germ cell tumors ( gcts ) represent a well - recognized group of heterogeneous neoplasms with diverse clinical , histopathological , diagnostic , and prognostic characteristics .
being the most common solid tumor in the 3rd and 4th decades , gcts assume a particular significance among young adult males .
gonads are the most common primary site of gcts , although a very small proportion is extragonadal in origin .
the most common site of the scarcer extragonadal gcts is the mediastinum , with retroperitoneum being the close runner - up .
immature teratomas , a subtype of gcts , are particularly rare in the mediastinum . in a review of 322 primary mediastinal gcts ,
only 6 immature teratoma cases were identified , which represented 1.8% of all mediastinal gcts and 4% of mediastinal teratomas .
even rarer is a gct with somatic malignant transformation , occurring in around 2% of all male gcts and in 10% to 20% of mediastinal teratomas .
we report herein a case of an aggressive , chemotherapy - resistant immature teratoma harboring foci of sarcoma , melanoma , adenocarcinoma , and squamous cell carcinoma .
a 21-year - old man was referred to our service from a local hospital for further management of a right hemithoracic extra - pleural mass with a provisional diagnosis of immature teratoma .
the patient  previously healthy  presented to the referring hospital with a 3-week history of productive cough with blood - tinged sputum , right - sided intermittent pleuritic chest pain , and mild shortness of breath .
he also experienced intermittent fever ( 38.5  c ) , nausea , vomiting , anorexia , and significant weight loss .
his past medical , family , travel , contact , and occupational histories are unremarkable . physical examination revealed a thin - built man with normal vital signs .
respiratory examination suggested a reduction of air entry on the right side with no rhonchi , wheezing , or crepitation .
general , cardiac , abdominal , testicular , and lymph - node examinations were unremarkable .
g / l , normal = 135180 ; mean corpuscular volume = 71  fl , normal = 7595 ; mean corpuscular hemoglobin = 23.3  pg , normal = 2430 ) , mild leukocytosis ( total leukocyte count = 12.49    10/l , normal = 3.911.0 ) , thrombocytosis ( platelets = 1061    10/l , normal = 155435 ) , and an elevated lactate dehydrogenase ( ldh ) level ( ldh = 567  u / l increased to 727 
notably , -fetoprotein ( afp ) and cancer antigen 199 were elevated ( afp = 9.13  g / l increased to 19.3  g /
l in few weeks , normal < 7 ; cancer antigen 199 = 38.5  u / ml , normal < 27 ) , while carcinoembryonic antigen and -human chorionic gonadotropin levels were within normal limits .
a chest radiograph showed a large , well - defined substernal mass obscuring the right cardiac border .
contrast - enhanced computed tomography ( ct ) at presentation revealed a large ( approximately 4    4    5  cm ) noncalcified , heterogeneous mediastinal mass extending to the right upper lobe and pleura ( fig .
several mediastinal and cardiophrenic lymph nodes were noted , with the largest measuring 1.2  cm in its widest diameter .
no focal lesions in the liver , spleen , pancreas , adrenals , or kidneys were identified .
whole - body combined 18f - fluorodeoxyglucose positron emission tomography / computed tomography ( fdg - pet / ct ) showed an fdg - avid mediastinal mass with a single fdg - avid superior mediastinal lymph node ( fig .
( a , b ) a contrast - enhanced computed tomography scan , using the mediastinal ( a ) and lung ( b ) windows , showing a mediastinal mass that is extending into the adjacent lung . ( a , b ) microscopic examination of needle core biopsy from the mediastinal mass showing predominant immature neuroectodermal elements forming glands and tubules lined by columnar embryonal cells with stratified hyperchromatic nuclei ( a ) and focal areas of a more mature neural tissue ( b ) . a whole - body combined 18f - fluorodeoxyglucose ( fdg ) positron emission tomography / computed tomography scan showing an fdg - avid mediastinal mass with an intense peripheral hypermetabolic activity .
combination chemotherapy with bleomycin ( 30 units iv on days 1 , 8 , and 15 ) , etoposide ( 100  mg / m iv on days 15 ) , and cisplatin ( 20  mg / m iv on days 15 ) was subsequently initiated
. however , notwithstanding the mild improvement initially , the patient showed steady symptomatic deterioration ; after completing two 3-week chemotherapy cycles , he presented to the emergency room with chest pain , cough , and hemoptysis .
although no evidence of pulmonary embolism ( pe ) was found , the study showed an interval progression of the tumor size , reaching around 12    13    12  cm .
the ill - bordered mass appeared to have invaded the lung parenchyma , superior vena cava , and pericardium ( fig .
