An extremely rare case of recurrent pleomorphic myxoidliposarcoma with response to eribulin chemotherapy – A case report

Abstract

Pleomorphic myxoid liposarcoma (PML) is a newly recognized entity with aggressive clinical behavior and a tendency to recur. It has histological features of both myxoid and pleomorphic liposarcoma and lacks the molecular and structural chromosomal abnormalities associated with myxoid and pleomorphic liposarcoma. The data about their response to chemotherapy is quite sparse. We report a case of incidentally detected pleomorphic myxoid liposarcoma of the mediastinum in a 32-year-old gentleman. After resection and adjuvant chemotherapy with doxorubicin and ifosfamide, there was no evidence of residual disease at the end of treatment. During a routine follow-up 5 months later, he was found to have a recurrence of the disease with histological confirmation. He received a trabectedin given its activity in myxoid liposarcoma. However, he had toxicities and progression leading to its discontinuation. Subsequently, eribulin was started as the next line of therapy. After 4 cycles of chemotherapy, response assessment was suggestive of partial response, which is still maintained after 7 cycles of eribulin. This is the first report of this entity responding to a newer chemotherapy regimen.

Introduction

Pleomorphic myxoid liposarcoma (PML) is a recently described entity that is exceedingly rare with distinct clinical presentation and behavior. The earliest reports of an aggressive tumor with mixed features of myxoid and pleomorphic liposarcoma were made in the seminal series of Kauffman and Stout as early as 1959 in 2 children with mediastinal masses. However, it has been acknowledged as a novel emerging entity only recently in the WHO classification of soft tissue tumors ¹ (2019).

Histologically, it is composed of areas of abundant myxoid matrix and bland round to-oval cells with lipoblasts and a plexiform capillary network. Interspersed in these areas are pleomorphic spindle to oval cells with hyperchromatic nuclei that may transition into sheets of pleomorphic cells with cytologic atypia and increased mitosis. Immune phenotyping studies reveal variable positivity for S100 with MDM2 and CDK4 negativity. It lacks the characteristic molecular hallmarks of myxoid liposarcoma (FUS-DDIT3 and EWSR1-DDIT3) and MDM2/CDK4 amplifications associated with well-differentiated liposarcomas. ²

This rare tumor has an association with li fraumeni syndrome.^1,3,4

3 case reports of pleomorphic myxoid liposarcoma with li Fraumeni syndrome and documented pathogenic variants of p. 53 mutation were reported with different sites of involvement (mediastinum, pelvis, and head and neck-all axial).

The data reported in the literature mainly consists of clinic pathologic reports with little information on treatment strategies for this clinically aggressive tumor variety.

We describe this case highlighting the aggressive pattern of behavior of this disease and success in achieving a response with Eribulin chemotherapy in this rare tumor.

The number of systemic therapies available for the treatment of STS has increased over the last decade, but prognosis in the metastatic setting remains poor due to the limited efficacy of treatment options. Trabectedin and eribulin were approved as histology-specific agents for liposarcoma a few years back.

The U.S. Food and Drug Administration approved the use of trabectedin for the treatment of unresectable or metastatic liposarcoma and leiomyosarcoma based upon an improvement in progression-free survival (PFS) in a randomized (2:1) open-label, active-controlled trial enrolling 518 patients with LMS or LPS comparing trabectedin to dacarbazine. The trial demonstrated an improvement in PFS, with a median PFS of 4.2 months in the trabectedin arm and 1.5 months in the dacarbazine arm.

The FDA approval of eribulin was based on results from a single, randomized, open-label, active-controlled trial enrolling 452 patients with advanced, locally recurrent, or metastatic liposarcoma or leiomyosarcoma. There was a significant improvement in overall survival for the overall population. The estimated median overall survival (OS) was 13.5 months in the eribulin arm and 11.3 months in the dacarbazine arm. The most common grade 3-4 toxicities of eribulin were neutropenia (35%) and anemia (7%). However, there is no report of eribulin efficacy in this rare subtype (PML).

Case presentation

A 32-year-old gentleman with no comorbidities and no family history of malignancy presented to the outside hospital for bilateral testicular swelling which was clinically diagnosed to be varicocele. During routine investigations as a part of the pre-operative workup, he was found to have a mediastinal mass on a chest X-ray. Contrast-enhanced computed axial tomography of the chest was suggestive of a large anterior mediastinal mass with chest wall involvement. In view of the possibility of malignancy, Positron emission tomography and computed tomography were done which revealed a large 12*9.8*9.8 cm heterogeneous mass (SUV max- 3.4) in the anterior mediastinum abutting the upper lobe of the right lung and pleural nodules in the area adjacent to mediastinum (SUV max-5.1) (Figure 1). A biopsy of the lesion was reported as a mesenchymal tumor with myxoid change.

Figure 1.

(a) – Maximum intensity projection image (MIP) of the FDG PET-CT showing increased tracer uptake in the thoracic region right to the midline conforming to middle mediastinum mass on axial CT thorax section (b) with increased FDG uptake on fused PET-CT image (c). (d) – (g) – Axial CT lower thorax and abdomen region respectively with no abnormal FDG uptake on fused PET-CT images.

