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Concurrent development of testicular seminoma and choriocarcinoma of the superior mediastinum, presented as cervical mass: a case report and implications about pathogenesis of germ-cell tumours
© Mountzios et al; licensee BioMed Central Ltd. 2006
Received: 08 April 2006
Accepted: 20 November 2006
Published: 20 November 2006
Synchronous presentation of more than one germ cell tumours of different histology in the same patient is considered to be very rare. In these cases of multiple germ cell tumours, strong theoretical and clinical data suggest an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic differentiation and maturation of the germ cell.
A 25 year-old young man presented with an enlarging, slightly painful left cervical mass. Despite the initial disorientation of the diagnosis to a possible thyroid disorder, the patient underwent complete surgical resection of the mass revealing mediastinal choriocarcinoma. Subsequent ultrasound of the scrotum indicated the presence of a small lobular node in the upper pole of the left testicle and the patient underwent radical left inguinal orchiectomy disclosing a typical seminoma. Based on these results, the patient received 4 cycles of Bleomycin, Etoposide and Platinum chemotherapy experiencing only mild toxicity and resulting in complete ongoing clinical and biochemical remission.
The pathogenesis of concurrent germ cell tumours in the same patient remains an area of controversy. Although the genetic instability of the pluripotent germ cell offers an adequate explanation, the possibility of metastasis from the primary, less differentiated tumour to a distant location as a more mature subtype cannot be excluded. Possible development of a metastatic site of different histology and thus biological behaviour (e.g choriocarcinoma) should be anticipated. Furthermore, urologists, pathologists and medical oncologists should be meticulous in the original pathological diagnosis in these patients, since there is a significant frequency of germ cell tumours with mixed or overlapping histological elements with diverse potential of evolution and differentiation.
Synchronous presentation of more than one germ cell tumors (GCTs) in the same patient is considered to be quite rare. It usually involves almost identical histological subtypes, the possibility of metastasis from the one site to another being the most probable explanation . Here we describe a case of concurrent presentation of left testicular seminoma and choriocarcinoma of the upper mediastinum presenting as an enlarging, painless, left cervical mass.
GCTs are generally malignant and represent 93% of all testicular neoplasms . At least half of them are of seminomatous cell origin, being either "typical" seminomas or containing mixed elements of non-seminomatous origin (embryonal or choriocarcinoma elements such as syncytiotrophoblasts) which do not usually affect the good prognosis of seminomas . On the other hand, non-seminomatous GCTs, represent a more heterogenous group comprising four main subtypes (embryonal carcinoma, teratoma, choriocarcinoma and yolk sac tumor) with significant overlapping and increased frequency of mixed histological pictures .
It is thought today that these common histological elements between seminomatous and non-seminomatous GCTs and also between the different subtypes of non-seminomatous GCTs reflect their common embryonic origin from the same primitive, pluripotent germ cell which has the capacity to mature and differentiate to neoplastic endodermal or ectodermal components, imitating thus the procedures of normal embryonic development . Consequently, each type of germinal cancer is considered to be the "counterpart" of each stage of normal embryo development: Seminoma is the neoplastic counterpart of the spermatocyte and represents the more undifferentiated type. The next stage is that of the fertilized ovum and the formation of the blastocele which gives rise to both the embryo and the placenta: the neoplastic counterpart is the embryonal cell carcinoma, which produces high levels of a-FP concentration. At a more mature stage of embryonic development, malignant transformation of the developing embryo will lead to teratomas (a-FP and β-hCG production), whereas neoplastic transformation of the embryonic yolk sac cells leads to the homonymous tumours, overproducing a-FP. Finally, syncytiotrophoblastic and cytotrophoblastic components of the placenta will give rise to pure choriocarcinomas, that overproduce β-hCG. Although choriocarcinomas represent a more differentiated malignant counterpart, they are characterised by an aggressive biological behaviour with tendency for haematogenous metastasis, probably reflecting the capacity of its normal counterpart (the placenta) to invade blood vessels . The last observation suggests that malignant transformation of a more mature element during embryonic development does not necessarily predict either a benign biological behaviour of the tumour or a more favourable clinical outcome.
Based on the above mentioned data, the hypothesis that the concomitant development of two different histological types of germ cell tumour in the same patient is random, does not seem probable. Interestingly, synchronous or metachronous development of multiple germ cell tumours in the same patient insinuates an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic germ cell differentiation and maturation. A number of genetic abnormalities, the most common being isochromosome 12, have been described in patients with germ cell tumours and have also been implemented in the diagnostic procedure of undifferentiated mediastinal tumours of uncertain histological origin . It seems that germ cells of the testicles (or the ovaries), as well as the primitive embryonic germ cells that have remained in extragonadal locations in the midline of the body (mediastinum, retroperitoneum), can undergo malignant transformation and mimic procedures of normal embryonic development by differentiating towards various embryonic or extra-embryonic elements.
