Malignant Triton Tumor in a Child: Case Report and Literature Review

Introduction

Malignant triton tumor (MTT) is a histological subtype of malignant peripheral nerve-sheath tumors (MPNST) that contains rhabdomyoblasts. It is an extraordinarily rare and highly malignant tumor, to date approximately 170 cases of MTT have been reported.^1–3 And, data on clinical features and optimal treatment strategies for MTT are rarely, so the tumor is associated with poor clinical outcome.⁴

The average age of patients with MTT is 31.7 years, and the morbidity rates are approximately equal among men and women. The tumor usually occurs in the head, neck, and trunk. Thus far, the lack of information on the incidence of MTT in the literature has made the tumor unfamiliar to most pediatricians and surgeons. Here, we report an unusual case of MTT in a child, and discuss the clinical features of this tumor as well as its treatment and prognosis in children.

Case Report

Patient Case

A 2-year-old girl presented with a large mass in the right shoulder, gradually increasing in size over 2 months. Upon physical examination, the patient was found to be normal. There were no signs of neurofibromatosis (NF), such as café au lait spots or subcutaneous nodules, or a family history thereof. Physical examination revealed an obvious, firm, subcutaneous, nontender, incompressible, and immobile mass measuring approximately 4.0 × 3.0 × 3.0 cm located on the medial side of the right shoulder. There was no palpable axillary lymphadenopathy. The findings of enhanced computed tomography revealed a large posterior mediastinal mass; the lesion was unevenly enhanced, and there was no clear boundary between the lesion and surrounding tissue. There was another nodular soft-tissue mass located at the tip and middle of the right lung, near the diaphragm (Figure 1A–D). A differential diagnosis of neurogenic tumor was made on the basis of imaging findings. The patient underwent a wide range of laboratory investigations, the results of which were all negative.

Figure 1 Preoperative image. (A) Axial unenhanced CT scan revealed a large posterior mediastinal mass. (B) The lesion was uneven enhanced. (C and D) There was another nodular soft tissue located in the right lung. Abbreviation: CT, computed tomography.

The patient underwent surgery for tumor resection both for alleviating the symptoms and confirming the diagnosis. During surgery, the tumor was found to be located in the supraclavicular fossa; it was solid, oval in shape, and lacked a complete capsule. However, because a part of the tumor was wrapped around a nerve, the solid mass was only partially resected.

The resected tumor was hard and light red in color, with moderate blood supply. Histological findings of multiple sections revealed spindle cells with wavy nuclei and scattered or focal large cells that were round or elongated and contained abundant and deep eosinophilic cytoplasm. A few cells exhibited cross striations, and mitotic figures were scarce (Figure 2A).

Figure 2 Immunostaining of the resected lesion. (A) Under the microscope, the tissue illustrated a remarkably uniform histological feature (hematoxylin and eosin, ×100). Immunohistochemical staining showed the tumor was strong positive for Desmin (×100) (B), Myoglobin (×100) (C), Myogenin (×100) (D), S-100 (×100) (E), and Ki-67 (×100) (F), which the Ki-67 index was 30%. The tumor was negative for other markers.

Upon immunohistochemical staining, the spindle cells showed focal positivity for S-100 protein, while the large cells were positive for vimentin, myoglobin, and myogenin, with a Ki-67 proliferation index of 30%. Both cell types showed negative staining for glial fibrillary acidic protein, neuron-specific enolase, cytokeratin, epithelial membrane antigen, alpha-fetoprotein, CD30, SM-actin, and CD34 (Figure 2B–F). Therefore, on the basis of existing evidence and diagnostic criteria, a diagnosis of malignant peripheral nerve-sheath tumor with rhabdomyoblastic differentiation, i.e., MTT-was made. The diagnosis of MTT was mainly based on the histopathological and immunohistochemical characteristics of the tumor.

Although it is a highly malignant tumor, there is no standardized chemotherapy strategy for MTT currently. Therefore, we used the generally accepted multiagent MTT chemotherapy regimen, including vincristine, actinomycin, and cyclophosphamide, for treatment in the present case. The patient tolerated chemotherapy well. Although radiotherapy was also considered, her parents did not consent to it. Therefore, the patient was recommended continued chemotherapy. However, the patient died 14 months after surgery.

Ethical Requirements

This study protocol was approved by the Ethical Committee of the Zhengzhou University. Written informed consents were collected from all participants involved in the study. The patient’s parents or legal guardians provided written informed consent for the case details and images to be published.

Review of the Literature

We searched the PubMed, Medline, Embase and Web of Science databases for relevant articles published between 1938 and 2017, using the following terms: “triton tumor”, “rhabdomyosarcoma”, and “malignant peripheral nerve sheath tumor”. There was no exclusion for languages, details regarding patient characteristics was extracted from the articles. According to existing reports, Kaplan–Meier analysis was used and the log rank test was performed for comparison. The chi-square test was used to determine statistical significance, with P<0.05 being considered statistically significant. All statistical analyses were performed using the SPSS statistical software.

Result

Only 42 eligible cases of MTT in children (birth to 18 years; mean age, 8.3 years) were retrieved from available data, details regarding patient characteristics are summarized in Table 1.^4–19 Among these 42 cases of MTT, the highest frequency of occurrence was in 12–16 years, and the male-to-female ratio was 1.7:1.

Table 1 Characteristics, Treatment, and Outcome of Pediatric Patients with MTT

The treatment protocols were varied, and some patients received more than one type of therapy. Although there were 42 reported cases of MTT in children, only 33 (including the present report) provided complete treatment details (Table 1). In these 33 cases, 11 patients received treatment by surgery alone; 2 received both surgery and chemotherapy; 4 received both surgery and radiation therapy; 14 received surgery, chemotherapy, and radiation therapy; 1 case received chemotherapy and radiation therapy; and 1 received supportive care only.