4a and b ) , while abutting on the carina , right main bronchus , right pulmonary artery , as well as the anterior , inferior , and superior pulmonary veins .
( a , b ) axial ( a ) and coronal ( b ) contrast - enhanced computed tomography scans  obtained after receiving 2 chemotherapeutic cycles  showing interval progression of size , reaching around 12    13    12  cm in its maximum dimensions .
the case was thoroughly reviewed and discussed in a multidisciplinary team meeting , whose recommendation was to proceed with surgical resection .
the patient underwent clamshell thoracotomy with an r0 resection of the mass along with the right middle and lower lung lobes .
however , he presented 2 months later with extensive liver and bone metastasis , for which he received 1 cycle of palliative radiation .
therefore , the decision was taken to treat him as a case of metastatic melanoma .
one 5-day cycle temozolomide ( 150  mg / m po qday for 5 days ) was administered .
unfortunately , the patient passed away5 and a half months after the initial diagnosis was made .
macroscopic examination of the resected mediastinal mass revealed solid and mucoid - filled cystic components with hemorrhagic cut surface measuring 18    14    13  cm in its maximum dimensions .
microscopically , the tumor consisted of a mixture of various ectodermal , endodermal , and mesodermal elements , of which immature neuroectodermal tissue areas were predominant .
anaplastic , pleomorphic glial tissues with marked nuclear atypia , and brisk mitosis were noted .
these areas stained positive for glial fibrillary acidic protein and represented a glioblastoma component ( fig .
c ) . ( a  c ) neural tissue with pleomorphic atypical cells and high nuclear - to - cytoplasmic ratio consistent with glioblastoma ( a , b ) .
immunohistochemical staining of the tissue with glial fibrillary acidic protein ( gfap ) showing positive reaction ( c ) .
other areas of the tumor contained pleomorphic spindle - to - round cells with large hyperchromatic nuclei , prominent nucleoli , and frequent atypical mitosis suggestive of malignant , undifferentiated spindle - cell sarcoma ( fig .
extensive immunohistochemical staining for relevant markers ( smooth muscle actin , desmin , myogenic differentiation 1 , cluster of differentiation [ cd]34 , cd31 , and synaptophysin ) were negative .
atypical , large pleomorphic cells with melanin pigment staining positive for s100 , human melanoma black ( hmb ) 45 , melan a , and microphthalmia - associated transcription factor-1 were present in other areas  indicating a melanocytic differentiation consistent with transformation to malignant melanoma ( fig .
areas of endodermal differentiation with glandular structures , some of which showed malignant features consistent with adenocarcinoma , were also noted ( fig .
besides , mature and immature cartilaginous tissues were seen in areas of the tumor ( fig .
regional lymph nodes adjacent to the tumor were positive for metastatic squamous cell carcinoma ( fig .
( a  h ) somatic - type malignancies : pleomorphic spindle to round cells and frequent atypical mitosis suggestive of sarcomatous differentiation ( a ) .
malignant spindle cells with melanin pigment ( b  d ) which were positive for melan - a ( e ) .
cartilage with numerous lacunae containing small chondrocytes , surrounded by immature mesenchymal cells ( g ) .
a 21-year - old man was referred to our service from a local hospital for further management of a right hemithoracic extra - pleural mass with a provisional diagnosis of immature teratoma .
the patient  previously healthy  presented to the referring hospital with a 3-week history of productive cough with blood - tinged sputum , right - sided intermittent pleuritic chest pain , and mild shortness of breath .
he also experienced intermittent fever ( 38.5  c ) , nausea , vomiting , anorexia , and significant weight loss .
his past medical , family , travel , contact , and occupational histories are unremarkable . physical examination revealed a thin - built man with normal vital signs .
respiratory examination suggested a reduction of air entry on the right side with no rhonchi , wheezing , or crepitation .
general , cardiac , abdominal , testicular , and lymph - node examinations were unremarkable .
g / l , normal = 135180 ; mean corpuscular volume = 71  fl , normal = 7595 ; mean corpuscular hemoglobin = 23.3  pg , normal = 2430 ) , mild leukocytosis ( total leukocyte count = 12.49    10/l , normal = 3.911.0 ) , thrombocytosis ( platelets = 1061    10/l , normal = 155435 ) , and an elevated lactate dehydrogenase ( ldh ) level ( ldh = 567  u / l increased to 727 
notably , -fetoprotein ( afp ) and cancer antigen 199 were elevated ( afp = 9.13  g / l increased to 19.3  g /
l in few weeks , normal < 7 ; cancer antigen 199 = 38.5  u / ml , normal < 27 ) , while carcinoembryonic antigen and -human chorionic gonadotropin levels were within normal limits .
