Primitive myxoid mesenchymal tumor of infancy in scrotum: A case report and literature review

Background Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare tumor and its molecular mechanism and prognosis remain unclear. We here report a case of PMMTI, and review the reported literature of PMMTI. A one-year-old boy found a lump in his right groin. The size of the mass was 1 cm×1 cm. Computed tomography showed a round, slightly dense shadow of 38 mm×32 mm in the right groin. The tumor was removed for pathological examination, and the size of the tumor was 6.0 cm×5.0 cm×3.0 cm. Tumor cells are diffusely distributed, mainly spindle cells. The blood vessels were abundant, many adipocytes can be observed in some areas, and focal lymphocyte inltration can be seen in a few areas. Immunophenotype was as follows: histone H3 at lysine 27 (H3K27me3), B-cell lymphoma 6 corepressor (BCOR) and Bcl-2 were positive, cluster of differentiation 99 (CD99) showed diffuse reactivity, BCL6 was scattered positive, Ki-67 proliferation index was 20%. Dual-color uorescence in situ hybridization (FISH) showed red and green signal nuclei caused by the deletion of ETV6 gene rearrangement. The patient underwent extensive surgical resection during the recurrence period and was in good condition 7 months later. at least low-grade malignancy. BCOR, BCL2, BCL6, and CD99 can be used as special IHC markers, and most PMMTI cases exhibit BCOR ITD change. H3K27me3 may be used as a new IHC marker for PMMTI. infants and young children. The different tumors occurring in infancy are congenital-infantile brosarcoma (CIFS), embryonal rhabdomyosarcoma (ERMS), clear cell sarcoma of kidney (CCSK), Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET), and infantile soft tissue undifferentiated round cell sarcoma (ISTURCS). In this study, we presented a case of an infant with well-dened PMMTI in the scrotum. This is the rst reported case of PMMTI occurring in the scrotum. We rst reported that the H3K27me3 is positive in PMMTI through immunohistochemical (IHC) staining. We summarized the clinical characteristics of all cases and analyzed the differential diagnosis of tumors, IHC characteristics, and molecular genetic changes to provide pathologists with several clinical, IHC, and molecular references in the diagnosis and differential diagnosis of tumors.


Introduction
Primitive myxoid mesenchymal tumor of infancy (PMMTI) was rst described as a primitive mesenchymal soft tissue sarcoma without distinctive lineage of differentiation by Allagio et al [1]. To date, less than 40 cases have been reported worldwide. In this study, we presented a case of an infant with well-de ned PMMTI in the scrotum. This is the rst reported case of PMMTI occurring in the scrotum. We rst reported that the H3K27me3 is positive in PMMTI through immunohistochemical (IHC) staining. We summarized the clinical characteristics of all cases and analyzed the differential diagnosis of tumors, IHC characteristics, and molecular genetic changes to provide pathologists with several clinical, IHC, and molecular references in the diagnosis and differential diagnosis of tumors.

Case Presentation
A 1-year-old boy with a large mass in the right scrotum was used as the case study. The patient's parents reported that a mass was found in the right groin 3 months ago. The mass size was 1 cm × 1 cm. Computed tomography examination showed a 38 mm × 32 mm round-like slightly dense shadow located in the right groin. Compared with the surrounding tissues, the lesion had slightly heterogeneous density (Fig. 1a), and no evidence of distant metastasis was found. The mass was removed for pathologic examination.
After 1 month, a nodule was found at the previous operation site (Fig. 1b). Extended surgical resection was then performed for pathologic examination. After 7 months, everything was normal.
The macroscopic dimensions of the primary and secondary tumors were 6.0 cm × 5.0 cm × 3.0 cm and 5.0 cm × 4.0 cm × 2.0 cm, respectively, and were partially encapsulated. The two tumors removed had gray-white color and soft myxoid. The tumor cells had relatively uniform morphology and consisted of primitive mesenchymal cells in a myxoid background at the microscopic level. At lowpower magni cation, the tumor cells were diffusely distributed and were mainly spindle cells (Fig. 2a). Blood vessels were abundant ( Fig. 2b), and many fat cells were observed in some areas (Fig. 2c). In ltration of focal lymphocytes was found in few areas (Fig. 2d).
High-power microscopic examination showed that the tumor cells had unclear boundaries, fat and spindle-shaped nuclei, homogeneous chromatin, occasional nucleoli, variable amounts of pale eosinophilic to clear vacuolated cytoplasm, and ssure-like blood vessels (Fig. 2e). The morphology of the recurrent tumor was similar to the rst one (Fig. 2f).

Literature Review
Literature We collected literature in the GeenMedical, PubMed, Web of Science, and Google Scholar databases regarding PMMTI. The search term used was "primitive myxoid mesenchymal tumor of infancy" OR "primitive myxoid mesenchymal tumor." We downloaded and read the paper for identi cation when its title or abstract contains the search term. A total of 36 cases, including our case, were reported from 2006 to 2019 and collected for analysis. One article examined the expression of Pan-TRK in 210 tumors, including 10 PMMTI cases, and only brie y summarized the clinical information [2]. Other available data regarding clinical characteristics and prognosis are summarized in Table 1.
The disease mostly occurred among people with age less than 1 year. In the 36 cases, 29 and 7 cases were less (79.5%) and more than 1 year old, respectively. The oldest patient was 4 years old. 17 cases were male, and 18 cases were female. The gender of one patient was unknown. The incidence approximately had equal men and women ( Table 2).
In the 36 cases, only one case had unknown tumor site. The best sites for the tumors were the torso and limbs, and 11 cases were found, accounting for 31.4%, followed by paraspinal with 8 cases, accounting for 22.9%. Eight cases were found in head and neck (22.9%). Six cases were reported in the abdominal cavity (15.8%). One neoplasm with multiple neonates and one in the scrotum were reported.
In the 26 cases, the tumor sizes ranged from 0.9 cm to 15 cm. 14 cases of tumors were larger than 5 cm, accounting for 53.9% and 12 cases of tumors were less than or equal to 5 cm, accounting for 46.1%. In the 36 cases, 19 patients had follow-up visits. 18 patients had relapsed or metastasized tumors. Recurrence or metastasis rate reached 56%. The tumors of three patients were incompletely removed because of their adhesion to the surrounding tissues or multiple tumors. Five patients (19.2%) died.

