risk of hematologic malignancies with primary mediastinal NSGCTsSales and Vontz first reported a case of acute megakayocytic leukemia (AML-M7) with mediastinal NSGCT in 1970 [42]. In 1985, DeMent et al. reported two cases of concurrent mediasti-nal NSGCTs with hematologic malignancies and reviewed nine additional cases in the literature [3]. Nichols et al. reviewed all patients with advanced GCTs between 1974 and 1983 at Indiana University (IN, USA) and Dana–Farber Cancer Institute (MA, USA) [4]. Among the 688 male patients, 34 had primary mediasti-nal NSGCTs (4.9%). All patients received similar cisplatin-based chemotherapy. None of the testicular or retroperitoneal GCT patients developed hematologic malignancies. Two mediastinal NSGCT patients developed AML-M7 approximately 6 and 39 months after the diagnosis of GCTs, and the third patient devel-oped myelodysplastic syndrome (MDS) 4 months after GCT diagnosis. Nichols et al. reviewed ten similar reported cases. Two had synchronous leukemia and mediastinal NSGCTs before any treatment. One case developed leukemia 2 months after GCT diagnosis and surgical resection. Four developed leukemia within 1 year of chemotherapy initiation. Not included in the review was a 20-year-old male diagnosed with AML-M7, 5 months after chemotherapy [43]. An autopsy case of a 35-year-old male revealed a mediastinal NSGCT with leukemic infiltration, suggesting that the leukemia-like cells originated within the tumor [44].

Nichols et al. reported 16 new cases of mediastinal NSGCTs with hematologic malignancies diagnosed between 1983 and 1988 [45]. Five had synchronous diagnoses, and eight were diagnosed within 12 months of GCTs. The authors also reviewed 28 similar cases in the literature. One case was not included in the review [46]. Thus,

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a total of 45 cases of hematologic malignancies associated with mediastinal NSGCTs were reported by 1990. From 1990 to 2000, approximately 52 cases of hematologic malignancies associated with mediastinal NSGCTs were documented [35,47–67]. However, only 20 new cases were added to the list after the year 2000 [68–84].

In the largest series, 635 extragonadal GCT patients at 11 cancer centers between 1975 and 1996 were evaluated [35]. Approximately 54 and 45% were in the mediastinum and the retroperitoneum, respectively. Seventeen (of 287) with mediastinal NSGCTs devel-oped hematologic malignancies within a median of 6 months (0–47 months) after GCT diagnosis. Five were diagnosed with AML-M7 and five had MDS with megakaryocytic differentia-tion. Two had acute undifferentiated leukemia and two had mast cell leukemia. AML-M2, AML-M4 and malignant histiocytosis were diagnosed in one patient each. The risk of developing hema-tologic malignancies appeared markedly increased in patients with mediastinal NSGCTs with a standardized incidence ratio of 250 in comparison with an age-matched general population (95% CI: 140–405). None of the 231 patients with retroperitoneal NSGCTs developed hematologic malignancies.

Relationship of mediastinal NSGCTs & the associated hematologic malignanciesEver since the recognition of an association of hematologic neo-plasia with mediastinal NSGCTs, several hypotheses were con-templated to explain their relationship. The first hypothesis is that the two malignancies develop independently. The second is that the hematologic malignancies result from chemotherapy or radiation therapy to GCTs. The third hypothesis is that the hematologic malignancies originate from the NSGCTs.

Although the first two hypotheses may have some merits, they cannot explain the relationship of the two associated malignancies in most cases. Mediastinal NSGCTs only constitute 1–5% of all GCTs, but they have most of the associated hematologic malig-nancies, with an incidence ranging from 5.9 to 17% [35,45,51,66]. On the contrary, none of the 654 patients with retroperitoneal and testicular NSGCTs had hematologic malignancies as reported by Nichols et al. [4]. No hematologic malignancies were discov-ered in 231 patients with retroperitoneal NSGCTs as reported by Hartmann et al. [35]. With a 50–100-fold difference in the incidence of hematologic malignancies between patients with mediastinal and other NSGCTs, the hypotheses of a coincidence to explain the two malignancies and therapy-related hematologic malignancies cannot stand.

