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August, 2024
Case of the Month
Clinical History: An 8-year old female presented with abdominal pain and was found to have an 11 cm anterior mediastinal mass. The patient had no significant past medical or surgical history. A radiology report described the mass as well demarcated with prominent calcifications and indicated that it abutted the pericardium and did not involve pulmonary parenchyma.
An excision was performed and histology shows a well-circumscribed spindled and focally epithelioid neoplasm arranged in fascicles and nests. At low power, the tumor has a vaguely nodular appearance (Figure 1). There are areas with increased cellularity alternating with areas with relatively less cellularity, some of which have a prominent hyalinized stroma, while others have a somewhat edematous appearance (Figures 2, 3). The cells have eosinophilic cytoplasm and ovoid nuclei with finely-stippled chromatin and small nucleoli. The cytomorphology is predominantly bland. Rare mitoses are identified (1 per 2 mm2) but necrosis is not conspicuous (Figure 4). There are occasional ectatic vessels as well as coarse calcifications of varying sizes scattered throughout, including small psammoma bodies (Figures 5, 6).
By immunohistochemistry, the tumor cells were positive for smooth muscle actin (SMA; Figure 7), desmin (Figure 8), and H-caldesmon (weak positivity). They were negative for pankeratin, S100, CD34, STAT6, and HMB45. Fumarate hydratase (FH) was retained and EBER was negative by in situ hybridization (ISH). Molecular studies were performed and revealed an SRF::RELA fusion
Q1. What is the most common mediastinal tumor in children?
- Germ cell tumor
- Thymic neoplasm
- Lymphoma
- Mesenchymal tumor
Q2. Which of the following fusion-associated mesenchymal tumors are more common in the pediatric and/or young adult population compared to older adults??
- Inflammatory myofibroblastic tumor
- Synovial sarcoma
- Cellular myofibroma
- All of the above
Q3. Which of the following findings most reliably distinguishes this tumor from a leiomyoma?
- Presence of SRF:RELA fusion
- Psammomatous calcifications
- Ectatic vessels
- Coexpression of SMA and desmin
Answers to Quiz
Q2. D
Q3. A
Diagnosis
Discussion
Myofibromas, like glomus tumors, are considered to be of pericytic origin. A subset of them with increased cellularity have been associated with molecular fusions involving the SRF gene, including SRF::RELA. There is no clear gender predilection and, while they can occur in a wide age range, they are more common in the pediatric population (Question 2). They can also present in a wide range of locations, including trunk, upper and lower extremities, head and neck, as well as visceral organs, and they more commonly occur in deep soft tissue. To our knowledge, there are no prior reported cases in the mediastinum.
They have morphologic overlap with a number of other mesenchymal tumors, including smooth muscle neoplasms, synovial sarcomas, and spindle cell rhabdomyosarcomas, which can lead to diagnostic confusion. Helpful morphologic features may include some combination of calcifications, fascicular and/or nested growth, areas of varying cellularity, and ectatic vasculature. Their mitotic activity can also be relatively high, which, given that they invariably express myoid markers including SMA and desmin, can lead to a misdiagnosis as a leiomyoma or leiomyosarcoma. Focal necrosis has been reported. Keratin staining may be absent to heterogeneous and focal CD34 positivity may be identified. They are negative for myogenin. The presence of an SRF fusion is the most reliable way to distinguish this tumor from mimickers (Question 3). In addition to SRF::RELA, other SRF fusion partners have been described.
Clinically, they are well behaved. Metastasis has not been reported and local recurrence is rare (approximately 5% of cases). Thus, it is critical to distinguish them from their more aggressive mimickers for appropriate treatment and prognostication.
Pediatric mesenchymal tumors can be difficult to classify. The realization that a number of these tumors harbor molecular changes, such as gene rearrangements, has greatly assisted with diagnosis. In addition to cellular myofibromas with associated fusions, a number of fusion-associated mesenchymal tumors, such as synovial sarcoma, inflammatory myofibroblastic tumor, alveolar rhabdomyosarcoma, and lipofibromatosis-like neural tumor, are more common in children and young adults compared to the older adult population (Question 2).Take-home message for trainees: Mesenchymal tumors of the mediastinum are rare, particularly in children. Cellular myofibromas with an associated fusion are also rare, but should be considered in the differential diagnosis of mesenchymal neoplasms with myoid differentiation, particularly in children and young adults. Morphologic features such as variable cellularity, calcifications, and ectatic vessels also raise consideration of this entity. If molecular testing is available, have a low threshold for ordering fusion studies in morphologically bland mesenchymal tumors in children and young adults.
References
Biko DM, Lichtenberger JP 3rd, Rapp JB, Khwaja A, Huppmann AR, Chung EM. Mediastinal Masses in Children: Radiologic-Pathologic Correlation. Radiographics. 2021 Jul-Aug;41(4):1186-1207. doi: 10.1148/rg.2021200180. Epub 2021 Jun 4. Erratum in: Radiographics. 2021 Sep-Oct;41(5):E164. doi: 10.1148/rg.2021219008. PMID: 34086496.
Karanian M, Kelsey A, Paindavoine S, Duc A, Vanacker H, Hook L, Weinbreck N, Delfour C, Minard V, Baillard P, Blay JY, Pissaloux D, Tirode F. SRF Fusions Other Than With RELA Expand the Molecular Definition of SRF-fused Perivascular Tumors. Am J Surg Pathol. 2020 Dec;44(12):1725-1735. doi: 10.1097/PAS.0000000000001546. PMID: 33021523.
Li Y, Huang D, Bi R, Yao Q, Ge L, Yu L, Zhou X, Yang W. Uterine tumours with myogenic differentiation harbouring SRF::RELA fusions. Histopathology. 2022 Oct;81(4):477-485. doi: 10.1111/his.14724. Epub 2022 Aug 3. PMID: 35852178.
Mullen B, Richardson JD. Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg. 1986 Sep;42(3):338-45. doi: 10.1016/s0003-4975(10)62751-8. PMID: 3530162.
Suurmeijer AJH, Kao YC, Antonescu CR. New advances in the molecular classification of pediatric mesenchymal tumors. Genes Chromosomes Cancer. 2019 Feb;58(2):100-110. doi: 10.1002/gcc.22681. Epub 2018 Oct 11. PMID: 30187985; PMCID: PMC6855396.Contributors
Jason Chang, MD; Assistant Attending Pathologist, Memorial Sloan Kettering Cancer Center, NY