Recently, it has been suggested that the synchronous or metachronous presentation of different types of GCTs in the same patient does not indicate two different primary tumours with common pathogenetic origin, but the more differentiated site might represent a possible metastatic location of the primary undifferentiated tumour, which has metastasised as a more mature type . Interestingly enough, this histological "conversion" into a more differentiated type at the metastatic location has been observed in a few series of patients with GCTs . We know today that metastatic sites are not always histologically identical with the primary location: histological conversion can occur, either as a normal maturation procedure mimicking embryonic development or as a result of therapeutic intervention. In the last case, chemotherapy can destroy the rapidly growing, chemosensitive embryonal components of a mixed GCT, sparing the more resistant teratomatous elements and resulting thus in a completely different histology compared to that of the primary tumour location .
The above mentioned hypothesis implies that GCTs may metastasise only as a more mature histological type in the procedure of embryogenesis and never in the opposite direction, which has been confirmed by numerous clinical observations: Metastases from embryonic carcinomas may be found to consist of both teratoma and choriocarcinoma elements, whereas choriocarcinomas metastasise only as choriocarcinomas, since they represent the more differentiated histological type of embryonic development . Seminomas possess the theoretical capacity of metastasising as various histological components since they represent the malignant counterpart of the more "primitive" cell, the spermatocyte. However, some authors suggest that "typical" seminomas always metastasise keeping their original histological features: those who do not are believed to represent GCTs of mixed histology, misdiagnosed as seminomas at the original histological examination. Supporters of this theory believe that histological "conversion" can not happen either automatically or after therapeutic intervention. Ayala and Ro suggest that all GCTs, including seminomas, consist of all embryonic elements, not always detectable at initial pathology examination and have thus the potential of giving rise to histologically different metastases consisting of one of the primary tumour elements, depending on their different metastatic potential and the therapeutic intervention including chemotherapy and radiotherapy .
Our patient developed almost concurrently testicular seminoma and pure choriocarcinoma of the mediastinum. Histological "conversion" of the original tumour site is theoretically possible since choriocarcinoma represents a more mature stage of embryonic development compared to seminoma. On the other hand, one could argue that the primary tumour was not a typical seminoma and that chorionic elements where present at the original histological examination including few giant cells with positive immunohistochemistry for β-hCG. Nevertheless, trophobalstic elements, whose presence is considered to be mandatory for the diagnosis of choriocarcinoma, were totally absent in the original pathology specimen.
The above mentioned potential of GCTs to metastasise as a more differentiated subtype is clinically meaningful, since the clinician should anticipate possible development of a metastatic site of a more aggressive biological behaviour (e.g. choriocarcinoma) compared to that of the original location. Thus, medical oncologists, urologists and pathologists should be very suspicious of the original pathological diagnosis in these patients, since there is a significant frequency of GCTs with mixed or overlapping histological elements with diverse potential of evolution and differentiation. Moreover, given the heterogeneity of these tumours, one could emphasize the necessity of obtaining multiple samples from different tumour areas in every case of GCT so as to minimize the risk of missing important particular components of the tumour who could potentially affect the diagnosis, prognosis or even the therapeutic intervention.
Summary of the published cases of synchronous or metachronous development of second GCT in patients with primary testicular cancer.
TYPE OF PRESENTATION
LOCALISATION OF SECOND TUMOUR
HISTOLOGY OF SECOND TUMOUR
Brain and Spleen
IVC and GI
Germ cell tumours represent a heterogeneous group of malignant cell lines with a variety of frequently overlapping histological pictures or with mixed components suggesting a common "precursor" embryonic cell dysfunction. Histological conversion to a more mature subtype is theoretically possible in a metastatic location with or without therapeutic intervention, as well as synchronous or metachronous development of two different primary germ cell tumours as a result of a common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic germ cell differentiation and maturation.
Written consent was obtained from the patient for publication of study. We wish to thank in particular the patient and his family for their collaboration. GS participated at the collection of data (surgeon). KR participated at the collection of data (pathologist). AB participated at the collection of data (medical oncologist). NN participated at the collection of data (physician). PP participated in the coordination of the study. JCS participated in the design of the study. MAD had the coordination and supervision of the study.
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