Primitive myxoid mesenchymal tumor of infancy, an enigmatic entity: A case report

Abstract

Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare soft tissue neoplasm of intermediate malignant potential occurring predominantly in infants and younger children. It can show aggressive local infiltration of surrounding structures and frequent relapses but rare metastasis. Morphologically, it is characterized by a proliferation of immature mesenchymal cells in a myxoid background with mild cytologic atypia and branching vessels. The tumor cells demonstrate immunoreactivity with vimentin and BCOR, however, are negative for more specific lineage markers. Its molecular hallmark is BCOR-internal tandem duplication. Previously classified as infantile fibrosarcoma/undifferentiated sarcoma, the association with BCOR-ITD has led to its reclassification as part of a distinct entity—”Sarcoma with BCOR Genetic Alterations”—in the 2020 WHO Classification of Soft Tissue Tumours. Here is a report of a case of a 2-year-old boy with a recurrent scalp mass identified as a primitive myxoid mesenchymal tumor of infancy.

INTRODUCTION

Primitive myxoid mesenchymal tumor of infancy (PMMTI) represents an entity in the spectrum of fibroblastic–myofibroblastic lesions with at least intermediate/low-grade malignant biologic potential.^[1] It is a tumor of infancy and childhood characterized by a primitive morphology, myxoid background, negativity of lineage markers, absence of the ETV6:NTRK3 gene fusion, locally aggressive clinical course, and poor chemosensitivity.^[1,2] Its clinical course is variable; most cases demonstrate a tendency to relapse; however, its metastatic potential is low.^[1,3] Its molecular hallmark is BCL6 corepressor gene (BCOR)-internal tandem duplication (ITD).^[3,4]

It is a very rare tumor with <40 cases described in the literature.

CASE REPORT

A 2-year-old male child presented with a recurrent swelling over temporal region of scalp. CT scan showed predominantly cystic lesion measuring 47 × 27 mm in scalp superficial to right temporal bone [Figure 1]. No gross details were available as it was a review case. Histopathological examination [Figure 2] revealed fibrocollagenous tissue exhibiting a moderately cellular tumor composed of cells arranged in diffuse pattern in a myxoid stroma. The cells were ovoid to spindled with scant to moderate vacuolated cytoplasm, fine chromatin, and inconspicuous nucleoli. Microcystic areas were evident. Numerous branched and dilated vessels were seen with areas of ischemic necrosis at the periphery of tumor. The tumor was seen to infiltrate into the bony fragments. Mitotic activity was 4-5/10 HPF. On immunohistochemistry [Figure 3], the tumor cells were positive for vimentin (strong), cyclin D1 (strong), SATB2 (strong), CD99 (strong), Bcl 6 (weak), Bcl 2 (weak), CD10 (patchy), BCOR (strong), TLE-1 (strong), and H3K27ME3 (strong), whereas tumor cells were negative for other lineage markers. The P53 expression was strong diffuse (mutant type). Ki-67 index was approximately 20%.

Figure 1: CT scan image shows predominantly cystic lesion measuring 47 × 27 mm in scalp superficial to right temporal bone

Figure 2: (a) The lobulated appearance and prominent vascularity of tumor is highlighted (H and E stain; magnification 100X) (b) The central hypo and peripheral hypercellular pattern and monotonicity of cells is highlighted (H and E stain; magnification 200X) (c) Microcystic areas are evident (H and E stain; magnification 200X) (d) ovoid to spindled tumor cells arranged in a myxoid stroma is seen (H and E stain; magnification 400X)

Figure 3: The tumor cells are immunoreactive for vimentin, CD99, BCOR, cyclin D1, Bcl2, Bcl6, CD10, TLE1, SAT B2, p53, Ki67 index 20%, CD34 highlights vessels

A final diagnosis of primitive myxoid mesenchymal tumor of infancy was rendered with advice for study of BCOR-ITD. Due to lack of adequate funds, molecular testing was not carried out. Since it is an already relapsed case, completion surgery followed by chemotherapy (ifosfamide–doxorubicin plus vincristine–cyclophosphamide–topotecan regimen) was provided. It has been 8 months since diagnosis and patient is doing well with no further relapses.

DISCUSSION

The most common paediatric sarcomas are embryonic rhabdomyosarcoma, Ewing sarcoma, congenital infantile fibrosarcoma, and undifferentiated sarcoma.^[2] Owing to a similar morphology and age profile, it was earlier thought that PMMTI belonged to the family of congenital infantile fibrosarcoma or infantile fibromatosis.^[1] However, with the advancement of molecular genetics, it was discovered that PMMTI lacks the characteristic molecular signature of congenital infantile fibrosarcoma–ETV6:NTKR3 gene fusion.^[1] It rather shares similarities with the newly described entity of “Sarcomas with BCOR genetic alterations.”^[5]

PMMTI predominantly affects infants (mean age 6.6 months) with few cases described in older children.^[2,3] No gender predilection is seen.^[3] The most common sites of involvement include deep soft tissues of trunk, extremities, head, and neck.^[2,3,5]