There are several lines of evidence for a GCT origin of hema-tologic malignancies. It was reported over 30 years ago that some NSGCTs contained clusters of extramedullary hematopoiesis [85]. Recently, Orazi et al. reported that four out of six mediastinal NSGCTs contained CD34-positive myelobasts, indicating that GCTs already produced leukemic cells before overt leukemia [52]. The most convincing evidence supporting a GCT origin of the hematologic malignancies came from cytogenetic data [86]. Chaganti et al. demonstrated that several components of a NSGCT and its associated leukemic cells had an identical karyo-type, including the presence of i(12p). Subsequently, numerous

studies reported i(12p) in GCT-associated leukemia, further con-solidating the postulate of a common origin of both malignancies [5,45,47,52,54, 57,59,62,65,66,70,78,87].

Possible mechanisms of development of GCT-associated hematologic malignanciesNSGCTs are able to give rise to many different cell types as they contain pluripotent EC cells. During early embryogenesis, PGCs and hematopoietic stem cells share common precursors. A single precursor cell can divide to produce one PGC and one founder cell of the hematopoietic lineage. This was demonstrated by cell fate mapping of prestreak and early streak mouse embryos [88].

The ability of EC cells to differentiate toward a hemato poietic lineage is a shared attribute of all NSGCTs. However, this attrib-ute does not explain the fact that GCT-related hematologic malig-nancies are predominantly associated with mediastinal NSGCTs. This is probably explained by a favorable niche for both GCT development and hematopoiesis within the developing anterior mediastinum. As discussed previously, several signaling path-ways present during thymopoiesis are known to be critical for PGC survival, proliferation and migration. These pathways have been shown to be essential for hematopoiesis as well, including but not limited to KITLG, BMP and Wnt signaling pathways [89–91]. Thus, the TECs of thymus primordium can theoretically contribute to the development of GCTs as well as GCT-derived hematologic malignancies through similar signaling pathways.

Types of hematologic malignancies associated with GCTsThere are several types of hematologic malignancies associated with NSGCTs, including AML, acute lymphoblastic leukemia, MDS, histiocytosis, non-Hodgkin’s lymphoma (one high-grade B-cell lymphoma and one not specified), Burkitt’s lymphoma, granulocytic sarcoma, essential thrombo cythemia and masto-cytosis. Among the reported 113 cases (Table 2), the most frequent hematologic neoplasia is AML-M7 (23). Additionally, all MDS cases (15) had a prominent megakaryocytic component [4,35,45]. With four cases of essential thrombocythemia also reported, the megakaryocytic differentiation occurs in 37% (42 out of 113) of the cases.

29% (33 out of 113) of hematologic malignancies reported are those with monocytic or histiocytic differentiation, 15 cases with AML-M4 and -M5 and 18 with histiocytosis. The group of other AMLs has 15 cases including AML-M0, -M1, -M2 and acute nonlymphocytic leukemia. It is also worth noting that three cases (each of AML-M3, AML and non-Hodgkin’s lymphoma) were believed to be derived from NSGCTs based on the presence of i(12p), in the absence of a primary GCT.

It is intriguing that GCT-derived hematological malignancies have a propensity toward megakaryocytic and monocytic or his-tiocytic differentiation. The mechanisms for these phenomena are not clear at all. However, one can speculate that these are the results of an intrinsic genetic network of the leukemia stem cells or GCT microenvironment to allow the leukemia stem cells to differentiate toward these lineages. Wnt5B and LRP6 (a coreceptor

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for Wnt) are located on chromosome 12p. The Wnt5B/Ca path-way has been implicated in the megakaryocytic differentiation pathway [92]. Thus, extra copies of 12p and the overexpression of Wnt5B by GCTs may lead the leukemic stem cells to differentiate to the megakaryocytic lineage. Male germ cells and GCT tumor cells are known to express granulocyte–macrophage colony-stim-ulating factor and macrophage colony-stimulating factor [93,94]. Both factors are well defined in their ability to promote mono-cyte and macro phage differentiation from myeloid precursor cells. Therefore, it is reasonable to hypothesize that GCTs may provide a micro environment to promote leukemia stem cells to differentiate toward megakaryocytic and monocytic lineages.

