Germ cell tumors (GCTs) account for 2% of human malignancies but are the most common malignant tumors among males aged 15-35. Since 1983, an association between mediastinal GCT (MGCT) and hematologic malignancies has been recognized.

We report a case in which malignant histiocytosis was associated with mediastinal GCTs. The clinical data of a male patient with MGCT admitted to Beijing Children's Hospital were collected retrospectively. The patient was first diagnosed according to imaging and pathological features as having MGCT, and was treated with surgery and chemotherapy. One year after stopping chemotherapy, imaging showed metastases in the right supraclavicular, mediastinum, hilar region and retroperitoneal lymph node, right pleura, right lung, and right para-cardiac margin. Pathological diagnosis of the liver nodular and hilar lymph nodes included systemic juvenile xanthogranuloma and Rosai-Dorfman lesions with malignant transformation (i.e., morphological characteristics and immunophenotype of histiocytic sarcoma). Following diagnosis, the patient accepted chemotherapy with vindesine, cytarabine and dexamethasone. Positron emission tomography–computed tomography showed partial remission. The patient was followed-up for 10 mo after the diagnosis of malignant histiocytosis, and no sign of progression or relapse was observed.

Physicians should recognize the possibility of hematologic malignancies being associated with MGCT. Suitable sites should be selected for pathological examination.

Germ cell tumors (GCTs) account for 2% of human malignancies but are the most common malignant tumors in males aged 15-35. Mediastinum and retroperitoneum are the two major sites of extragonadal GCTs[1]. Since Nichols et al[2] reported an association between hematologic malignancies and mediastinal GCTs in 1985, an association between mediastinal GCTs (MGCTs) and hematologic malignancies has been recognized[3]. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy[4].

We report here a case in which malignant histiocytosis was associated with MGCTs.

According to the imaging features and pathological conclusions, the patient was diagnosed with malignant histiocytosis associated with MGCT.

The patient accepted chemotherapy regularly, undergoing a total of 14 courses with vindesine, cytarabine and dexamethasone administered as 3 mg/m² of vindesine on day 1, 150 mg/m²/d of cytarabine on days 1-5 and 6 mg/m²/d of dexamethasone on days 1-5, with one course given every 3-4 wk. Allogeneic hematopoietic stem cell transplantation (HSCT) was suggested, but his family refused for economic reasons.

The patient has been followed up for 10 mo since the diagnosis of malignant histiocytosis, and both imaging examination and testing of tumor markers have shown no signs of progression or relapse for either GCT or malignant histiocytosis.

The association between GCTs and hematologic malignancies has been described by many clinical centers. Most of these cases were seen in young males[5] and have been described only for patients with nonseminomatous MGCTs, especially for those patients having evidence of yolk sac tumor differentiation[3]. Yolk sac or embryonal cell carcinoma in combination with teratoma was particularly common[6]. The risk of developing hematologic disorders was statistically significantly increased in patients with primary nonseminomatous MGCTs in comparison with the age-matched general population[7]. The hematologic diseases associated with MGCTs include myeloid neoplasm, acute lymphoblastic leukemia, histiocytosis[8], myelodysplastic syndrome, and mast cell leukemia[8]. For those cases associated with histiocytosis, most were not identified as specific pathologies. The remaining few cases were respectively confirmed as histiocytic sarcoma and Langerhans cell histiocytosis[9]. The median time from the diagnosis of the primary MGCT to the diagnosis of the hematologic neoplasia reported in the literature ranges from 4 mo to 6 mo, and most cases were within 1 year[4,6,7,8]. Ten percent to thirty percent of patients observed presented with a simultaneous onset of both disorders in two investigations[7]. The case presented in this report was that of a 13-year-old boy, in the age group with a high incidence of GCT, with a tumor originating in the mediastinum, the component of which includes yolk sac tumor. New lesions were found after treatment, which were confirmed to be several types of histiocytosis, including Juvenile yellow granuloma, Rosai-Dorfman disease, and histiocytic sarcoma. It is worth noting that we found multiple components in the liver and mediastinum lesions of the patient, and the malignancy degrees of them are different. In a previous case report, a mediastinal tumor was finally diagnosed as a mature teratoma with two malignant components 3/4 angiosarcoma and granulocytic sarcoma[10].

