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17 January 2024 - Case of the Month #535

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Thanks to Dr. Borislav Alexiev, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA for contributing this case and discussion and to Dr. Jefree J. Schulte, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA for reviewing the discussion.

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Case of the Month #535

Clinical history:
A 79 year old patient presented with a pulmonary arterial mass. The tumor showed the following findings.

Microscopic images:

What is your diagnosis?

Click here for diagnosis, test question and discussion:

Diagnosis: Intimal sarcoma

Test question (answer at the end):
Identification of which gene amplification can help confirm the diagnosis?

  1. EWSR1
  2. FUS
  3. MDM2
  4. PLAG1
  5. TGFBR3

FISH image:
<i>MDM2</i> gene in red

MDM2 gene in red

Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISAs) with MDM2 amplification as their molecular hallmark (Mod Pathol 2021;34:2122).

ISAs are rare tumors, with major pulmonary vessel sarcomas occurring twice as often as aortic tumors. The sex ratio is balanced (M:F = 1:1). Patient’s age at presentation ranges from 30 to 83 years, with a median age of 58 years (Mod Pathol 2021;34:2122).

Most patients with pulmonary ISA present with symptoms related to acute or chronic pulmonary hypertension, including dyspnea, chest pain, cough, hemoptysis and syncope (Ann Vasc Surg 2014;28:515, Clin Sarcoma Res 2015;5:3). Nonspecific symptoms of pulmonary hypertension in conjunction with misinterpreted imaging findings are the two main reasons why pulmonary intimal sarcoma is commonly misdiagnosed at clinical presentation.

There are clinical and radiological characteristics which may raise suspicion of this important differential diagnosis. These include disproportionately low D dimer, troponin T or NT proBNP, as well as characteristic findings on CT pulmonary angiography, such as the "wall eclipsing sign" and a nondependent position of filling defects in the large arteries (Respirol Case Rep 2022;10:e0897). The most useful imaging modalities for assessment of a suspected ISA include CT angiography, fluorine 18-fluorodeoxyglucose PET and MRI (Radiographics 2021;41:361).

Grossly, ISAs are mostly intraluminal polypoid masses attached to the vessel wall, resembling thrombi and extending along the branches of the involved vessels.

Morphologically, ISAs are characterized by endoluminal growth, fibrin layering with tumor overgrowth and intimal spread. The tumors are composed of spindle shaped, stellate, oval or polygonal tumor cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism, necrosis and frequent mitotic figures (Virchows Arch 2022;480:919). Prominent spindling and bundling may resemble leiomyosarcoma. Some tumors show myxoid changes or epithelioid morphology. By definition, ISAs lack specific lineage differentiation, although myofibroblastic and rarely osteogenic or chondroid differentiation may occur (Mod Pathol 2021;34:2122). Rare cases may show focal rhabdomyosarcomatous or angiosarcomatous features.

Immunohistochemically, variable expression of SMA, desmin, ERG and keratin AE1/AE3 is found. Rhabdomyosarcomatous differentiation is accompanied by expression of myogenin and MyoD1 (Virchows Arch 2022;480:919). ISAs exhibit immunohistochemical positivity for MDM2 (100%) and CDK4 (79%) (Pathol Res Pract 2021;224:153548).

Molecular studies on pulmonary artery ISAs revealed a high frequency of MDM2 amplifications, accompanied by co-amplifications of CDK4, PDGFRA, TERT, HDAC9, CCND1 and deletion of the tumor suppressor CDKN2A/B (Mod Pathol 2021;34:2122).

DNA methylation profiling may be valuable in increasing the diagnostic accuracy of these rare tumors. Recent studies identified a common methylation fingerprint in ISAs and cardiac undifferentiated pleomorphic sarcomas (Mod Pathol 2021;34:2122).

The prognosis for patients with ISA is poor, with a mean survival time of 5 - 9 months in patients with aortic sarcomas and 13 - 18 months in patients with pulmonary sarcomas (Virchows Arch 2001;438:57, Cancer 1993;71:1761, J Thorac Oncol 2008;3:907).

Test question answer:
C. MDM2. Answer C is correct because MDM2 amplification is the molecular hallmark of intimal sarcoma (Mod Pathol 2021;34:2122). Answer A is incorrect because EWSR1 alterations are associated with Ewing sarcoma, and other tumors. Answer B is incorrect because FUS alterations are associated with angiomatoid fibrous histiocytoma and other tumors. Answer D is incorrect because PLAG1 alterations are associated with lipoblastoma, pleomorphic adenoma and other tumors. Answer E is incorrect because TGFBR3 alterations are associated with pleomorphic hyalinizing angiectatic tumor and other tumors.

Image 01 Image 02