Case Report: Metastatic Dedifferentiated Liposarcoma Presenting as Hypereosinophilia in an Adolescent

Abstract

Soft-tissue sarcomas associated with eosinophilia are rare, with limited cases reported in adults, and even fewer in the pediatric population. In this report, we highlight the importance of malignancy in the differential of hypereosinophilia in an adolescent. A 17-year-old boy presented with incidental findings of multiple bilateral pulmonary nodules on chest computed tomography (CT), and hypereosinophilia (absolute eosinophilic count [AEC] 7029 cells/mm³, hypereosinophilia defined as AEC >1500 cells/mm³). Lung biopsy showed high-grade metastatic sarcoma. A positron emission tomography–computed tomography (PET-CT) demonstrated a 7.9-cm mass in the left thigh, with biopsy revealing dedifferentiated liposarcoma. Subsequently, the patient was diagnosed with liposarcoma, with lung, mediastinal, and brain metastases. He completed six cycles of ifosfamide/doxorubicin, followed by surgical resection of primary thigh tumor and brain lesion. Given widely metastatic disease, he received palliative chemotherapy, and later transitioned to hospice. The patient died of respiratory failure from malignant pleural effusions. In conclusion, this case demonstrates the importance of a having a broad differential for hypereosinophilia, including malignancy, to expedite the diagnosis and initiate appropriate management promptly.

INTRODUCTION

Soft-tissue sarcomas associated with eosinophilia are rare, with limited cases reported in adults, and even fewer in the pediatric population. In this report, we highlight the importance of including malignancy in the differential of hypereosinophilia in children as well as adults.

CASE DESCRIPTION

A 17-year-old male with mild persistent asthma initially presented to the emergency room following a head trauma. His head imaging was normal. However, owing to intermittent cough, a chest X-ray was obtained, and he was found to have a 1.8-cm nodule in his left middle lung and a 1-cm nodule in the right lung base. Complete blood count (CBC) was notable for total white blood cell (WBC) of 22,000 cells/mm³ with 33% eosinophils, and absolute eosinophil count (AEC) 7029 cells/mm³ (Fig. 1). This laboratory abnormality prompted further work-up to characterize the incidental lung nodules. A computer tomography (CT) scan of the chest was obtained at an outside facility, showing multiple bilateral pulmonary nodules (largest 2.1 cm). Per Fleischner Society's guidelines for evaluating small pulmonary nodules,[1] patient had follow-up imaging at 6 months (ideally should have been around 3 months per guidelines), showing enlargement of previous nodules by few millimeters, and appearance of new nodules as large as 3.3 cm in the left upper lobe (Fig. 2). At initial encounter, patient did not endorse any respiratory symptoms, weight loss, night sweats, fatigue, fever, or chills. He denied tuberculosis risk factors, sick contacts, recent travel, or smoking exposure. He denied family history of malignancy and other atopic diseases.

Figure 1.

Complete blood count trend from initial diagnosis through course of treatment. Abs: absolute; mets: metastases; WBC: white blood cells.

Figure 2.

Computed tomography chest scan showing multiple bilateral centrilobular pulmonary nodules with an elongated lesion in the left upper lobe suggesting mucoid impaction, measuring 3.3 cm (arrow).

The patient was followed in our allergy and immunology clinic as a clinical patient, and not research subject, and all testing reported was performed on clinical basis, and consent form to obtain clinical testing was done when indicated.

RESULTS

Given findings of pulmonary nodules and eosinophilia, investigation of hypereosinophilia was initiated. An infectious workup was essentially unremarkable, including fungal serologies of Aspergillus antibody (Ab) and antigen (Ag), Blastomyces Ab, Cryptococcus Ag, Coccidoides Ab, Histoplasmosis Ab and Ag and Toxoplasmosis Ab, parasitic serologies of Toxocara Ab, Strongyloides Ab, and Trichinella Ab, and stool ova and parasites. Bone marrow biopsy was negative for any evidence of malignancy, and flow cytometry of bone marrow aspirate did not have evidence of CD3⁻CD4⁺ T cells. Peripheral blood flow cytometry showed normal CD3, CD4, CD8, CD19, and CD56 subsets. Additional testing to evaluate for an underlying rheumatologic condition also came back negative, including normal antineutrophil cytoplasmic antibodies, antinuclear antibody, erythrocyte sedimentation rate, and C-reactive protein (Table 1). Bronchoscopy with bronchoalveolar lavage was performed showed no eosinophilia. Lung nodule biopsy revealed high-grade metastatic sarcoma with overexpression of murine double minute 2 homolog (MDM2). Positron emission tomography–computed tomography (PET-CT), demonstrated a 7.9-cm mass in the left posterior thigh with metastases to the brain, lungs, and mediastinum (Fig. 3). Biopsy of the thigh mass revealed dedifferentiated liposarcoma, confirming the primary tumor. Both biopsies were performed at Texas Children's Hospital.

