Adult Primary Pineal Alveolar Rhabdomyosarcoma With FOXO1 Gene Rearrangement and OLIG2 Expression: a Case Report and the Literature Review

Introduction: Alveolar rhabdomyosarcoma (ARMS) is a common malignant soft tissue tumor in child and adolescents. When diagnosed in adults, it is an aggressive, often fatal disease. Intracranial ARMS in adults is rare, especially in the pineal region. Case presentation: A 36-year-old Chinese man presented with a 3-month history of dizziness and 1-month history of headache and unsteady walking. Magnetic resonance imaging of the brain revealed a pineal region lesion with obstructive hydrocephalus. He received ventricular-abdominal shunt and endoscopic-assisted pineal lesion resection. The tumor appears as a solid sheet-like growth of medium-sized round or oval cells with map-like necrosis and some rhabdomyoblasts. Immunohistochemical test revealed that tumor cells were diffusely positive for desmin, myogenin, MyoD1, ALK and CD56. Notably, the tumors were diffusely positive for OLIG2. Fluorescence in situ hybridization conrmed the FOXO-1 gene rearrangement. The nal diagnosis of the present case is ARMS of the pineal gland. Conclusions: We presented an extremely rare case of primary ARMS in adult pineal region particularly with expression of OLIG2 and conrmed by PAX3/7-FOXO1 fusion gene detection.


Introduction
The 2020 World Health Organization (WHO) classi cation of bone and soft tissue tumors divides rhabdomyosarcoma (RMS) into embryonic RMS (ERMS), alveolar RMS (ARMS), pleomorphic RMS, and spindle cell RMS. ARMS is charactered by alveolar growth pattern with expression of myogenic markers and speci c molecular changes including PAX3/7-FOXO1 [1] and PAX3-NCOA1/2 fusion gene [2]. Recently, some research con rmed that OLIG2 is a new speci c marker for ARMS [3,4]. ARMS primarily originating from pineal region is extremely rare. Here we present a primary ARMS of the pineal gland in an adult Chinese man with expression of OLIG2 and con rmed by FOXO1 gene rearrangement.

