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[5–8]. The 2020 WHO classification 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 significant 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 fibrovascular 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 fibrovascular septa, and may lack of rhabdomyoblasts, which is difficult to distinguish with various small round cell malignancies. For the really difficulty 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 first PAX3/7-FOXO-1 related primary ARMS in pineal region.
Table 1
Summary of the clinical and pathological features of reported primary pineal RMS in adults.
Case
|
Age
|
Sex
|
Morphology
|
IHC
|
Fusion gene
|
Tumor type
|
Post-op
treatment
|
Post-op
|
Survival
(months)
|
Laul (2015)
|
33
|
F
|
solid sheet-like;
loose round cells with rhabdomyoblasts
|
Desmin, Myogenin
MyoD1
|
None-done
|
RMS with alveolar
morphology
|
Chemotherapy
|
Intra-cranial failure
|
5, D
|
Scull (2016)
|
43
|
F
|
solid sheet-like;
spindle cells with rhabdomyoblasts
|
Desmin, Myogenin
MSA
|
None-done
|
RMS
|
none
|
Rapid local recurrence
|
4, D
|
Jour (2019)
|
22
|
F
|
solid sheet-like;
spindle and round cells,
no rhabdomyoblasts
|
Desmin, Myogenin
|
PAX3-NCOA2
|
ARMS
|
none
|
Recurrence with spinal metastasis
|
14, D
|
Pandey (2020)
|
44
|
M
|
Solid sheet-like;
round cells
|
Desmin, Myogenin
|
None-done
|
RMS
|
Chemotherapy +
Radiation
|
Rapid local recurrence
|
6, D
|
Present case
|
36
|
M
|
Solid sheet-like;
adhesive round cells with rhabdomyoblasts;
focal spindle cells;
some with clear cytoplasm
|
Desmin, Myogenin
MyoD1,
OLIG2
ALK
|
PAX3/PXA7-
FOXO1
|
ARMS
|
Chemotherapy
|
No recurrence
|
8, A
|
IHC: immunohistochemistry; RMS: rhabdomyosarcoma; ARMS: alveolar rhabdomyosarcoma; MSA: muscle-specific actin; D = dead; A = alive |
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 difficult 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 specific 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 specific marker for diagnosis and identification 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.