Computed Tomography Imaging Features of Malignant “Triton” Tumor for Its Clinical Diagnosis: Report of Two Cases

Background: malignant triton tumors (MTTs) are an extremely rare subtype of malignant periphery nerve sheave tumors (MPNSTs). Clinical diagnosis of MTTs is dicult before surgery due to its low incidence and the lack of knowledge. Therefore, to describe and summarize the computed tomography (CT) imaging characteristics of malignant triton tumors (MTTs) is of great assistance for early and preoperative diagnosis. Case presentation: Two case reports were closely observed in our hospital, with the presumptive diagnosis of MTT by CT scan examination before surgery. The diagnosis of MTT was eventually conrmed by immunochemical (IHC) assay, which veried speculation of CT scans. Huge, irregular, well-circumscribed lobulated mass-like shadows can be observed from these patients by CT scans. Besides, heterogeneity of density within the body of tumor was well-established by CT scans, together with linear septum. Meanwhile, CT scans demonstrated that calcications were remarkable at the margin of tumor body. Conclusions: Some CT image features from two cases admitted to our hospital were presented as a reference for the preoperative diagnosis of MTTs: (i) enormity of mass-like shadow; (ii) presence of well-circumscribed lobulated shape; (iii) septum within the well-dened mass accompanied with hemorrhage, necrosis and cystic changes as well as calcication, especially within neurobromatosis type 1 (NF-1) patients.


Background
Malignant schwannomas with rhabdomyosarcomatous differentiation, originally described by Masson 1 and now designated malignant "Triton" tumors (MTTs), appear as neurogenic sarcomas with skeletal muscle differentiation in squamous epithelium, bone and possibly fat tissues. 2 MTT is an extremely rare malignant periphery nerve sheave tumors (MPNSTs), with a worldwide incidence of fewer than 200 cases reported to date. 3 Of these, 69% of MTTs have been diagnosed in young male patients with neuro bromatosis type 1 (NF-1) and 31% are sporadic cases mostly occurring in older women. [4][5] At present, treatment scenarios for MTTs include radical surgical resection, adjuvant chemotherapy and radiation, with the latter consideration as the standard protocol for MPNST or soft tissue sarcoma. [6][7] In respect of tumor location, MTTs primarily arise in head, neck and trunk regions, but also infrequently observed in lung, mediastinum, abdomen and prostate tissues, [8][9] which invariably culminates with the untimely demise of the infected individual.
Recurrence of MTT after excision is common and with a 5-year survival rate of merely 12%, prognosis remains extremely unfavorable for a icted individuals. 4,6,10 Moreover, in the absence of suitable awareness and education concerning a disease of intrinsically low incidence within the general human population, pre-surgical misdiagnoses of MTT are all to frequent. Early identi cation and analysis of the clinic pathology of MTTs is, therefore, of critical importance. The rst truly indicative criteria for a positive diagnosis of tumorigenic MTTs were derived in 1973 and include location along a peripheral nerve ganglioneuroma, Schwann cell tumor characteristics and observation of rhabdomyoblasts within the body of tumor. 11 Subsequent immunohistochemical (IHC) analyses for the skeletal muscle-speci c markers myogenin or Myo-D1 are then used as con rmation of malignancy. 9 Unfortunately, assays for the presence of rhabdomyoblasts with MTTs are prone to error being reliant upon objective separation of MTTs with sample that contain signi cant numbers of Schwann cell that negatively stain for desmin and myogenin and/or Myo-D1. 2 Such investigations are further impeded as IHC assessments are performed post-surgery, although pathological evaluation still provides a reliable tool for neurogenic tumor classi cation.
Until recently, computed tomography scanning diagnostics for MTTs were underused. As a medical imaging procedure, multiple X-ray measurements are combined into images of speci c areas within the body. This enables discernment of anatomical features to be made with high precision leading to increased accuracy of diagnosis, staging and monitoring of morphological changes in MTTs during preoperative periods. Overall, the technique is a noninvasive pre-surgical alternative for diagnosis of MTTs that ultimately allows for improvements in both palliative care and longevity of patients.

