Soft tissue tumors characterized by a wide spectrum of kinase fusions share a lipofibromatosis-like neural tumor pattern

Abstract

Gene fusions resulting in oncogenic activation of various receptor tyrosine kinases, including NTRK1-3, ALK, and RET, have been increasingly recognized in soft tissue tumors (STTs), displaying a wide morphologic spectrum and therefore diagnostically challenging. A subset of STT with NTRK1 rearrangements were recently defined as lipofibromatosis-like neural tumors (LPFNTs), being characterized by mildly atypical spindle cells with a highly infiltrative growth in the subcutis and expression of S100 and CD34 immunostains. Other emerging morphologic phenotypes associated with kinase fusions include infantile/adult fibrosarcoma and malignant peripheral nerve sheath tumor-like patterns. In this study, a large cohort of 73 STT positive for various kinase fusions, including 44 previously published cases, was investigated for the presence of an LPFNT phenotype, to better define the incidence of this distinctive morphologic pattern and its relationship with various gene fusions. Surprisingly, half (36/73) of STT with kinase fusions showed at least a focal LPFNT component defined as >10%. Most of the tumors occurred in the subcutaneous tissues of the extremities (n = 25) and trunk (n = 9) of children or young adults (<30 years old) of both genders. Two-thirds (24/36) of these cases showed hybrid morphologies with alternating LPFNT and solid areas of monomorphic spindle to ovoid tumor cells with fascicular or haphazard arrangement, while one-third (12/36) had pure LPFNT morphology. Other common histologic findings included lymphocytic infiltrates, staghorn-like vessels, and perivascular or stromal hyalinization, especially in hybrid cases. Mitotic activity was generally low (<4/10 high power fields in 81% cases), being increased only in a minority of cases. Immunoreactivity for CD34 (92% in hybrid cases, 89% in pure cases) and S100 (89% in hybrid cases, 64% in pure cases) were commonly present. The gene rearrangements most commonly involved NTRK1 (75%), followed by RET (8%) and less commonly NTRK2, NTRK3, ROS1, ALK, and MET.

Keywords: MET; NTRK; RET; lipofibromatosis-like neural tumor.

FIGURE 1

Lipofibromatosis-like neural tumor with kinase gene fusions. Spindle cells infiltrating adipose tissue, A, and skeletal muscle, B. Focal lipoblast-like cells resembling those of lipofibromatosis are seen in some cases, C. The tumor cells are usually relatively monotonous ovoid to short spindle cells with vesicular chromatin and indistinct cell borders, C, and some cases show mild atypia and hyperchromasia, D. Scattered cellular aggregates of round and primitive-appearing cells are also present in rare cases, D. (A–C, case 5; D, case 30) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Tumors with hybrid lipofibromatosis-like neural tumor (LPFNT) and solid patterns. Many cases show solid areas of compact spindle cell proliferation as well as lipofibromatosis-like pattern, A,B. Some cases have the solid area in the dermis and LPFNT pattern in the subcutis (A, case 17), and others have both components in the subcutis (B, case 15). The solid areas often show sheets of spindle to ovoid cells in a fascicular or haphazard arrangement (C, case 21). Skeletal muscle involvement is also seen in some cases (D, case 14). A minority of cases show occasional nuclear atypia and hyperchromasia (E, case 15). Other accompanying features include staghorn vessels (F, case 15), lymphocytic infiltrate (F,G, cases 15 and 24), perivascular hyalinization (H, case 13), and ropey collagen fibers admixed with tumor cells (I, case 29) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

A congenital superficial back lipofibromatosis-like neural tumor (LPFNT) harboring TFG-MET fusion (case 34). The tumor shows solid areas in the dermis, A, and an infiltrative, lipofibromatosis-like pattern in the subcutis, B. A triphasic pattern with hypocellular collagenous areas alternating with loosely arranged primitive ovoid cells within the adipocytic component, C,D [Color figure can be viewed at wileyonlinelibrary.com]