The patient went to an outside center and was evaluated for the same. Underwent excision of chest wall tumor along with reconstruction of the chest wall and lung biopsy in 2019. Histopathological examination of the surgical specimen revealed a high-grade pleomorphic myxoid liposarcoma (PLS) (Figure 4). Patient had R1 resection, Mitosis- 18/10 HPF, no necrosis, no LVI, Bone margins were free and medial margins were positive. Diaphragmatic deposits and pericardial deposits were positive for tumor.

The patient was given the option of surgery or observation both for renal mass as the mass size was constant in images.

In view of the aggressive nature of the disease and lack of literature on optimal treatment strategies, the patient was suggested to undergo MSK-IMPACT testing (next-generation sequencing) on the tumor tissue to identify any targetable mutations to select suitable adjuvant therapy. The test revealed a tumor mutational burden of 4.4 per Mb, a splicing mutation in TP 53 at exon 10, and amplification of KMT2B and NOTCH3 with no available targetable therapy for these genetic alterations.

The patient received adjuvant chemotherapy with 6 cycles of doxorubicin and ifosfamide as per protocol because of positive surgical margins. No chemotherapy-related toxicity was documented. Response assessment done at the end of chemotherapy with Positron emission tomography revealed no residual disease (Figure 2). The patient remained in follow-up with visits every 3 months with physical examination and imaging at each encounter.

Figure 2.

(a) Scantily spread cells among myxoidstroma showing positivity fordesmin (top left). (b) S-100 focal positivity seen in cells interspersed with myxoidstroma (top right). (c) High power view showing S-100 focally positive cells (bottom left). (d) Solid sheet like arrangement of pleomorphic cells which are CD34+ - characteristic of pleomorphic myxoidliposarcoma (bottom right).

After a treatment-free interval of 5 months, a follow-up PET-CT scan done revealed a 3.5*1.8 cm lesion in the posterior diaphragmatic crus (SUV max – 3.16) (Figure 3). A biopsy of the lesion was diagnostic of tumor recurrence. Patient underwent Foundation One next-generation sequencing testing which revealed stable microsatellite status with a tumor mutational burden of 2 mutations/Mb. It also revealed PIK3CA –E542K mutation and TP3 splice site mutation, NOTCH2-M1 mutation. He was given trabectedin as the next line of therapy. After 2 cycles of trabectedin, he developed excessive fatigue and a radiologically mild increase in size which resulted in discontinuation of therapy. Subsequently, he was started on eribulin. After 4 cycles of chemotherapy with eribulin, response assessment with a CT scan revealed a partial response (size reduced to 0.8*1.2 cms) and was planned to continue eribulin (Figure 5). The patient has completed 7 cycles and the response is maintained. This represents the first case report documenting the chemo-sensitive nature of eribulin for this tumor variety. There was no toxicity so far other than grade 1 neuropathy and grade 1 fatigue.

Figure 3.

(a) – MIP image of FDG PET-CT after surgery showing no abnormal FDG uptake in the middle mediastinum on axial CT images of thorax (b), lower thoracic region (d) and abdomen (f) and fused PET-CT images (c, e and g).

Figure 4.

(a) – MIP image of the follow-up FDG PET-CT after 6 months of surgery showing faint area of radiotracer uptake in the upper abdomen region conforming to nodular lesions in the diaphragm (d) and (f), white arrows0 showing FDG uptake in the fused PET-CT images (e) and (g), white arrows).

Figure 5.

(a) - CT abdomen showing nodular lesions in the infra diaphragmatic surface. 1.2 × 1.8 cm on right side and 2.5 × 1.8 cm on left side. (b) - CT abdomen showing nodular lesions in the infradiaphragmatic surface measuring 0.8 × 1.0 cm on right side and 1.5 × 1.2 cm on left side showing mild, FDG uptake on fused PET-CT images (c).

Discussion

Pleomorphic myxoid liposarcoma (PML) is a rarely described entity which was first described in detail in a paper by Alaggioet al ⁵ (Table 1). The unique histological features and its propensity to metastasize and have an aggressive course with poor outcomes in young patients have made it stand apart. According to Creytens et al, a consensus is yet to be made on the precise classification and terminology of this novel subtype of liposarcoma which is slated to be included in the upcoming edition of the WHO classification of soft tissue and bone tumors. ⁶

Table 1.

Review of cases of pleomorphic myxoidliposarcoma across case series and their characteristics.