Hematologic malignancies associated with GCTs at other sitesAlthough GCT-associated hematologic malignancies predomi-nantly occur with mediastinal NSGCTs, rare cases were reported with GCTs at other sites.

It is important to note that the concurrent testicular GCTs and hematologic malignancies are extremely rare. Only a few cases were reported with one case showing a common cytoge-netics, suggesting clonality [87,95–97]. On the basis of two large studies, the incidence of hematologic malignancies in patients with retroperitoneal GCTs and testicular GCTs are similarly low [4,35]. Concurrent diagnosis of retroperitoneal GCTs and hematologic malignancy before treatment initiation has not been found (through a Medline search). There were also rare reports of suprasellar germinoma-associated mixed-lineage AML and MDS [98,99]. GCTs in females are infrequent and mainly asso-ciated with gonadal dysgenesis. Thus, ovarian dysgerminoma-associated hematologic malignancies are rarely reported in the literature [100–108]. Significantly, three of the nine cases showed a karyotype of 46,XY with gonadal dysgenesis [101,102,107], raising a possibility of Y chromo somal components present in the genome of other patients, a scenario comparable to that of TS patients with dysgerminoma.

Hematologic malignancies secondary to GCT chemotherapy and/or radiation therapyIn the mid-1980s, 16 cases of testicular GCT-associated hema-tologic malignancies were reported after patients had received chemotherapy and/or radiation therapy for GCTs [4,109]. The mean intervals between the two malignancies were 60 months (9–264 months), much longer than that of mediastinal GCT-associated conditions (6 months), suggesting most of these hematologic malignancies were treatment related. A case–control study of a population-based cohort of 18,567 patients of testicular cancer from 1973 to 1990 was conducted by Travis et al. [110]. A total of 39 patients developed secondary hematologic malig-nancies. History of treatments with chemotherapy and radia-tion are associated with an increased risk of leukemia. There is also a dose relationship for both radiation and chemotherapy. In the largest series of 42,722 patients with testicular cancers from 14 cancer registries in North America and Europe, secondary hematologic malignancies developed in 89 patients [111]. Excess

cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis.

A progressive increase in standardized incidence ratio of acute leukemia was reported from pre-1970 to the 1980s as better chemotherapy regimens became available for GCTs. Cisplatin-based therapy began in the 1970s, and etoposide-based therapy became available in the 1980s [112]. The risk is correlated with the total cumulative dose. Leukemias following cisplatin (an alkylating agent) containing regimens usually occur after 5–7 years and are often preceded with MDS which eventually progresses to AML-M1 or -M2. Etoposide (a topoisomerase II inhibitor) induced hematologic malignancies are usually diagnosed 2–3 years after treatment, with AML-M4 or -M5 as the predominant phenotype.

Prognosis of patients with NSGCT-associated hematologic malignanciesMost GCTs are considered curable with chemotherapy contain-ing cisplatin and etoposide. Regardless of histology, patients with testicular GCTs have a 5-year survival of >90% [113,114]. For extra gonadal GCTs, the outcomes with standard treatment vary considerably. Retroperitoneal GCTs and primary medi-astinal SGCTs enjoy an outcome similar to that of testicular GCTs. However, mediastinal NSGCTs fare poorly with current

Table 2. Types of hematologic malignancies associated with mediastinal germ cell tumors†.

Hematologic diagnosis Cases (n = 113)

Cases confirmed to have i(12p) (n = 27)

Acute megakaryoblastic leukemia (AML-M7)

23 3

Malignant or benign histiocytosis

18 1

Acute myelomonoblastic/monoblastic leukemia (AML-M4 or -M5)

15 4

Other acute myeloid leukemia (AML): M0, M1, M2 and unspecified

15 9

Myelodysplastic syndrome 15 6

Mastocytosis 8 0

Acute lymphoblastic leukemia

5 0

Acute erythroblastic leukemia (AML-M6)

4 1

Essential thromocythemia 4 0

Non-Hodgkin’s lymphoma 2 2

Granulocytic sarcoma 2 0

Burkett’s lymphoma 1 0

Acute promyelocytic leukemia (AML-M3)

1 1

†Four cases with idiopathic thrombocytopenia in [45] were excluded from the table as it is difficult to distinguish them from the classical immune thrombocytopenic purpura.