Case Presentation
A 36-year-old Chinese man presented with a 3-month history of dizziness and 1-month history of headache and unsteady walking. After admission, enhanced magnetic resonance imaging (MRI) of the brain revealed space-occupying lesions in the pineal region with obstructive hydrocephalus ( Figure. 1). He received ventricular-abdominal shunt immediately after admission to relieve the symptoms of acute hydrocephalus and endoscopic-assisted pineal lesion resection 14 days after. The lesion was completely removed and totally sampled for pathological observation. Hematoxylin and eosin (H&E)-stained sections showed a solid sheet-like growth of neoplastic cells accompanied by map-like necrosis, and rich in thin-walled vessels ( Figure.     No 1p/19q deletion or IDH1/2 gene ampli cation was detected, and FISH detection with the EWSR1 break-apart probe was negative. The nal diagnosis was primary alveolar rhabdomyosarcoma (ARMS) of the pineal gland. The patient received six courses of temozolomide therapy after the operation, and there was no recurrence or metastasis for 8 months after the operation which was con rmed by MRI scanning of the brain. Discussion rhabdomyosarcoma (RMS) is a relatively common malignant tumor of the soft tissue in children and adolescents. Adult RMS that originates in the brain is rare, with most of the cases occur in the cerebrum and cerebellum, and extremely rarely occur in the brain stem, ventricle, meninges, basal ganglia and pineal gland [5]. Primary RMS occurs in the adult pineal region is extremely rare and has only been reported in a few individual cases. This study summarizes recently reported adult RMSs of the pineal region, as shown in Table 1 [5][6][7][8].
The 2020 WHO classi cation of bone and soft tissue tumors divides RMS into ERMS, ARMS, pleomorphic RMS, and spindle cell RMS, of which ARMS is the second most common type, accounting for approximately 25% of all RMSs. The peak age of onset for ARMS is 10-25 years old, and there is no signi cant gender difference. It is a highly malignant soft tissue tumor with poor prognosis. The typical morphological feature of ARMS is alveolar pattern with the presence of dis-cohesive round cells arranged in nests separated by brovascular septa, accompanied by varying numbers of rhabdomyoblasts. The immunohistochemical feature of the tumor cells is a diffuse expression of myogenic markers such as desmin, myogenin, and MyoD1. The rarely seen solid-type cases, like the present case, appear as a completely solid sheet-like growth, lack of brovascular septa, and may lack of rhabdomyoblasts, which is di cult to distinguish with various small round cell malignancies. For the really di culty cases, molecular detection may assist in differential diagnosis. The most common molecular change in ARMS is the PAX3/7-FOXO1 fusion gene, which is seen in about 70% of the cases, and this type of fusion gene suggests a worse prognosis [1]. The second most common molecular change is the PAX3-NCOA1/2 fusion gene [2]. There were two previously reported cases of primary ARMS in pineal region with PAX3-NCOA1/2 fusion gene [3,4]. The present case is the rst PAX3/7-FOXO-1 related primary ARMS in pineal region. OLIG2 is a transcription factor that is required for appropriate development of motor neurons and oligodendrocytes [9]. Accordingly, immunohistochemical staining of OLIG2 is widely used in diagnosis of glial neoplasms and "neuronal neoplasms", including oligodendroglioma, astrocytoma, and ependymoma, medulloblastoma, central neurocytoma and neuroepithelial tumors. Although the tumor cells of the present case do not express GFAP, because the tumor cells diffusely express OLIG2, it was di cult for us to rule out the diagnosis of glial tumors, especially oligodendroglioma. However, subsequent molecular testing showed that there was no deletion of 1p/19q and no mutations in the IDH1/2 gene, which helped to rule out the diagnosis of glial cell tumors. Recent studies have shown that OLIG2 is not a hindrance to the diagnosis of ARMS but may be a new and speci c diagnostic marker for ARMS. Kaleta et al. [3] found that 7 of 45 cases of RMS were positive for OLIG2; it was accompanied by the PAX3/PAX7-FOXO1 fusion gene in 6 cases, and 5 cases with the morphological appearance of ARMS. Raghavan et al.
[10] also made similar observations. They studied 73 cases of rhabdomyosarcoma and found that among 28 PAX3/PAX7-FOXO1 fusion gene-positive patients, 27 were positive for OLIG2, and the average proportion of positive cells was 49%, with < 5% in only one patient. Among the 45 PAX3/7-FOXO1 fusion gene-negative cases, only three were positive for OLIG2, and the proportion of positive cells was less than 5%. These studies show that OLIG2 expression is highly correlated with PAX3/7-FOXO1 fusion gene-related ARMS, suggesting that OLIG2 can be used as a speci c marker for diagnosis and identi cation of PAX3/7-FOXO1 fusion gene-related ARMS. Similar with the above studies, our results also indicate that immunohistochemical detection of OLIG2 can serve as a surrogate marker for PAX3/7-FOXO1 fusion gene-related ARMS. In addition, there was one case of PAX3-NCOA2 fusion gene-related ARMS that occurred in the pineal gland of a 12-year-old boy, which also expressed OLIG2 [4]. The researchers speculated that because PAX3 is an important transcription factor in the development of the central nervous system, related fusion genes activate a variety of neurodevelopment-related genes, including neurodevelopment-related OLIG2, leading to the up-regulation of OLIG2 expression.

Conclusion
To summarize, we presented the rst case of primary ARMS in adult pineal region con rmed by PAX3/7-

Consent for publication
The consent for publication of images and information about the patient from his wife has been obtained.

Availability of data and materials
All data generated or analyzed during this study are included in this article and its supplementary information les.

Competing interests
The authors declare that they have no competing interests.  Figure 1 Images of enhanced MRI of the head. A: Axial contrast-enhanced T1-weighted image shows slight enhanced lesion in the pineal region. B: Axial T2-weighted image shows quasi-circular isointense lesion in the pineal region, with strip-like hyperintensities inside, but the main body is not obviously enhanced. MRI, magnetic resonance imaging