Clinical Features, Treatment, and Outcome of Tumor Lysis Syndrome in Germ Cell Tumors

Background: Tumor lysis syndrome (TLS) is an oncologic emergency that can occur spontaneously or triggered by cancer treatment. This life-threatening condition is most commonly seen in hematologic cancers but is sometimes described in solid tumors such as germ cell tumors (GCTs). The objective of this study is to investigate the clinical characteristics and outcomes of TLS in GCTs. Methods: Retrospective review and pooled analysis. Result: Seventeen cases of TLS related to GCTs were identified. These included nonseminomatous GCT (7), seminoma (5), choriocarcinoma (2), ovarian (2), and intracranial germinoma (1). Nine cases (53%) of TLS were treatment-related and eight cases (47%) occurred spontaneously. The median age of patients was 34 years (range: 13-58), excluding one newborn baby. The median time from treatment to TLS was 2.1 days. Seven patients (41%) had liver metastases, but all patients had bulky disease. All of the patients received supportive measures; 4 (24%) patients received rasburicase and 11 patients (64%) underwent hemodialysis. The mortality rate was 44.4% among the nine cases of treatment-related TLS. The mortality rate was 37.5% in the eight patients with spontaneous TLS (STLS). Conclusion: TLS can occur in GCTs that have a high tumor burden. Almost 50% of TLS in GCTs happened spontaneously. Considering the life-threatening nature of TLS in GCTs, health professionals should be alert and monitor for TLS in order to prevent or treat this potentially fatal complication.


Introduction
Tumor lysis syndrome (TLS) is an oncologic emergency in which tumor cells are lysed, either spontaneously or in response to treatment, releasing their intracellular contents and resulting in metabolic disturbances like hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. TLS is most commonly seen in rapidly proliferating tumors like hematologic malignancies.
Massive cell death due to chemotherapy and the subsequent rapid release of cytokines potentially contribute to multi-organ failure [1][2][3][4][5]. It is crucial for clinicians to be aware of TLS and to prevent, detect and treat TLS early to prevent life-threatening complications.
While cancers are generally seen as diseases of the elderly, germ cell tumors (GCTs) typically affect men between the ages of 18 and 40.

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gonads; ∼5% of GCTs develop at extragonadal locations along the midline of the body [6,7]. GCTs are highly proliferative and sensitive to chemotherapy. Even in patients with metastatic disease, cure rates of 80% can be achieved with multi-agent, cisplatin (CDDP)based combination chemotherapy [7]. As germ-cell tumors are among the fastest growing solid tumors [8] and show an exquisite response to combination chemotherapy, it is not surprising that GCTs are among the few types of solid tumor that have high risk of TLS. TLS has been noted particularly in patients with bulky disease and highly elevated tumor markers, sometimes showing a fatal outcome [9,10]. Currently, there is limited information on the incidence, clinical presentation and outcome of TLS in GCTs.
The objective of this case series was to analyze the published case studies on the clinical characteristics, management and results of TLS in patients diagnosed with GCTs.

Data Collection and Statistical Analysis
Information regarding the patient (patient age at diagnosis, presentation and comorbidities), the tumor (symptoms, histology), tumor markers (serum alpha fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase), treatment modalities (chemotherapy), treatment response and outcomes (survival, death) were recorded, when available. Descriptive statistics, such as frequency counts, medians, and ranges, were used to characterize the pooled sample.  Table 1. The median age of patients was 34 years (range: 13-58), excluding the one newborn baby. Male to female ratio was 12:5. The majority of cases were nonseminomatous GCT (7), followed by seminoma (5), choriocarcinoma (2), ovarian (2), and intracranial germinoma (1). Nine cases (53%) were associated with chemotherapy treatment and 8 cases (47%) had STLS. Seven patients (41%) had extensive liver metastases, but all patients had bulky disease. The median time from treatment to TLS was 2.1 days.

Results
All of the patients had elevated LDH, uric acid, creatinine, potassium, and phosphorous. Each of these cases received supportive measures; 4 (24%) patients received rasburicase and 11 patients (64%) underwent hemodialysis. The mortality rate for the entire cohort was 41.1%. The mortality rate for patients with and without liver metastases were 57.1% and 30%, respectively. The mortality rate was 44.4% among nine cases of treatment-related TLS, with a median survival from diagnosis of TLS to death of 14 days (1-34).
The mortality rate was 37.5% in the eight patients with STLS. GCTs are highly curable and even a majority of patients with metastatic GCTs may expect to be cured [7]. The high cure rates of GCTS are due to their high sensitivity to chemotherapy, which was thought to be related to several factors. Tp53 alteration, a frequent finding in cancers in general, has implications for chemotherapy resistance and is not commonly seen in GCTs [23]. A recent study demonstrated another key to chemo-sensitivity of GCTs appears to lie in their stem cells, which are more sensitive to chemotherapy than stem cells in non-GCT cancers [24]. In Table 2

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Our case series highlights a rare but potential life-threatening oncological emergency of GCTs. As there will never be randomized trials elucidating the optimal management of TLS, our findings underscore the importance of real-world data to provide a better understanding of the prevention and treatment of this complication. It is our hope that the information presented here can raise awareness among community physicians to the detection and management of TLS in GCTs. Since all fatal TLS occurred during first cycle chemotherapy, a dose modification of first cycle of chemotherapy can be considered in the high risks of TLS. However, the optimal management of TLS will require a better understanding of the underlying pathophysiology of the lethal form of TLS.

Conclusion
Our current case series consists of the largest reported cohort of TLS in GCTs. Our study provides the most current information regarding the clinical features and outcome of TLS in GCTs. There is an urgent need for better understanding of lethal TLS and for the development of optimal multidisciplinary management strategies for this rare, but potentially fatal oncologic emergency.