Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations

Summary:

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR-rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR::CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR, including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a “hybrid morphology” in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

BACKGROUND

Soft tissue sarcomas (STS) are more common in infancy compared with later childhood.¹ Non-rhabdomyosarcoma soft tissue sarcoma accounts for two thirds of STS in this age group, with infantile fibrosarcoma (IFS) being the most common diagnosis.¹ Relatively poor outcomes among infantile STS have been attributed to unique tumor biology, advanced stage, and obstacles to delivering effective local control.^2,3 Remarkably, the development of tropomyosin receptor kinase (TRK) inhibitors has largely negated the need for neoadjuvant cytotoxic chemotherapy and mutilating surgeries for locally advanced and metastatic IFS.⁴ However, considerable challenges remain for other STS typically encountered in young children.

Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a recently described ultrarare tumor.⁵ Along with undifferentiated round cell sarcomas (URCS), PMMTI has been found to harbor internal tandem duplication (ITD) of BCOR or YWHAE::NUTM2B/E fusion.⁶ B-cell lymphoma-6 (BCL-6) corepressor (BCOR), located on chromosome X, encodes a nuclear protein that functions as an epigenetic modifier when bound to BCL-6.^7,8 BCOR is also a member of the chromatin-modifying complex polycomb repressive complex (PRC1) that functions as a transcriptional repressor.^7,8 ITD of exon 15, involving PCGF ubiquitin-like fold discriminator domain of BCOR, is recognized as a recurrent alteration in PMMTI and URCS.⁶ Not described in infants previously, the paracentric inversion of the short arm of chromosome X, results in BCOR::CCNB3. Ultimately, both alterations lead to BCOR protein overexpression, which can be screened for immunohistochemically.⁹

These tumors are associated with dismal outcomes,¹⁰ with a high propensity to recur locally in the setting of incomplete surgical resection.^11,12 URCS tumors have the capacity to metastasize distantly.¹⁰ Previous publications have largely focused on the pathologic characteristics or individual single case reports of this emerging entity. Given the rarity of the tumor, unique obstacles to effective local control, and lack of standard treatment guidelines, we undertook a comprehensive multi-institutional analysis of clinical, pathologic, and radiologic features of infantile BCOR-altered STS in early childhood.

METHODS

A retrospective, multi-institutional study of the clinical presentation, Intergroup Rhabdomyosarcoma Study Group (IRSG) staging,¹³ radiologic features, histologic and molecular findings, and treatment course of infantile STS carrying somatic BCOR alterations was undertaken. Central review of imaging and pathology, where applicable, occurred at Cincinnati Children’s Hospital Medical Center. All cases but one were confirmed by molecular testing; of those, 6 patients had a combined tumor DNA and RNA next-generation sequencing.¹⁴ The latter case was reviewed by an external sarcoma pathologist and was consistent with classic PMMTI histomorphology and positive nuclear BCOR staining. One case was previously published by our group and was added to this series for long-term outcome data.¹² Median event-free survival data was measured from the last administered therapy until the last observed time.

RESULTS

Patient Characteristics

Five males and 4 females were diagnosed at a mean age of 7 months with a range of 6 weeks to 15 months. Two patients demonstrated relevant physical findings within the first month of life. Seven patients had IRSG stage 3 disease at diagnosis. Tumors were located in the axial soft tissue of the torso in 5 patients and extremities in 2 patients.

Radiographic Appearance

At diagnosis, all patients had anatomic imaging to the primary site. Six patients underwent a chest computed tomography. Functional imaging with a positron emission tomography scan was completed on 3 patients. Magnetic resonance (MR) images were reviewed by pediatric radiologists, with 6 magnetic resonance imaging studies reviewed centrally by a dedicated musculoskeletal radiologist. Location of the tumors include thigh (n = 2), orbit (n = 1), spine (n = 2), and pelvic cavity (n = 1). All lesions demonstrated a lobulated contour with bright T2 and low T1 signal intensity. Three of 6 cases exhibited internal septations. Five tumors occupied the anatomic space and compressed adjacent structures without direct invasion (Figs. 1, 2).

FIGURE 1.

Radiographic appearance of undifferentiated round cell sarcoma. A, Bright T2 signal mass in the calf with multiple internal septations. B, Postcontrast image demonstrates geographic enhancement.

FIGURE 2.

Radiographic appearance of primitive myxoid mesenchymal tumor of infancy. A, Axial T2 with fat suppression image demonstrates a large lobulated mass in the pelvic cavity. B, The mass extends to the right sciatic notch (arrows).