a chest radiograph showed a large , well - defined substernal mass obscuring the right cardiac border .
contrast - enhanced computed tomography ( ct ) at presentation revealed a large ( approximately 4    4    5  cm ) noncalcified , heterogeneous mediastinal mass extending to the right upper lobe and pleura ( fig .
several mediastinal and cardiophrenic lymph nodes were noted , with the largest measuring 1.2  cm in its widest diameter .
no focal lesions in the liver , spleen , pancreas , adrenals , or kidneys were identified .
a ct - guided core needle biopsy was suggestive of immature teratoma ( fig . 2a and b ) . whole - body combined 18f - fluorodeoxyglucose positron emission tomography / computed tomography ( fdg - pet / ct ) showed an fdg - avid mediastinal mass with a single fdg - avid superior mediastinal lymph node ( fig .
( a , b ) a contrast - enhanced computed tomography scan , using the mediastinal ( a ) and lung ( b ) windows , showing a mediastinal mass that is extending into the adjacent lung . ( a , b ) microscopic examination of needle core biopsy from the mediastinal mass showing predominant immature neuroectodermal elements forming glands and tubules lined by columnar embryonal cells with stratified hyperchromatic nuclei ( a ) and focal areas of a more mature neural tissue ( b ) .
a whole - body combined 18f - fluorodeoxyglucose ( fdg ) positron emission tomography / computed tomography scan showing an fdg - avid mediastinal mass with an intense peripheral hypermetabolic activity .
combination chemotherapy with bleomycin ( 30 units iv on days 1 , 8 , and 15 ) , etoposide ( 100  mg / m iv on days 15 ) , and cisplatin ( 20  mg / m iv on days 15 ) was subsequently initiated
. however , notwithstanding the mild improvement initially , the patient showed steady symptomatic deterioration ; after completing two 3-week chemotherapy cycles , he presented to the emergency room with chest pain , cough , and hemoptysis .
although no evidence of pulmonary embolism ( pe ) was found , the study showed an interval progression of the tumor size , reaching around 12    13    12  cm .
the ill - bordered mass appeared to have invaded the lung parenchyma , superior vena cava , and pericardium ( fig . 4a and b ) , while abutting on the carina , right main bronchus , right pulmonary artery , as well as the anterior , inferior , and superior pulmonary veins .
( a , b ) axial ( a ) and coronal ( b ) contrast - enhanced computed tomography scans  obtained after receiving 2 chemotherapeutic cycles  showing interval progression of size , reaching around 12    13    12  cm in its maximum dimensions .
the case was thoroughly reviewed and discussed in a multidisciplinary team meeting , whose recommendation was to proceed with surgical resection .
the patient underwent clamshell thoracotomy with an r0 resection of the mass along with the right middle and lower lung lobes .
however , he presented 2 months later with extensive liver and bone metastasis , for which he received 1 cycle of palliative radiation .
therefore , the decision was taken to treat him as a case of metastatic melanoma .
one 5-day cycle temozolomide ( 150  mg / m po qday for 5 days ) was administered .
unfortunately , the patient passed away5 and a half months after the initial diagnosis was made .
macroscopic examination of the resected mediastinal mass revealed solid and mucoid - filled cystic components with hemorrhagic cut surface measuring 18    14    13  cm in its maximum dimensions .
microscopically , the tumor consisted of a mixture of various ectodermal , endodermal , and mesodermal elements , of which immature neuroectodermal tissue areas were predominant .
anaplastic , pleomorphic glial tissues with marked nuclear atypia , and brisk mitosis were noted .
these areas stained positive for glial fibrillary acidic protein and represented a glioblastoma component ( fig .
c ) . ( a  c ) neural tissue with pleomorphic atypical cells and high nuclear - to - cytoplasmic ratio consistent with glioblastoma ( a , b ) .
immunohistochemical staining of the tissue with glial fibrillary acidic protein ( gfap ) showing positive reaction ( c ) .
other areas of the tumor contained pleomorphic spindle - to - round cells with large hyperchromatic nuclei , prominent nucleoli , and frequent atypical mitosis suggestive of malignant , undifferentiated spindle - cell sarcoma ( fig .
extensive immunohistochemical staining for relevant markers ( smooth muscle actin , desmin , myogenic differentiation 1 , cluster of differentiation [ cd]34 , cd31 , and synaptophysin ) were negative .
atypical , large pleomorphic cells with melanin pigment staining positive for s100 , human melanoma black ( hmb ) 45 , melan a , and microphthalmia - associated transcription factor-1 were present in other areas  indicating a melanocytic differentiation consistent with transformation to malignant melanoma ( fig .
e ) . areas of endodermal differentiation with glandular structures , some of which showed malignant features consistent with adenocarcinoma , were also noted ( fig .
besides , mature and immature cartilaginous tissues were seen in areas of the tumor ( fig .
regional lymph nodes adjacent to the tumor were positive for metastatic squamous cell carcinoma ( fig .