Case Presentation
The rst scenario presented pertains to a 41-year-old female whom had complaints relating to progressive deterioration in thoracic distress and shortness of breath over two months prior to hospital admission. Representative hematoxylin and eosin (H&E) staining of a postoperative biopsy are presented ( Fig. 1). A tumorous growth was clearly identi ed as a discrete mass of hyperchromatic spindle cells with indistinct cytoplasm after H&E staining. The overall architecture appeared to be either diffuse or alternate hypo-/dense-cellular regions (Fig. 1A). The tumor tissue could therefore be assigned microscopically as a malignant schwannoma of variable cellular distribution with non-homogenous rhabdomyosarcomatous features (Fig. 1B). In addition, rhabdomyoblasts with a dense eosinophilic cytoplasm and cytoplasmic cross striations were observed scattered throughout the stroma and mainly comprised of pleomorphic spindle cells (Fig. 1C). The IHC assay was positive for S-100 protein, Myo-D1 and Desmin and when combined, these ndings supported a diagnosis of MTT, comparable to previous studies. 3 Further con rmation for MTT was derived from preoperative CT imaging scans of the chest region which revealed the presence of a distinctive and large non-MPNSTs/soft tissue sarcoma mass of size 7.7 cm × 6.0 cm located within the medial basal segment of lower lobe of the right lung ( Fig. 2A). Additional imaging analyses obtained using contrast-enhanced CT scans of the thoracic region re-a rmed the presence of an irregular hemorrhagic or necrotic, well-circumscribed lobule (Fig. 2B). A low-density cyst was also evidenced by absence of mediastinal and hilar node enlargements in the surrounding region and a distinct septate demarcation within the cellular mass at the lesion periphery (Fig. 2B). The patient was not subjected to postoperative chemo or radiotherapy and after ve months appeared to have recovered su ciently with only minor refractory movement disorders, limb numbness, backache and dysuria discomfort were noted. Initially, long-term prognosis appeared to be positive, as postoperative re-examination of the chest area in CT scans revealed no recurrence of the mass-like shadow within the operative region. However, several well-de ned and differentially sized homogeneous nodules were seen as persistent within the bilateral lungs which raised concerns of MTT metastasis and possible malignancy (Fig. 2C). Thus, further investigations of patient discomfort arising from clinical symptoms were performed through MRI upon the spinal cord. In these, a homogeneous tissue mass were observed to be expanding within the vertebral index at the 4th and 5th thoracic (T4-T5) segments causing microbleeds (Fig. 2D). Rather more radical anatomical consequences of MTT metastasis within thoracic region were also noted and included severe destruction of bone tissue on the right thoracic pedicle, plate and transverse processes of the T4 and T5 segments alongside tumor invasion of adjacent ribs, pleura and soft tissues (yellow arrow in Fig. 2D). Aside these, an outward dispersal of the lesion from the spinal dura mater and uncontrolled growth within the thoracic spinal cord were also observed (red arrow in Fig. 2D). Unfortunately, these symptoms were indicative of rapid multiple distal metastasis of MTT and the patient passed away two months later.
In a second scenario, a 37-year-old male presented with a persistent lower left quadrant dull abdominal pain over two months. There was a paternal familial predisposition of NF-1 inclusive of an uncle and grandfather. CT scanning of the abdominal region revealed the presence of a heterogeneous hemorrhagic or necrotic discoid mass 10 cm × 6.3 cm in size located within the left-side abdominal cavity (Fig. 3A). Calci cations were also evidenced in CT scans occurring at the margin of the cyst. In contrast-enhanced CT scans, the cyst margin was more prominent within the patient's chest region (Fig. 3B) and similarities to the aforementioned case with the presence of a linear septum within the cellular mass were noted (white arrow, Fig. 3B). Furthermore, an irregular hypodense nodule was observed in between the T12 and the 1st lumbar (L1) vertebral canal interspersed with the left foramen intervertebral disc of the spinal cord (Fig. 3C). The lesion also resulted in signi cant compression of the adjacent vertebral bodies and adnexal bones and nodule elongation. Similar nodules also appeared posterior to the pancreas body and proximal to the right iliopsoas muscle and abdominal aortic branch (Figs. 3D and E, respectively). Originally the cyst was deemed to be a neuro broma, however, resection, additional pathological analysis and positives for Desmin, Myo-D1 and S-100 protein IHCs were more consistent with a diagnosis of MTT.
The patient was not subjected to post-excision chemotherapy and radiotherapy, although be experienced progressive dysuria for a period of ve months. Upon re-examination of the chest and abdominal regions by CT scans, multiple irregular nodules and masses within the abdominal cavity and retroperitoneal space were observed, consistent with a diagnosis of the recurrence of MTT (Fig. 4A). Once again, it was apparent that changes in cyst morphology, necrosis, hemorrhage and presence of septate lesions were, therefore, characteristics unique to MTT tumorigenesis. We noted that resurgence of tissue mass after excision was accompanied by invasion of the perirenal spaces and blockage of both ureters resulting in pelvicalyceal dilatation and hydronephrosis by enlargement of nodules in the perinephric space (yellow arrow, Fig. 4B). Tumor embolus features in bilateral iliac veins, postcava and right atrium were also observed (red arrow, Fig. 4B). In post excision contrast-enhanced CT scans of the chest area, the large, 5.2 cm × 3.2 cm well-de ned lobulate mass adjacent to the right-side pulmonary hilum (Fig. 4C) appeared to be unchanged from preoperative conditions (Figs, 3C, D and E). The patient was subsequently discharged and the case followed up with a post clinical study. The two patients had been informed consent to publish this paper.