Pathologic Findings

Eight cases were reviewed by a central pathologist (S.S.). Cases with morphology classic for PMMTI demonstrated relatively monotonous low-to-moderate cellularity stromal tumors, with small primitive round to oval nuclei and variably abundant extracellular myxoid matrix. In contrast, the case with classic URCS morphology displayed a highly cellular proliferative tumor, small-to-medium–sized round nuclei with delicate chromatin and inconspicuous nucleoli, including regions with vesicular nuclei, and scant to small amount of eccentric light eosinophilic to clear cytoplasm, but only focal scant myxoid matrix. Two tumors displayed a morphology we termed “hybrid morphology,” with large areas displaying classic morphology for PMMTI but regionally transitioning to distinct but nondemarcated areas of higher cellularity and scant myxoid matrix, with intermediate features closer to URCS (Fig. 3). The BCOR::CCNB3 tumor showed a moderate to marked cellularity, predominantly composed of spindle cells with plump oval nuclei and light eosinophilic to clear cytoplasm. The tumor was mitotically active (to 10 per HPF) with a Ki-67 proliferative activity regionally > 80%. All the tested tumors (7 specimens) showed diffuse and strong nuclear immunoreactivity for BCOR by immunohistochemistry. In 2 cases, immunostaining for panTRK showed light positivity, but no NTRK gene fusions were detected on genetic testing. The URCS case displayed strong expression for BCL2 and EGFR. The response to chemotherapy was evaluated by histology in 3 cases. The treatment effect was characterized by posttreatment stromal fibrosis, hypocellular fibroblastic reactivity, focal capillary proliferation, and focal delicate hemosiderin deposition, but no histomorphological recognizable viable tumor.

FIGURE 3.

Primitive myxoid mesenchymal tumor of infancy, classic histomorphology (A, B), hybrid morphology (D, E), and undifferentiated round cell sarcoma morphology (G, H). Immunohistochemical stain for BCOR (C, F).

Molecular Alterations

Seven cases carried BCOR::ITD and 1 case harbored BCOR::CCNB3 fusion. Concurrent alterations were rare. The URCS case displayed an additional somatic mutation in the Fanconi anemia complex (FANCG Q215) and 1 PMMTI tumor carried CD36 Y325* mutation.

Treatment

The majority of patients underwent surgical resection (8 of 9), and most surgical margins were reported to be positive (7 of 8). The patient with an unresectable retroorbital tumor received definitive proton beam radiotherapy with a dose of 64.8 Gy. Six patients received radiotherapy in the relapsed setting with doses ranging between 50 and 64.8 Gy. Of those, all but 1 received proton beam radiotherapy.

All patients were treated with systemic chemotherapy for measurable disease, and 2 patients received 3 different regimens. Neoadjuvant chemotherapy was utilized in 3 unresectable tumors and 1 URCS tumor. The most common chemotherapy regimens were vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide and etoposide (IE) every 2 to 3 weeks for 6 to 8 cycles. Other regimens used were National Wilms Tumor Study Group (NWTS) regimen I,¹⁵ ifosfamide and doxorubicin (ID), ifosfamide or cyclophosphamide combined with carboplatin and etoposide (ICE) for 3 to 6 cycles, and vincristine and actinomycin (VA). At diagnosis, 4 patients were treated with 50% chemotherapy doses. Of those, 2 patients were escalated to the full dose. Chemo was generally given every 3 weeks and was well tolerated. Beyond myelosuppression, febrile neutropenia admissions, and ifosfamide-induced Fanconi syndrome (1 case), no other grade 3 or 4 toxicity reported. The response to chemotherapy was assessed by the Response Evaluation Criteria in Solid Tumors 1.1 ¹⁶complete radiographic response was achieved in 2 of 5 patients treated with VDC/IE, 1 of 2 treated with NWTS regimen I, and 1 of 2 with ICE. Three patients achieved a partial response with either VDC/IE, ID, or ICE. Two patients progressed on chemotherapy, 1 patient on VA, and another on VDC/IE. The patient with URCS received 6 cycles of ICE in the first relapse with a complete, albeit short-lived remission. Salvage, off-label, therapy with combined targeted and traditional chemotherapy was then utilized based on EGFR and BCL2 overexpression documented by IHC. Erlotinib, a small-molecule EGFR tyrosine kinase inhibitor, was administered in combination with irinotecan and temozolomide. However, the patient developed grade 3 elevated serum alanine aminotransferase and aspartate aminotransferase, and erlotinib was stopped after only 2 cycles. Subsequently, she was treated with cyclophosphamide, topotecan, and bevacizumab. Most recently, the patient received a single agent BCL2 inhibitor, venetoclax. Table 1 is a summary of the 9 reported cases.