Table 1.

Hypereosinophilia workup^a

Test	Result
Absolute eosinophilic count, cells/mm3	7029 ↑
Total IgE, kU/L	147
CMP	Normal
ESR	Normal
FIP1L1/PDGFRA mutation	Normal
T-cell clonality test	Normal
B-cell clonality test	Normal
Tryptase level	Normal
Fungal serology	Normal
B12 level	Normal
Stool ova and parasites	Normal
Trichinella serology	Normal
Toxocara serology	Normal
Strongyloides serology	Normal
Troponin	< 0.01
Bone marrow biopsy	Unremarkable
Cardiac echo	Normal
EKG	Sinus rhythm
PFTs	No obstructive/restrictive pattern
CT chest	Bilateral pulmonary nodules
CT abdomen/pelvis	2 small splenic calcifications
Tissue biopsy	Left thigh: dedifferentiated liposarcoma; lung: metastatic high-grade sarcoma with overexpression of MDM2
T cell CD3−CD4+, CD3+CD4−CD8−, and CD4+CD7−	Normal

↑ indicates critically high level; CMP: complete metabolic panel; ESR: erythrocyte sedimentation rate; FIP1L1: factor interacting with PAPOLA and CPSF1; PDGFRA: platelet-derived growth factor receptor A; EKG: electrocardiogram; PFT: pulmonary function test; CT: computed tomography; MDM2: murine double minute 2 homolog

^aLung nodule and thigh mass biopsy findings were critical to the diagnosis of secondary eosinophilia from metastatic malignancy

Figure 3.

Whole-body positron emission tomography demonstrating diffuse metastatic disease in the lungs, mediastinum, brain, and left femoral lymph nodes, with left popliteal mass.

He underwent four cycles of ifosfamide/doxorubicin, followed by resection of the primary thigh tumor. In addition, he underwent craniotomy for resection of brain metastatic lesion, followed by gamma knife therapy. He completed two more cycles of ifosfamide/doxorubicin postsurgery to complete a six-cycle course, but unfortunately, he had persistent lung nodules on repeat imaging. Repeat wedge resection of the lung for diagnostic purposes, continued to show persistent disease, and he was started on pazopanib. Given MDM2 amplification of tumor, he was enrolled in a clinical trial with palbociclib with no response, so he was switched to gemcitabine/docetaxel, and later switched back to pazopanib. Unfortunately, his disease continued to progress, and he developed malignant pleural effusions, requiring several hospitalizations. Patient and family eventually opted for home hospice. Patient met his demise secondary to increased tumor burden causing respiratory distress 18 months after diagnosis. See Table 2 for timeline of events.

Table 2.

Timeline of events

Date	Event
January 25, 2017	Chest CT—multiple lung nodules, hypereosinophila
April 19, 2017	Pulmonology consult—nodules may reflect atypical infection, treatment for asthma
July 28, 2017	Repeat CT chest—multiple bilateral centrilobular pulmonary nodules
August 16, 2017	Bronchoalveolar lavage performed
November 3, 2017	Assessed in hematology clinic for eosinophilia
November 7, 2017	Assessed in ID clinic for eosinophilia and lung nodules
November 14, 2017	CT chest—interval development of multiple new pulmonary nodules in addition to enlarging pulmonary nodules since July 28, 2017
December 1, 2017	Lung nodule biopsy—metastatic high-grade sarcoma with MDM2 overamplification
December 2, 2017	Bone marrow biopsy
December 6, 2017	Assessed in allergy and immunology clinic
December 7, 2017	CT abdomen and pelvis—no mets noted
December 13, 2017	CT brain—evidence of necrotic intra-axial mass in the right with moderate surrounding vasogenic edema anterior frontal lobe
December 14, 2017	X-ray femur—a 6-cm oval soft tissue density posterior to the distal femur, without bony involvement
December 14, 2017	Biopsy of left thigh mass—dedifferentiated liposarcoma
December 15, 2017	PET CT: a 7.9-cm left thigh mass, distant metastatic disease to the lungs, mediastinum, and brain.
December 17, 2017	Cycle 1: doxorubicin/ifosfamide
January 10, 2017	Cycle 2: doxorubicin/ifosfamide
January 31, 2017	Cycle 3: doxorubicin/ifosfamide
February 22, 2017	Cycle 4: doxorubicin/ifosfamide
March 14, 2018	Resection of thigh mass
March 22, 2018	Resection of brain mets
April 9, 2018	Cycle 5: doxorubicin/ifosfamide
May 7, 2018	Cycle 6:iIfosfamide
June 5, 2018	Repeat lung biopsy—metastatic high-grade sarcoma
June 20, 2018	Cycle 1: pazopanib
July 18, 2018	Cycle 2: pazopanib
August 16, 2018	Taken off pazopanib, started palbociclib
September 1'6, 2018	Admitted with left hemorrhagic pleural effusion, progression of lung nodules
September 26, 2018	Cycle 1: gemcitabine/docetaxel
October 24, 2018	Cycle 2: gemcitabine/docetaxel
November 11, 2018	Cycle 3: gemcitabine/docetaxel
December 3, 2018	Clinical progression of disease in left thigh and lung, restarted on pazopanib
December 17, 2018	Two masses bursting through the skin in the left thigh
January 24, 2019	CT chest: stable pulmonary nodules
January 25, 2019	MRI of left thigh: interval response to therapy with decreased size of masses in the left inguinal region/proximal thigh with overlying skin defects
March 25, 2019	CT chest: new pulmonary nodule in the right upper lobe, evolution of the cavitary lesions.
April 20, 2019	Electing for hospice
June 20, 2019	Respiratory failure from malignant pleural effusions