( a  h ) somatic - type malignancies : pleomorphic spindle to round cells and frequent atypical mitosis suggestive of sarcomatous differentiation ( a ) .
malignant spindle cells with melanin pigment ( b  d ) which were positive for melan - a ( e ) .
cartilage with numerous lacunae containing small chondrocytes , surrounded by immature mesenchymal cells ( g ) .
a 40-year , population - based review of finland cancer registry suggested an incidence of 1.8 and 1.0 per 1,000,000 person - years among males and females , respectively .
despite the increasing incidence of gonadal gcts , no temporal change was observed in the incidence of its extragonadal counterpart  a finding that is consistent across the studied populations .
several reports suggested the mediastinum to be the most common site of origin of extragonadal gcts in males , while others found the central nervous system to be more common .
teratomas account for 40% to 60% of all mediastinal gcts , with the overwhelming majority being histologically mature .
mediastinal teratomas are more common in males than females , except during the first few years of life .
an uncommon but well - recognized phenomenon that may accompany gcts is the somatic - type malignant transformation , in which a non - gct malignant component is found within the bulk of a cgt or in its metastatic foci .
somatic - type malignancy arising specifically in a teratoma setting remains an exceptionally rare event .
given the remarkable chemo - sensitivity of gcts , chemotherapy is thought to eliminate the bulk of gcts  exposing the non - gct , chemo - resistant malignant components when present . possibly due to the pluripotency of gct components
the most common histological subtype of malignant transformation is sarcoma ( predominantly rahbdomyosarcoma ) , followed by adenocarcinoma and primitive neuroectodermal tumors .
squamous cell transformation is rare but may be relatively more common in ovarian teratomas , especially in the mature cystic variants .
an international , multicentric review of 635 patients with extragonadal gcts identified secondary melanoma in 2 cases , which occurred few years later after the primary diagnosis .
few other cases of melanoma either occurring as secondary tumors or in conjugation with the primary mediastinal gct have been reported ( table 1 ) . to our knowledge , this is the first report of combined sarcomatous , carcinomatous , and melanomatous malignant transformation arising in the setting of immature mediastinal teratoma .
clinicopathological characteristics of primary medistinal gcts cases reported in the literature with an associated melanomatous degeneration .
clinically , gcts with somatic - type malignancy tend to be more symptomatic than pure gcts , although symptoms are clinically indistinguishable when present .
symptoms may arise from compression , invasion , or rupture and include chest pain , dyspnea , and cough .
patients may also experience weight loss , fever , malaise , night sweats , nausea , hemoptysis , postobstructive pneumonia , dysphagia , hoarseness , and superior vena cava syndrome .
radiologically , attenuation heterogeneity is a common characteristic of the mass , due to the presence of somatic malignancy ( i.e. , a solid mass ) along with areas of teratomatous , necrotic , or hemorrhagic zones .
invasion to adjacent structures , such as the great vessels , lung , and heart can also be seen .
metastasis to regional lymph nodes , lung , brain , liver , and spleen may be evident at the time of diagnosis or as a recurrence .
since no evidence of testicular involvement was found on physical examination or ultrasonography , testicular biopsy was deemed unnecessary in this case .
the patient 's clinical presentation featured postchemotherapy disease progression  that is , tumor growth and symptomatic deterioration .
syndrome and teratoma rupture , respectively , which are infrequently but characteristically seen in mature mediastinal teratomas . however , the rapid tumor progression in this case is likely due to the aggressive nature of the underlying non - gct malignant transformation , especially sarcoma .
in fact , it is likely that the tumor 's poor response to cisplatin - based therapy was due to the presence of sarcomatous component .
elevation of afp or -human chorionic gonadotropin is not uncommon in gcts with malignant transformation .
busmanis and tay suggested the lack of immunohistochemical correlation with the afp serum levels in a pure immature ovarian teratoma with extra - ovarian implants .
the possibility of yolk sac component being present in our case ( given the elevation of afp ) could not be ruled out .
although chemotherapy might have accounted for the eradication of yolk - sac components , the absence of histological evidence led to the designation of this case as an immature teratoma .