Author	Case	Age/sex	Location	Association with li fraumeni syndrome
Alaggio et al	1	17/F	Thigh	NA
	2	18/M	Leg	NA
	3	12/F	Thigh	NA
	4	18/F	Mediastinum	NA
	5	22/M	Mediastinum	NA
	6	10/F	Thigh	NA
	7	20/F	Retroperitoneal	NA
	8	-/F	Mediastinum	NA
	9	17/M	Back	NA
	10	14/M	Mediastinum	NA
	11	15/F	Abdomen	NA
	12	14/F	Head	NA
Francom et al	13	11/M	Head and neck	YES
Zare et al	14	34/M	Chest wall	YES
Sinclair et al	15	15/F	Perineum	YES

Boland JM et al reported the median age of the cases as 30 years.^7,8 It is reported to be more common in young females (M: F=1:2) ⁵ with predilection for axial sites especially the mediastinum. ⁵

In a review of pediatric liposarcomas by Alaggio et al, ⁵ 12 of the 82 cases (approximately 15%) were reported as PML. Of these 12 cases, 5 of them were located in the mediastinum. Out of these majority of them had the unresectable disease and finally succumbed to their disease within 8 months to a year diagnosis. ⁵ Other common sites being head & neck and abdomen. ⁶ In our case, both the primary tumor and its local recurrence were located in the mediastinum similar to that mentioned in the literature. ⁶

The SUV max of myxoid liposarcoma on PET-CT was reported around 3.5+/−1.5 whereas in case of pleomorphic liposarcoma it was 5.6+/−5.8. ⁹ In our case the primary mediastinal lesion had a SUV max of 3.4 and at recurrence was 3.14. A study by Brenner et al, had reported that the likelihood of early relapse and inferior survival was seen in tumors whose SUV max in the PET-CT at presentation was above 3.6. ¹⁰

The gross appearance of the tumor was reported as a mass with a thin membrane on the anterior aspect and deficient on the posterior aspect which is similar to the description Creytens et al mentioned. On IHC the cells were positive for desmin, focally positive for S-100 and CD34. The typical appearance described in the literature is that of conventional myxoid liposarcoma-like areas with abundant myxoid matrix, bland round cells, and a plexiform capillary network. These areas usually transform into cellular, solid sheet-like, high-grade pleomorphic liposarcoma-like areas with severe cytologic atypia and occasional necrosis. Variable expression of S-100 was noted and MDM2 and CDK4 negativity was also described similar to our case. ²

Array-based comparative genomic hybridization analysis of a case of PML by Creytens et al revealed losses on multiple chromosomes ⁹ which is in contrast to a conventional PML which is characterized by gains of multiple chromosomes and myxoid liposarcoma shows the gain of chromosome 8 as the most frequent chromosomal aberration. ¹¹

Pediatric PML has been known to display genomic instability rather than specific mutation. Our patient had demonstrated PIK3CA-E542K mutation which has been described in case reports. Targeted therapy for this particular mutation in the form of PIK3CA inhibitors such as apitolisib, copanlisib, alpelisib, and taselisib have been suggested based on their clinical activity in metastatic breast cancer and advanced solid tumors.^12–15 However no clinical trials have been conducted in this tumor subtype with these agents to suggest their efficacy. These mutations are commonly seen with high frequency in myxoid liposarcomas. ²

The more common mutations classically reported with PML are RB1 and p 53.^1,11 Germline mutations of p. 53 are known to result in early, aggressive soft tissue sarcomas with a familial pattern of inheritance. It is yet to be seen if more cases of PML are associated with Li Fraumeni syndrome. Our case had a pathogenic variant (somatic) of p. 53 mutation on next-generation sequencing. Family history was non-contributory to malignancies. The pattern of early and aggressive local recurrence in our case was consistent with that described in the literature. ⁵

In a study by Valentina Fausti et al, single-centre retrospective analysis of ninety-nine patients with STS were enrolled. After progressing to anthracycline, all patients had received second-line treatment. Trabectedin-treated patients have a better PFS when Lymphocyte/Monocyte Ratio was low, while patients treated with other regimens have a worse PFS when lymphocyte/monocyte ratio was low. This ratio has, therefore, been shown to be a specific predictor for treatment with Trabectedin and could be adaptable in daily practice as a second-line treatment. However, in our case report, trabectedin didn’t work and lymphocyte/monocyte ratio information was not available, but patient had a response to eribulin. ¹⁶

The lack of efficacy of available treatments for this subtype makes it difficult to manage such cases. Most of the PML were treated with resection wherever possible. ⁷ Resection was attempted in one case of head and neck PML for close margins. Adjuvant radiotherapy was also considered in some cases of mediastinal PML with one case receiving single agent doxorubicin for adjuvant therapy with no signs of disease following adjuvant chemotherapy. ¹⁷ In our case, the disease recurred less than 6 months after the completion of adjuvant therapy. We believe this is the first case of PML which had a good and sustained response to eribulin. The toxicity observed in our patient was similar to the literature and was grade 1 only, thus maintaining his quality of life. However, more data is certainly needed to ascertain the type of effective chemotherapy in this poor prognostic disease.

Conclusion

Pleomorphic myxoid liposarcoma (PML) is an exceedingly rare tumor in young adults with a propensity for mediastinum. It lacks characteristic molecular abnormalities found in myxoid and well-differentiated liposarcoma. It has an aggressive course in the form of early recurrences as exemplified by our patient. This might respond to novel chemotherapy agents like eribulin as in our patient. However, more literature is certainly needed. ¹⁸

Ethical statement

Ethical approval

Our institute doesn’t require ethical approval for reporting individual case.