TABLE 1.

Summary Table of 9 Cases

Case	Sex	Age at diagnosis (mo)	Histologic diagnosis	Molecular alteration	Primary site of disease	IRSG stage/group	First line of therapy	Subsequent therapies
1	Female	4	URCS	BCOR-ITD (NGS)	Extremity	Stage 3/group III	VDC/IE (8 cycles)—complete surgical resection	ICE (6 cycles). Erlotinib+TEM/IRI. Cyclo/Topo+ bevacizumab. Venetoclax
2	Male	13	Hybrid	BCOR-ITD (NGS)	Extremity	Stage 3/group II	Incomplete surgical resection (positive margins)	Four subsequent surgeries. ID and IE chemotherapy. Proton radiation.
3	Male	15	Hybrid	BCOR-ITD (RT-PCR)	Scalp	Stage 1/group II	Incomplete surgical resection (residual disease in the regional lymph nodes)	Three subsequent surgeries. 7 cycles of regimen I. proton radiotherapy
4	Female	5	PMMTI	BCOR-ITD (RT-PCR)	Retroorbital (parameningeal)	Stage 2/group III	VDC/IE (6 cycles)—proton radiotherapy	NA
5	Male	2	PMMTI	BCOR-CCNB3 (NGS)	Paraspinal	Stage 3/group II	Incomplete surgical resection (gross residual)	8 cycles of regimen I. Proton radiotherapy
6	Male	1.5	PMMTI	BCOR-ITD (NGS)	Pelvis	Stage 3/group III	ID (6 cycles)—incomplete surgical resection (gross residual)	NA
7	Female	13	PMMTI	BCOR-ITD (NGS)	Paraspinal	Stage 3/group II	Incomplete surgical resection (positive margins)	Two subsequent surgeries. VA (2 cycles). VDC/IE (6 cycles). Proton radiotherapy
8	Female	1.5	PMMTI	NA	Paraspinal	Stage 3/group III	CCE (4 cycles). Incomplete surgical resection (positive margins)	3 cycles of VDC/IE. Surgery. Photon radiotherapy
9	Male	6	PMMTI	BCOR-ITD (NGS)	Paraspinal	Stage 3/Group II	Incomplete surgical resection (positive margins)	6 cycles of VDC/IE. Proton radiotherapy

CCE indicates cyclophosphamide, carboplatin, and etoposide; Cyclo/Topo, cyclophosphamide/topotecan; ID, Ifosfamide and doxorubicin; IE, Ifosfamide and etoposide; NGS, next-generation sequencing; Regimen I, VDC with cyclophosphamide and etoposide; RT-PCR, reverse transcription polymerase chain reaction; TEM/IRI, temozolomide/irinotecan; VA, Vincristine and actinomycin; VDC, Vincristine, doxorubicin, and cyclophosphamide.

Outcome

Four of 5 patients with classic PMMTI histomorphology and the patient with BCOR::CCNB3 tumor developed local recurrence with a median of 2.5 months after incomplete surgical resection. The patient with a pelvic tumor achieved long-term remission with incomplete surgical resection after receiving neoadjuvant ID chemotherapy. Interestingly, the treated tumor was composed of a fibrocollagenous matrix without a viable tumor. The 2 patients with hybrid morphology experienced multiple recurrences in the resection site, as well as the regional lymph nodes and soft tissue along lymph node chains. The URCS patient developed distant brain metastases 4 months after completing therapy. At the time of study analysis, all patients but 1 were alive without evidence of disease with a median of 24 months since the last administered therapy. Figure 4 is the swimmer plot for the entire cohort.

FIGURE 4.

Swimmer plot survival analysis for the entire cohort. PMMTI indicates primitive myxoid mesenchymal tumor of infancy; URCS, undifferentiated round cell sarcomas.

DISCUSSION

The present case series demonstrates an excellent overall survival rate for infants with BCOR-altered tumors, although toxic multimodal therapy was generally required to achieve durable disease control. In the largest patient series published to date, the outcome of BCOR::ITD PMMTI and URCS of infancy was generally poor.¹⁰ Although single patient case reports have subsequently highlighted effective therapeutic strategies, such studies are likely heavily weighted with patients experiencing favorable outcomes, neglecting the potential pitfalls of therapy. In 2016, BCOR::ITD was recognized as the unifying genetic alteration and presumed driver of PMMTI, molecularly linking PMMTI/URCS to clear cell sarcoma of the kidney (CCSK)⁶ and further justifying the use of multiagent chemotherapy regimens similar to that established for CCSK.^15,17,18 As described in the present patient series, multiagent neoadjuvant chemotherapy similar to the regimen I used for CCSK or VDC/IE was generally effective for patients with unresectable BCOR::ITD tumors and the URCS patient.