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treatment regimens. In a group of 64 patients with mediastinal NSGCTs treated in France from 1983 to 1990, the 2-year over-all survival rate was 53% [115]. In a larger study, a 5-year overall survival rate of 45% was documented among 141 patients with mediastinal NSGCTs treated from 1975 to 1996 [5]. A recent smaller study with 37 patients from 1998 to 2005, showed a 54% long-term progression-free survival [116].

On the basis of available clinical and pathobiological data, the primary mediastinal NSGCTs clearly display a behavior rather different from that of testicular or retroperitoneal NSGCTs. In addition to their poor response to chemotherapy, they are more likely to give rise to hematologic malignancies. Hartmann et al. contrasted the overall survival of patients with medias-tinal NSGCTs with and without hematologic malignancies using Kaplan–Meier analysis. The median overall survival was 14 months (4–52 months) for the 17 cases with associated hema-tologic malignancies, while the median overall survival for the 270 patients without hematologic malignancies was 51 months (0–178 months) [35]. A literature review of 34 additional pri-mary mediastinal NSGCT patients with hematologic malig-nancies, treated with chemotherapy or no treatment from the 1980s to 2010, revealed a median overall survival of 5 months (0–48 months) after the diagnosis of a hematologic malignancy. All the data point to a rather dismal prognosis.

Treatment of NSGCT-associated hematologic malignanciesOwing to the infrequency of NSGCT-associated hematologic malignancies, there are no guidelines for treatment. For most metachronous cases, patients typically received standard chemo-therapy or radiation for NSGCT, and subsequently received treat-ment for the hematologic malignancy [4,53,54,58,59,65,66,70,75,81,109,

117,118]. However, due to the fulminant nature of many of the presentations, 40% of the patients never received treatment for their hematologic malignancies prior to their death [35].

In one incidence, AML was diagnosed first and treated with induction chemotherapy; then, a mediastinal NSGCT was dis-covered 14 months later [119]. Three additional metachronous cases of hematologic malignancies with i(12p) were presumed to be GCT derived. One patient with a mediastinal centroblastic lymphoma went into complete remission (CR) after being treated with eight cycles of cyclophosphamide, vincristine, doxorubicin and prednisone [120]. A second patient diagnosed with AML-M3 treated with induction chemotherapy followed by consolidation with daunorubicin and cytarabine. He eventually received an allogeneic hematopoietic stem cell transplant (HSCT) from a matched sibling donor and remained in CR by the time of report [62]. The third patient with AML-M1 was treated with chemo-therapy followed by auto-HSCT and remained in CR by the time of report [62].

For patients with synchronous malignancies, physicians were often faced with a dilemma as it was hard to balance the treatment of the two [121]. In recent reports, some cases were treated for leuke-mia first, then for GCTs [78,80]. In others, chemotherapy covering both diseases was tried concurrently [73,74,83]. For one case with

AML-M7, Dopico Vazquez et al. treated the patient with a cycle of BEP (CDDP 20 mg/M2 × 5 days, VP-16 100 mg/M2 × 5 days, bleomycin 30 U), then on day 6 with induction therapy for AML with idarubicin and Ara-C. Consolidation chemotherapy with Ara-C and mitoxantrone was given subsequently. CR was achieved with respect to his AML. However, the patient died from his NSGCT progression after three more cycles of BEP, second-line (ifosfamide and paclitaxel) and third-line therapy (gemcitabine and oxaliplatin). In another case of synchronous mediastinal NSGCT and AML, the patient was treated with a combination of Ara-C, daunorubicin, cisplatin and etoposide every 4 weeks. After two cycles, the patient had normalized AFP and β-HCG, and 3.5% blasts in bone marrow, but the mediastinal mass continued to enlarge. He was then treated with brachytherapy combined with Ara-C and etoposide followed by surgical resection. However, he eventually died from the leukemia 4 months after diagnosis and 1 month after surgery [83].