given the significant resistance to cisplatin - based chemotherapy , motzer et al suggested using chemotherapeutic agents based on the transformed histology as the strategy of choice for regimen selection .
others advocated initiating gct - standard cisplatin - based regiment and reserving chemotherapeutics of the specific somatic - type transformed malignancy for relapses .
although the rarity of gcts with malignant transformation have not permitted the generation of a strong body of evidence , it is agreed that an aggressive surgical approach with complete resection may be beneficial whenever deemed feasible , since it appears to afford the best survival . as demonstrated by the case
presented herein , the radiologic evidence of postchemotherapeutic interval growth in the context of a known immature teratoma may serve as a useful clue as to the presence of somatic - type transformation , favoring urgent surgical intervention over other treatment modalities ( e.g. , salvage chemotherapy ) .
in fact , it was shown that such a tumor may harbor hematopoietic stem cells within its bulk , providing a possible explanation for the source of the hematologic derangements . with the exception of thrombocytosis
, there were no overly aberrant blood indices in our case that would warrant further investigation .
it is worth mentioning that gcts may predispose to thrombotic events especially during chemotherapy treatment , and a sudden occurrence of hemoptysis raises the suspicion of pe .
ct pulmonary angiogram may be deemed optimal in an emergency setting , it aids in pe diagnosis and , if pe is ruled out , delineation of any structural alterations of the underlying pathology .
favorable factors include younger age , limited disease extent at diagnosis , feasibility of complete resection , the absence of somatic - type malignancy ( especially metastatic sarcoma - type histological transformation ) , and the response to standard chemotherapeutic regimens .
teratomas with malignant transformation have an aggressive course , high recurrence rate , and poor survival when present in the mediastinum . nonetheless , when confined to primary site , such tumors tend to carry mortality risk that is comparable to its teratomatous counterpart with no malignant transformation .
for gcts with somatic - type malignancy , the survival - determining factor may be the histopathological component that is most aggressive .
the patient had an overall survival of around 6 and 2 months from the initial diagnosis and metastasis , respectively .
this seems to mirror the survival of melanoma with metastasis to the liver , brain , or bone , whose median survival was found to be 4.4 months .
the patient also had several of the poor prognostic indicators , including an elevated ldh and leukocytosis .
however , what determines the metastatic potential in gct - associated melanomas remains largely unknown .
although our patient presented with metastatic disease 4 months after the diagnosis , 13 months elapsed before metastatic disease occurred in a previously reported gct - associated melanoma .
somatic - type malignant degeneration is a rare but well - recognized phenomenon that occurs in the settings of gcts . due to its rarity , distinct nature , and remarkable heterogeneity ,
this disease warrants comprehensive reporting of the clinical , radiological , and pathological features . in case of more - than - single transformation
, the clinical outcomes and overall survival may well correlate with that of the most aggressive and poorest prognosis tissue type .
the presence of melanomatous transformation , as illustrated by this case , likely confers aggressive biological behavior .
as the literature is enriched with additional studies , understanding the clinical implications of the distinct malignant transformations will expectedly aid in clarifying the optimal , possibly tailored , management lines .
 abstractgerm cell tumors ( gcts ) represent a well - recognized group of heterogeneous neoplasms with diverse clinical , histopathological , diagnostic , and prognostic characteristics . 
 we present a rare case of a locally aggressive , chemotherapy - resistant immature mediastinal teratoma with a peculiar histological finding of a multilineage somatic - type malignant degeneration . a 21-year - old male patient presented with a 3-week history of persistent , blood - tinged productive cough and shortness of breath . 
 a contrast - enhanced computed tomography ( ct ) scan of the chest showed a heterogeneous mass occupying the right hemithorax and abutting on adjacent structures . 
 ct - guided biopsy was consistent with immature teratoma . 
 combination chemotherapy with bleomycin , etoposide , and cisplatin was initiated , albeit without success ; the mass showed interval progression in size , and surgical resection through clamshell incision was performed . 
 histological assessment of the resected mass confirmed the diagnosis of immature teratoma and revealed an extensive multilineage malignant differentiation into sarcomatous , carcinomatous , and melanomatous components . 
 the patient underwent an uneventful recovery but presented 2 months later with extensive liver and bone melanomatous metastases . in this report , 
 relevant findings from the literature are also highlighted . despite being exceptionally rare , 
 such tumors carry poor prognosis . understanding the clinicopathological characteristics and biological behavior of such tumors 
 may provide an insight into interventions tailored to improve the otherwise dismal disease outlook . 