Cytogenetic and molecular mechanisms of the relevance between GCTs and hematologic malignancies has been investigated in the past decades. Research findings imply that hematologic malignancy and MGCTs arise from a common progenitor cell. MGCTs, unlike gonadal and retroperitoneal GCTs, contain areas of yolk sac tumor that have a mesenchyme-like pluripotent component. These areas may be the location at which GCTs are transformed into malignancies typical of nongerminal tissues. In addition, teratocarcinoma cells have been shown to differentiate along hematopoietic lineages in vitro and to form hematopoietic tissue in mosaic mice[7]. As for the molecular mechanisms, isochromosome 12p is a cytogenetic marker in MGCT[8] and was commonly seen in MGCTs with hematologic malignancies, whereas it was never observed in de novo acute myelocytic leukemia (AML). In addition, mutations in TP53 were present in 91% of patients with MGCTs with hematologic malignancies vs 61% of patients with MGCTs lacking hematologic malignancies and in only 9% of patients with de novo AML. Activating mutations in KRAS and NRAS accounted for 63%, 37% and 13% in the three conditions above, respectively. Moreover, the reason why the association between these two diseases was obviously more common in male adolescents has not been revealed clearly.

Hematologic malignancies associated with MGCTs have to be distinguished from therapy-related secondary leukemias. Leukemias caused by alkylating agents or topoisomerase II inhibitor, are typically diagnosed 5-7 years and 2-3 years following therapy, respectively. Taking into account that the time between the onset of two diseases in our case was only 1 year, malignant histiocytosis was considered to be associated with GCT, instead of a second tumor related to treatment.

Although the relevance of these two diseases has been recognized for nearly 30 years, it has been marked by a very poor outcome, despite modern therapy for both of the cancer types[4]. These patients usually demonstrate a clinically fulminant course[5]; patients either die before treatment, do not respond to antileukemic therapy, or achieve only short remissions[7]. In the case we presented above, PET/CT showed that metastatic lesions obviously increased within 3 mo, and components of juvenile yellow granuloma, Rosai-Dorfman disease, and histiocytic sarcoma were found in the pathological examination. The prognosis of juvenile yellow granuloma and Rosai-Dorfman disease is relatively favorable[11,12]. On the other hand, the median overall survival for histiocytic sarcoma is only 6 mo and the rate of survival does not improve over time[13]. Seven cases of malignant histiocytosis associated with MGCTs available in the literature all died or were lost to follow-up within 5 mo after diagnosis of malignant histiocytosis[1,7,8]. The information above suggests a dismal outcome for our patient.

Due to the short survival time of MGCT associated with malignant histiocytosis, little experience in treatment can be acquired from the literature. Two cases diagnosed as malignant histiocytosis accepted chemotherapy based on cisplatin, bleomycin and etoposide[1], and the treatment of another one was not described[7]. Two cases with hemophagocytic lymphohistiocytosis (HLH) accepted chemotherapy aimed at HLH (no exact details)[8] and two cases with histiocytic sarcoma did not accept treatment[3]. Six of the seven patients above died, and the other was lost to follow-up. Considering that few patients benefit from HSCT, some of them were recommended to accept HSCT but none were given the opportunity, for different reasons. The case we presented did not accept HSCT, but was still in good condition on the last follow-up, 10 mo since the diagnosis of malignant histiocytosis. That may be associated with the relatively atypical and lesser components of histiocytic sarcoma, and perhaps suggests a sensitive response to vincristine and cytarabine.

Physicians who care for patients with MGCT should be aware of the possibility of associated hematologic malignancies, especially in those patients with nonseminomatous MGCT. Regular monitoring with blood routine and imaging examinations during the 1^st year of MGCT diagnosis is recommended to detect associated hematologic disorders. Multiple parts of the tumor may be involved in different stages of evolution, and clinicians should select suitable sites of sampling according to the characteristics of the patient, and take samples from multiple sites when necessary.

All of the authors would like to express their gratitude to the patient and his parents.