In the 33 cases that provided data on prognosis, the average OS and 5-year OS probability were 23.9 months (range, 0.3–156 months) and 27.5 ± 4.3%, respectively (Figure 3A). Postoperative radiotherapy had been administered in 16 cases, patients who received radiotherapy most often received radiation doses of 40–60 Gy. Furthermore, there was a significant difference in survival between patients whose treatment protocols did and did not include radiation therapy (P =0.001, Figure 3B).

Figure 3 KaplanMeier survival analysis of the available data. (A) Overall survival. (B) Comparison of survival for patients who received radiation versus no radiation, p=0.001. (C) Comparison of survival for patients who received chemotherapy versus no chemotherapy, p=0.012. (D) Comparison of survival for patients who received operation only versus postoperative adjuvant therapy, p=0.004.

Patients described in these studies were often treated with postoperative chemotherapy alone or in combination with radiotherapy. Postoperative chemotherapy had been administered in 15 cases, and the chemotherapy regimens varied but often included V, ACT, C, ADR, IFO, etc. There was a statistically significant association between treatment protocols that did and did not include chemotherapy (P=0.012, Figure 3C).

Patients in these studies often received treatment by surgery alone or in combination with postoperative adjuvant therapy (including chemotherapy and/or radiation therapy). In eight cases, postoperative first-line treatment involved surgery. One of the patients, who had received postoperative chemotherapy and radiation therapy, was still alive 13 years after treatment.¹⁹ Patients who received postoperative chemotherapy and/or radiation therapy had a significant association with prognosis than those who received treatment by surgery alone (P =0.004, Figure 3D).

Discussion

Malignant triton tumor is a subgroup of MPNSTs which have been reported to exhibit rhabdomyosarcomatous differentiation and follow a particularly aggressive disease course. The diagnosis of MTT was mainly based on the histopathological and immunohistochemical characteristics of the tumor. It exhibits the growth characteristics of Schwann cells; rhabdomyoblasts can be demonstrated within the peripheral nerve tumor, but they do not originate from extension or metastasis of an extrinsic rhabdomyosarcoma.¹⁹ Daimaru et al⁶ later broadened the definition of MTT: 1) Tumors without NF-1 that are microscopically compatible with a malignant schwannoma and contain focal rhabdomyoblasts and 2) tumors consisting predominantly of rhabdomyoblastic differentiation with focal Schwann cell elements occurring within a nerve or in patients with NF-1. However, the cell type of origin of MTT remains unclear. Immunohistochemical staining helps demonstrate the origin of cells. There is a consensus that MTT can be diagnosed on the basis of morphological findings, supported by positive staining results for S-100 protein.¹⁶

Including the present case, only 42 such cases of MTT in children have been reported (Table 1). In this study, we have reported a case of MTT in a 2-year-old girl and reviewed the relevant literature. Comparison of clinical data among relevant studies is possible only to a limited degree, because MTT is a very rare tumor and has been reported either in single case reports, frequently with no or only scant data on treatment and follow-up, or as part of larger reports on MPNSTs. Moreover, the outcomes are not usually elaborated upon separately.

As the rarity of this entity and the lack of prospective trials, there is no standard treatment regimen for this rare tumor. The more popular treatments include radical excision only, radical excision followed by postoperative irradiation and chemotherapy, and excision in conjunction with radiotherapy. Data collected in the present literature review demonstrate that patients in previous reports received various types of therapy and had varying prognoses. We also found that postoperative radiotherapy, chemotherapy, and combined chemotherapy and radiotherapy could improve survival (Figure 3B–D).

Analysis of published reports on MTT revealed a trend towards better outcomes among patients undergoing complete tumor resection. Some authors have reported that complete tumor resection with or without adjuvant therapy tends to portend better survival than incomplete resection with or without adjuvant therapy.⁴ One of the patients, who had received postoperative chemotherapy and radiation therapy, was still alive 13 years after treatment.

The Oncology Consensus Group recommends postoperative radiotherapy as part of a uniform treatment policy for MTT. For patients who received radiotherapy for MTT in previous studies, the radiation doses varied considerably but were mostly between 40 and 60 Gy, depending on the clinical context.^3,12,15 It is worth noting that radiotherapy, as a part of primary treatment for MTT, seemed to have a positive effect on survival (P=0.001, Figure 3B).

The value of chemotherapy for MTT remains questionable since published accounts of clinical experience are limited. Proposed chemotherapy regimens include CEI (cisplatin, etoposide, and ifosfamide) as first-line treatment and IA (ifosfamide and adriamycin) or MDID (mesna, doxorubicin, ifosfamide, and dacarbazine) as second-line treatment. In studies included in the present review, we also found a statistically significant association between treatment included chemotherapy and treatment did not include chemotherapy (P=0.012, Figure 3C). Thus, neoadjuvant chemotherapy potentially plays an important role in a multimodal treatment approach for a subset of patients with high-grade, metastatic, primarily unresectable MTT.⁵

Conclusions

Children with MTT have extremely poor prognosis, and optimal treatment strategies have yet to be established. When possible, complete tumor resection with adjuvant radiotherapy and/or chemotherapy should be recommended. We believe that the present findings will help attain a greater understanding of this rare tumor, but this study is limited due to the small sample size. Further research is required on the clinical behavior, tumor biology, and potential prognostic factors of MTT. Additionally, effective risk-adapted treatment recommendations and optimization of the balance between treatment intensity and adverse effects are needed.