Grossly, most of the tumors are unencapsulated and have a multinodular appearance with focal infiltrative growth.^[1] The spectrum of tumors with BCOR-ITD abnormalities shows variable degrees of cellularity ranging from solid sheets of small primitive cells to hypocellular areas of dispersed spindle cells, within a myxoid stroma.^[5] The tumor cells display a vaguely nodularity with a peripheral collagenized and centrally cellular stroma with a delicate vascular network^[1] Tumor cells have uniform nuclei with fine chromatin and inconspicuous nucleoli with an average mitotic rate of 4.1 mitoses (range: 1 to 20 mitoses) per 10 HPF.^[3] Microcystic spaces lined by tumor cells have been described.^[6] Electron microscopy demonstrates a poorly differentiated fibroblastic phenotype.^[1]

The tumor cells immunoreact with vimentin and may express smooth muscle actin.^[6] They usually demonstrate strong and diffuse nuclear BCOR and BCL6 positivity and may also express SATB2, TLE1, cyclin D1, FLI1, TLE1, BCL2, and CD 10.^[5,8,10] They are also seen to often express CD99, CD117, and nestin, which may highlight the primitive nature of the tumor and may serve as ancillary markers for differential diagnosis from the other infantile tumors.^[7] H3K27me3 is another new IHC marker for PMMTI.^[9] Other specific markers for myogenic, neural, and epithelial lineage are negative in PMMTI.^[6]

BCOR-ITD was identified as a molecular driver that underlies most PMMTIs. BCOR gene is a part of the non-canonical polycomb repressive complex 1.1 (PRC1.1). It is hypothesized that BCOR-ITD results in disruption of the complex leading to the depression of target promotors and consequent oncogenic effects. The BCOR gene encodes a protein that selectively interacts with BCL6 as a corepressor.^[4] Hence, BCOR can be a useful if not perfect immunostain that equates to a sarcoma with BCOR genetic alteration.

The differential diagnosis of PMMTI includes congenital infantile fibrosarcoma, infantile fibromatosis, low-grade fibromyxoid sarcoma, lipoblastoma/myxoid liposarcoma, and monophasic synovial sarcoma. Congenital IFS can be excluded on the basis of the absence of (12; 15) (p13; q25) translocation in PMMTI.^[1] The diffuse mesenchymal type of infantile fibromatosis resembles PMMTI but varies from it in showing interspersed adipose cells, peripheral lymphocytes, higher cellularity, greater mitotic activity, and the presence of beta-catenin (CTNNB1) gene mutation.^[1] Low-grade fibromyxoid sarcoma is another close mimic of PMMTI, but it shows MUC4 positivity and a specific translocation t (7; 16) (q32-34; p11) translocation.^[1] The presence of vacuolated cells in PMMTI might raise a possibility of lipoblastoma or myxoid liposarcoma, but the absence of definitive lipoblasts and S-100 protein reactivity is useful for differential diagnosis.^[1] Synovial sarcoma is another entity, which needs to be excluded, as a subset of synovial sarcoma may be BCOR positive and most cases of synovial sarcoma are TLE1 positive.^[11] However, negativity for CK, EMA, and SS18-SSX along with the comparatively hypocellular pattern with a low proliferation index in contrast to a very uniformly cellular monomorphic appearance and a high proliferation index in synovial sarcoma helps to conclusively exclude it.

Since PMMTI is a rare tumor, consensus treatment protocols are lacking.^[3] Complete surgical excision was the most common and best modality of treatment in most cases described in literature.^[3] Radiotherapy has failed to produce desirable results and is associated with significant morbidity so is less commonly prescribed.^[6] The understanding of BCOR alteration as tumor driver might facilitate targeted therapy for better outcomes.^[6]

PMMTI is characterized by a long clinical course with frequent relapses. Recurrences were often associated with incomplete initial excision of the lesion with microscopic involvement of margins.^[1] Transformation to undifferentiated sarcoma can be a rare occurrence.^[3] Literature review revealed only three cases exhibiting metastasis.^[3]

In conclusion, PMMTI is a rare mesenchymal tumor of early childhood characterized by aggressive local infiltration of surrounding structures, rare metastases, and poor response to chemotherapy. Previously classified variably as infantile fibrosarcoma/undifferentiated sarcoma, the association with BCOR-ITD has led to its reclassification as part of a distinct nosological entity—”Sarcoma with BCOR Genetic Alterations”—in the 2020 WHO Classification of Soft Tissue Tumours. Owing to its rarity, treatment protocols are yet to be standardized, but its association with targetable BCOR alterations offers promise of cure as they are potentially targetable by drugs. This can reduce the morbidity and relapse rates associated with these tumors. So, we aim to highlight the importance of recognizing this entity for adequate and timely management. These tumors can be adequately triaged by histomorphology and immunohistochemistry using BCOR and BCL6. However, molecular studies are ultimately confirmatory and necessary for appropriate therapy.

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Conflicts of interest

There are no conflicts of interest.