As detailed above, the outcome of mediastinal NSGCTs with hematologic malignancies treated with conventional therapy has been poor. The only long-term survivors were those who had received HSCT. The first reported successful outcome with HSCT was a patient with a metachronous MDS that developed 10 months after the NSGCT diagnosis. He was in CR for both malignancies and had 100% donor-derived bone marrow 3 months after the transplant from a matched unrelated donor [70]. A second patient who received a HSCT was a 13 year old with KS. He had synchronous NSGCT and AML-M7, first treated with induction with Ara-C, etoposide and mitoxantrone, fol-lowed by five courses of high-dose Ara-C, etoposide, idarubicin and mitoxantrone with cisplatin (every 4 weeks). Eventually, he received a serologically matched cord blood transplant. Bone mar-row aspiration at 1 month revealed 100% donor origin. Surgical resection was performed 56 days after HSCT and he remained disease free 3.5 years after the onset of disease [80].

Expert commentaryThe vast majority of hematological malignancies are of bone marrow origin, and only a small percentage of these malignancies develop from the stem cells of NSGCT. Interestingly, primary mediastinal NSGCTs are associated with a much higher incidence of hematological malignancies than GCTs of other sites, which is probably attributed to the favorable microenvironment of the developing thymus for the tumor stem cells to survive and differentiate toward the hematopoietic lineage. Current literature surveys has revealed a rather grave picture of GCT-associated hematologic malignancies because of their fulminant presentation and refractoriness to the available treatment regimens. So far the best long-term survivors of GCT-associated hematological malignancies have been those who received allogeneic HSCT or cord blood transplant. Therefore, it is reasonable to treat these patients as if they have AML with poor prognostic features, and they should be considered for allogeneic HSCT as soon as possible, even with delayed definitive therapy for GCTs. In addition, autologous HSCT to treat GCT-associated hematologic malignancies has not been reported in the literature. In cases

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that a matched donor cannot be obtained for allogeneic HSCT, autologous transplant should be attempted.

Five-year viewGCT-associated hematologic malignancies are derived from the stem cells within the NSGCTs. The response of these malignan-cies to current chemotherapy is poor compared with the bone marrow-derived counterparts. This is probably attributed to their different genetic mechanisms of leukemogenesis. All the literature on this subject have been case reports or case series. Owing to the low incidence of the diseases, it has been difficult to conduct pro-spective clinical trials. Up until now, the best outcome for patients with GCT-associated hematologic malignancies was achieved through allogeneic HSCT. It is not clear why these malignancies are refractory to chemotherapy. It will be necessary to conduct comparative investigations between GCT-derived hematological malignancies and their bone marrow-derived counterparts, in

the areas of genetic alterations through next-generation DNA sequencing and epigenetic modifications in DNA methylation, histone modification and micro-RNA patterns. These studies can be attempted on previously stored frozen blood or bone mar-row aspirates as cases are rare. However, the utility of fixed and paraffin-embedded samples is uncertain as the DNA and RNA integrity may not be well preserved. Data obtained from such studies will probably open up the possibility of new therapeutic approaches for these malignancies.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Extragonadal germ cell tumors are derived from transformed displaced primordial germ cells.

• Primary mediastinal nonseminomatous germ cell tumors have a propensity to give rise to hematologic malignancies.

• Hematologic malignancies associated with germ cell tumors usually present with a fulminant course.

• Germ cell tumor patients with hematologic malignancies have a much worse prognosis than patients without hematologic malignancies.

• Hematologic malignancies derived from germ cell tumors are refractory to chemotherapies used to treat bone marrow-derived counterparts.

• Prospective clinical trials for germ cell tumor-derived hematologic malignancies are difficult to conduct due to the low incidence.

• Patients with hematologic malignancies derived from germ cell tumors should be evaluated for hematopoietic stem cell transplant as soon as possible.

• Genetic and epigenetic studies are needed to understand the pathobiology of germ cell tumor-associated hematologic malignancies in order to obtain better treatment regimens.

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Malignancies associated with germ cell tumors