As has been described in infants with BCOR::ITD STS,¹⁰ CCSK patients less than 12 months of age have fared poorly.^15,19 Inadequate chemotherapy dosing and hesitancy to deliver necessary local control may contribute to poor outcomes among infants. Unlike IFS tumors, which were optimally treated with modest intensity chemotherapy (VA or VAC) and general avoidance of morbid surgeries and radiotherapy before the advent of TRK inhibitor therapy,⁴ effective therapy of PMMTI has proven to be more challenging. In the present series, local recurrences were common.

Adjuvant radiotherapy has played a key role in the management of CCSK. The use of postoperative radiotherapy as outlined in the NWTS 5 protocol has decreased the risk of local recurrences. In fact, 95% of relapses were metastatic, highlighting the role of adjuvant local radiotherapy in maintaining long-term local remission.²⁰ As we previously reported the effective role of radiotherapy in local control,⁹ we continue to observe a critical role for radiotherapy in maintaining long-term remission. Despite the potentially considerable morbidity in this young age group, radiotherapy was often necessary to achieve durable disease control. Postoperative residual disease carried a particularly high risk of recurrence in our case series. However, the initiation of chemotherapy and radiotherapy was deferred in 5 patients, likely because of their young age. The relapses occurred shortly after surgery rendering the repeat resection more challenging with a higher risk of perioperative complications.

Presently, there are no guidelines to reliably define risk status for patients with BCOR-altered tumors. Antonescu et al¹⁰ described a histologic spectrum of tumors with BCOR::ITD, with URCS histology portending a particularly poor prognosis. In our cohort, the patient with URCS tumor was the only one not to achieve durable disease control. In this study, a histomorphologic spectrum we designated as “hybrid morphology” was observed in 2 tumors, each demonstrating a more clinically aggressive behavior than the others with classic morphology of PMMTI. The analysis of larger patient series will be necessary to confirm this population as distinct from PMMTI.

Distant brain metastases are a relatively rare event in childhood sarcoma, only occasionally reported in rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma.²¹ In contrast, CCSK has a predilection for CNS metastasis.¹⁵ Similarly, hematogenous spread to the brain was reported in URCS and a single case of relapsed PMMTI.^10,20,22 In the present case series, the URCS patient demonstrated brain metastases shortly after the completion of therapy. Frequent brain imaging during and after CCSK therapy is currently recommended due to the risk of brain metastases.¹⁵ Similarly, evaluation with brain magnetic resonance imaging before and during therapy for patients with BCOR::ITD URCS should be considered. ICE chemotherapy was used in patients with relapsed CCSK. Most patients had a second complete response.^23,24 Local control with surgery and/or radiation was also often utilized.²³ Similarly, the URCS patient with brain metastases achieved complete response after 6 cycles of ICE chemotherapy. Unfortunately, the patient experienced severe electrolyte wasting followed by rapid manifestation of new CNS metastases.

There are no established targeted therapies for tumors harboring BCOR activation, and concurrent mutations were rare in this series. The URCS case overexpressed EGFR without gene-copy number variation.²⁵ Because of the short duration of therapy, any benefit of erlotinib could not be determined. Further studies are needed to elucidate the effect of targeting EGFR in BCOR-altered tumors.²⁶ BCL2 overexpression could also be a potential target.^27,28

This study inherently carries several limitations, including the retrospective nature of the analysis and varied therapeutic strategies. All cases but one were consults to our tertiary sarcoma center. Thus, this study is subject to referral bias. Multiple case reports described BCOR-rearranged tumors of infancy, but this is the first series focused on treatment and outcomes, evaluated in a collaborative, multi-institutional case series. Larger collaborative efforts are needed to investigate the role of chemotherapy and radiotherapy in the treatment of infantile BCOR-altered tumors.

In conclusion, infantile BCOR::ITD STS represents a spectrum of disease, with PMMTI being a locally aggressive tumor. Hybrid and URCS histomorphology are associated with the risk of regional or distant metastases, respectively. Neoadjuvant chemotherapy was necessary in URCS and unresectable BCOR::ITD STS in this series. Tumors were generally sensitive to chemotherapy including doxorubicin-containing regimens and ICE. Despite the potential morbidity in this young age population, radiotherapy was necessary for treatment of residual or unresectable tumors. This study highlights the value of collaboration among invested clinicians treating such complex rare tumors. We anticipate that this endeavor will further inform the therapy of newly diagnosed infants with BCOR-altered tumors and form a framework for the development of guidelines of treatment.