Discussion
MTTs account for 5% among MPNSTs which display different patterns of malignancy in areas of mesenchymal differentiation. 3,12 Of these, two subcategories are further re ned according to clinical status of associated neuro bromatosis type 1 (NF-1). [13][14] To date, de nition of MTT etiology, pathogenesis and genetics is imprecise and identi cation of clinical symptoms is somewhat subjective depending upon the location, size and presence or absence of nerve compression and adjacent tissue metastasis. Prognosis for many MTT sufferers is certainly less favorable than for more classical MPNSTs especially, where a correct diagnosis must be accurately informed from familial and clinical history and knowledge of the complexities of individual MTT subtypes. Generally, a de nitive diagnosis for an MTT is based upon observations from histological staining and true positives for S-100 protein, Myo-D1 and Desmin in post-surgical IHC assays. [2][3][8][9] Clinical histories of most patients with MTT cases typically range between several months to more than ten years in all age groups. [15][16] In the two cases exempli ed in this present work, the patient ages were 37 and 41 years, respectively. In both scenarios, MTTs arose in rare locations of lung and abdomen. Interestingly, two MTT subtypes were clearly distinguishable in CT imaging analyses and while a rmation in the younger male patient was also through a familial predisposition of NF-1, this was absent within the older female.
Diagnosis of MTTs is, at best, di cult prior to surgery and recent occurrence where imaging analyses were applied for reporting of the clinical manifestations of MTTs, are scarce. [17][18] Owing to the diversity of these tumors, image features tend to be non-speci c and low in descriptive clarity. In previous studies, CT imaging analyses revealed MTTs could be identi ed by the presence of a prominent discoid shadow with a well-circumscribed lobulated morphology. In addition, MTTs were invariably of an irregular shape and of higher density at the margin of the cystic mass in comparison to the majority of MPNSTs. On occasion, MTTs presented with some high density stripe-like entities distributed throughout the mass. Unfortunately, the structural characteristics of rhabdomyosarcomas are frequently ill-de ned or generally unobserved within CT images. Although, it is plausible that some CT imaging features are masked or obscured in the presence of an abundant blood supply whereby the mass of the MTT increases rapidly and disproportionally within a short time frame or in the presence of a Schwann cell metaplasia of neural crest during a state high-malignancy. 2,19 On occasion, hemorrhage, necrosis and cystic morphological changes are observed in the lesions with a distinct high-density calci cation shadow. 20-21 Importantly, contrast-enhanced CT scans enable mild enhancement of cyst peripheral features and thus, speci city of MTT classi cation based on cyst heterogeneity and linear or annular morphology of the septal shadow.
Interestingly, some characteristics of MTTs including, hypointense mass and presence of septum-like structures on T1-and T2-weighted images were available from MRI studies as early as 2009 1 and these can be added with certainty to the repertoire of features typically observed within modern CT scans to increase accuracy for diagnosis of MTTs.

Conclusion
Accurate diagnosis to separate out MTTs from other conventional MPNSTs presents a paradox. Both present as a large soft tissue mass on image examination and conventional MPNSTs are also generally heterogeneous. Other image features in common include ill-de ned margin, intratumoral lobulation, peritumoral edema, calci cation lesions and destruction of adjacent bone tissues. For an accurate and rapid diagnosis of MTTs in the preoperative state, we have re ned CT imaging analyses to reliably allow clear distinction between speci c features from two unique clinical cases. We thereby present the rst reliable clinical references features from CT analyses for diagnosis of MTTs based upon: (1) Enormity of mass-like shadow; (2) presence of well-circumscribed lobulated shape; (3) septum within the well-de ned mass accompanied with hemorrhage, necrosis and cystic changes as well as calci cation, especially within NF-1 patients. Whilst these may not be regarded as "golden standard", they are prerequisite as indicators at an early clinical stage for the accurate diagnosis for differential MTTs.    Five months after radical mass excision, the 37-year-old male has complained of dysuria. (A) Contrastenhanced abdominal CT scan shows multiple irregular nodules and masses in abdominal cavity and retroperitoneal spaces. (B) It is observed that reappeared mass grows into the perirenal spaces and blocks ureters on both sides, which give rise to pelvicalyceal dilatation and hydronephrosis, outlined by yellow arrow. And we can see tumor embolus in bilateral iliac veins, postcava and right atrium shown by res arrow. (C) Chest CT scan demonstrates a huge well-de ned mass appears adjacent to the right-side pulmonary hilum with a mediastinal window.