CT: computed tomography; MDM2: murine double minute 2 homolog; MRI: magnetic resonance imaging; PET: positron emission tomography

DISCUSSION

Mild eosinophilia (defined as absolute eosinophil count AEC 500–1000 cells/mm³) is common and is caused by variety of conditions, including allergic disease, drug hypersensitivity, or parasitic infections. On the other hand, hypereosinophilia (AEC > 1500 cells/mm³) is uncommon, which when present should prompt a thorough evaluation to identify the underlying cause, and to assess if there is evidence of eosinophilic-induced end-organ damage.[2] Differential diagnoses for hypereosinophilia include myelodysplastic syndromes, leukemias, lymphomas, other hematologic or solid malignancies, immune disorders, and systemic mastocytosis, to name a few. In this particular patient, the mild persistent asthma alone does not sufficiently explain the extent of hypereosinophilia. Therefore, it was crucial to further investigate other causes that could contribute to this abnormal lab value. Malignancy workup should be initiated when initial history is not necessarily sufficient to point toward an obvious etiology of hypereosinophilia.

Paraneoplastic hypereosinophilia (hypereosinophilia associated with malignancy), is generally more common in hematologic malignancies, including Hodgkin's lymphoma and leukemia,[3] and is rarely found in solid tumors and is usually associated with poor prognosis.[4] Some cases of hypereosinophilia have been noted in solid tumors through few case reports, including renal cell carcinoma, lung adenocarcinoma, and so on. Paraneoplastic syndromes themselves are very rare in patients with soft tissue sarcomas. Previous case reports review soft tissue sarcomas and its association with peripheral eosinophilia in adults, including 1 case report describing eosinophilia that is present in an adult patient with spindle cell sarcoma,[5] and another case describing eosinophilia in an adult with pleomorphic soft tissue sarcoma of the elbow.[6]

The role of eosinophils in solid tumor progression remains yet to be well defined. Tumor cells themselves secrete cytokines that recruit eosinophils. These commonly tend to occur in areas of necrosis. Once eosinophils infiltrate the tumor tissue, their effector mechanism is not completely established. In some malignancies, such as colon cancer, there is evidence for a synergistic cytotoxic effect with eosinophils and tumor cells, through release of toxic cationic proteins, such as MBP, or increase in the release of chemotactic factors that leads to further recruitment of eosinophils.[7,8]

Through this case, we display the finding of hypereosinophilia in an adolescent found to have metastatic dedifferentiated liposarcoma, initially presenting with multiple lung nodules. To the best of our knowledge, there are no reported cases of paraneoplastic eosinophilia in the pediatric population, especially in the context of soft tissue sarcomas. Given this is a clinical case description, one of our limitations of this study is elucidating the mechanism of eosinophilia in solid tumor progression. Although there are proposed ideas, as mentioned above, future experimental studies should be conducted to further explore the role of eosinophils in the tumor microenvironment. Defining the effector functions of eosinophils can potentially provide novel therapeutic options for cancers associated with eosinophilia.

Though rare in children, eosinophilia should always prompt a thorough evaluation of the underlying cause and assessment of end-organ damage. Without appropriate assessment, the root cause of hypereosinophilia might be missed, leading to adverse outcomes. Therefore, it is important to maintain a broad differential and investigate all causes of eosinophilia, including malignancy.

Funding Statement

Source of Support: None.