Discussion
Since the rst report in 2006, the number of PMMTI cases has not exceeded 40. The biological behavior of PMMTI remains unclear. PMMTI develops in newborns or infants aged less than 1 year. In the 36 cases, 29 cases were less than 1 year old. The oldest patient was 4 years old. 17 cases were male, and 18 cases were female. The incidence had approximately equal men and women. The tumor was mainly located in the torso and limbs, paraspinal, head and neck, and abdominal cavity. In the 29 cases, the tumor sizes ranged from 0.9 cm to 15 cm. 14 tumor cases were larger than 5 cm, accounting for 54%. 12 tumor cases were less than or equal to 5 cm, accounting for 46%. Fourteen out of 26 patients had relapsed or metastasized tumor. Recurrence or metastasis rate reached 56%. The tumors of three patients were incompletely removed because of their adhesion to surrounding tissues. Five patients died (19.2%).
During gross examination, the tumor principally presented as unencapsulated and frequently exhibited focal in ltration. The cut surface usually showed gray-white myxoid. The tumor cells had relatively uniform morphology and consisted of primitive mesenchymal cells in a myxoid background at the microscopic level. The tumor cells were diffusely distributed and were mainly spindle cells. We occasionally found many fat cells and in ltration of focal lymphocytes. The tumor cells had unclear boundaries, fat and spindle-shaped nuclei, homogeneous chromatin, occasional nucleoli, and variable amounts of pale eosinophilic to clear vacuolated cytoplasm.
PMMTI diagnosis was based on morphologic features. Therefore, it should be distinguished from other tumors that occur in infants and young children. Tumors that frequently need to be identi ed include CIFS, CCSK, ERMS, EWS/PNET, and ISTURCS. CIFS is a pediatric spindle cell tumor of the soft tissues, and the majority of age is before 2 years. CIFS histologically displays sheets of spindle cells, and its myxoid areas are less than those in PMMTI. Molecular and cytogenetic studies have shown that t (12,15) with ETV6-NTRK3 gene fusion occurs in CIFS [21], but is absent in PMMTI. Bourgeois et al. studied a large series of childhood pediatric spindle cell lesions for ETV6-NTRK3 gene fusions, including 11 cases of CIFS, 13 adult-type brosarcoma, and 38 benign spindle cell tumors (including infantile bromatosis and myo bromatosis). Ten out of 11 cases of CIFS showed the ETV6-NTRK3 gene fusion, whereas none of the 51 other tumors demonstrated this gene fusion [22].
CCSK is an aggressive primary pediatric renal tumor, and the age of occurrence frequently ranges from 2 years to 3 years [23]. CCSK show strong and diffused nuclear BCOR immunoreactivity [13]. BCL6 and BCOR proteins demonstrated diffused nuclear positivity in more than 90% of tumor cells in all ve PMMTI cases, whereas they were negative in all CIFS cases [17]. BCL6 is a molecular target of BCOR and is used as a con rmatory marker [27]. Therefore, the expression levels of BCOR and BCL6 observed in PMMTI can serve as a useful marker. showed that the incidence of complete H3K27me3 loss is substantial in high-grade MPNST and is low in MPNST-mimics [34]. In this case study, we found that the diffused nuclear expression of H3K27me3 may indicate improved prognosis for patients. This study is the rst to investigate H3K27me3 expression in PMMTI.
ISTURCS is usually an exclusionary diagnosis, and its morphology occasionally overlaps with PMMTI and CCSK. However, several differences are found in IHC and molecular genetics.

Conclusion
We reported a rare case of PMMTI in the scrotum and reviewed all reported PMMTI cases. We found that PMMTI mainly occurs in young children aged less than 1 year, and the ratio of male to female is similar. The main tumor sites are the torso and limbs, followed by paraspinal, head, and neck. Recurrence or metastasis rate reaches 57.7%. The mortality rate is 19%. PMMTI is at least a low-grade malignancy. BCOR, BCL2, BCL6, and CD99 can be used as special IHC markers, and most PMMTI cases exhibit BCOR ITD change (Table   3). H3K27me3 may be used as a new IHC marker for PMMTI.

Informed consent statement
Informed consent was obtained from the patient.

Con ict-of-interest statement
The authors declare that there is no con ict of interest related to this report. Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor in-Chief of this journal.

Declaration of Competing Interest
Authors have declared that no competing interests exist. This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors.     Figure 1 Imaging ndings of the patient. CT scan reveals an abnormal lamellar density mass of 4 cm×3cm and 4 cm × 2 cm (arrow) in the right groin for the rst occurrence (a) and recurrence (b), respectively.