Timetable with key events in studies on myxoid tumors of soft tissue. Though Müller already mentioned tumors with a macroscopically gelatinous appearance in 1838 [3], it was in 1858 when Virchow introduced the term myxoma to describe tumors which morphologically resembled the jelly structure of the umbilical cord [1]. Ever since, the term myxosarcoma, introduced by Bryant in 1802 was reserved for the malignant counterparts [4]. Because of their morphologically overlapping features, both terms were used interchangeably, which was mentioned by Stout in 1948 as unwise, warranting for macroscopical and microscopical criteria for the reliable differential diagnosis between the two entities [5]. The relationship between myxomas and fibrous dysplasia was first described in 1926 by Henschen [90], though it was Mazabraud who proposed it as a syndrome in 1967 [91]. The association of cardiac/cutaneous myxomas, hyperpigmentation of the skin, and endocrine overactivity was only recognized in 1985 by Carney [43]. Progress in the study of the myxoid ECM was made by the invention of the alcian blue staining in 1950 by Steedman [9], and Scott who developed the CEC method to distinguish the different GAGs in 1965 [10]. Based upon this technique, Kindblom showed in 1975 that different bone and soft tissue tumors (including myxoid ones) contained different GAGs [11]. From the late 1980s, it became clear that the ECM is a key player in tumor development and tumor progression, sustained by an exponentially growing number of publications [40]. As myxoid areas were now being recognized as an intrinsic part of a subset of tumors, Weiss and Angervall simultaneously described the myxoid variant of malignant fibrous histiocytoma/myxofibrosarcoma as a distinct entity [92, 93]. Parallel to morphological classification, an increasing number of myxoid tumors showed specific molecular genetics aberrations, such as (activating) mutations and translocations. The concept of malignant progression in myxoid tumors of soft tissue (i.e., myxoid liposarcoma) due to chromosomal instability and subsequent secondary genetic events was described in 1990 by Orndal et al. [94]. Nowadays, classification of myxoid tumors of soft tissues is based upon clinicopathological and molecular/cytogenetic aberrations as published in the 2002 WHO classification [7]

Myxoid ECM is a ubiquitously histological feature in physiological and pathological conditions. Myxoid ECM is a morphological feature in physiological and pathological conditions, such as in myxedema due to increased production of HA. Myxoid areas/changes are also commonly present in tumors (both of epithelial and mesenchymal origin). In epithelial tumors, myxoid changes are often a secondary phenomenon, whereas in mesenchymal tumors, they are more frequently an intrinsic part of the tumor entity. This group of so-called myxoid tumors of soft tissues contains an increasing number of entities (e.g., myxofibrosarcoma, formerly called myxoid variant of malignant fibrous histiocytoma), sometimes sustained by specific distinct molecular/cytogenetic aberrations (e.g., myxoid liposarcoma)

Characteristic macroscopy and histomorphology of the myxoid ECM. Rudolph Virchow introduced the term myxoma for those tumors morphologically resembling Wharton’s jelly of the umbilical cord (a), which contains large amounts of GAGs as detected by alcian blue (b). High-power image of Wharton’s jelly showing abundant myxoid ECM containing fibrillary collagens, interspersed between myofibroblast-like stroma cells (c). Intramuscular myxoma characteristically has a gelatinous appearance on cut surface (d) and is well circumscribed towards its peripheral tissue (e). On higher magnification, it shows the same abundant myxoid ECM as the umbilical cord (c) and no significant atypia of the sparse tumor cells (f). Histological criteria are still a hallmark of diagnosis, showing characteristic lobulated, hypocellular morphology of grade I myxofibrosarcoma at low magnification (g).Curvilinear blood vessels are often seen in grade I myxofibrosarcoma (but are not diagnostic), whereas tumor cells show vesicular, slightly atypical nuclei compared to intramuscular myxoma (h). Another hallmark of myxofibrosarcoma is areas with abrupt transition of grade (i) which was already mentioned by Mentzel et al. [95]