GLI1 -altered malignant neoplasms are an emerging group of tumors characterized by predominantly epithelioid morphology and GLI1 gene alterations, including gene fusions and amplifications. Tumors harboring GLI1 alterations were first described by Dahlén et al. in 2004, who reported as “pericytomas with t(7;12)” five distinctive tumors of the tongue, stomach, and calf, harboring ACTB::GLI1 fusions. Fusion events involving the GLI1 gene are also seen in two distinctive tumors of the gastrointestinal tract, plexiform fibromyxoma ( MALAT1::GLI1 ) ^, and gastroblastoma ( MALAT1::GLI1 and ACTB::GLI1 ) ^, (see Chapter 18 ). This section will discuss only GLI1 -altered tumors in somatic soft tissue locations, some of which have been reported as “distinctive nested glomoid neoplasms”.

These are rare tumors, with 108 reported cases, including 80 tumors with GLI1 -rearrangement and 28 tumors with GLI1 amplification. They have a wide age range, with median patient ages of 38 and 46 years, for rearranged and amplified tumors, respectively. ^, The gender distribution appears to be approximately equal. Most arise in soft tissues, including the head and neck region, including the tongue, but they can also originate in a variety of other locations such as the gastrointestinal tract, bone, and female genital tract. Clinically, they are usually painless, slowly growing tumors.

Gross and Microscopic Findings

Grossly, the tumors are solid and cystic and sometimes hemorrhagic. They vary in size depending on the site of origin (tongue tumors usually being small), but most are less than 10 cm.

Microscopically, GLI1 -rearranged and amplified tumors show overlapping features, and it is not possible to predict the underlying molecular genetic event by histopathological evaluation alone. They typically grow in a relatively circumscribed, multinodular pattern, with delicate intervening fibrous septae. They are most often composed of uniform, round to epithelioid cells, sometimes mimicking a glomus tumor or a neuroendocrine tumor. ^, Less often, the tumors are composed of spindled cells or a mixture of cell types. A variety of architectural patterns may be present, including nodules, small nests, cords of nests, pseudopapillae, or microcystic/reticular, sometimes with extracellular myxoid areas ( Figs. 36.1–36.5A ). Rarely, more spindled tumors display whorled or storiform patterns, reminiscent of a perineurial tumor or dermatofibrosarcoma protuberans. Intravascular extension may be prominent, and when present is a useful clue to this diagnosis. The mitotic rate is highly variable, and necrosis is sometimes present.

A GLI1 -rearranged tumor composed of tumor cells with a corded and nested growth pattern mimicking a neuroendocrine tumor, as well as microcystic spaces.

GlI1 -amplified tumor arising in the finger. The tumor is cellular and lobular with fibrous septae (A). At higher power magnification, the tumor cells are oval to spindle shaped and not arranged in any particular pattern (B).

A GLI1- amplified tumor arising in the tongue. The tumor has reticulated growth pattern with extracellular myxoid matrix.

GLI1 -rearranged tumor illustrating nested (A) and pseudopapillary (B) areas.

GLI1- rearranged tumor composed of non-pleomorphic round cells (A) that express S100 protein (B).

The immunohistochemical profile of GLI1 -altered tumors is, for the most part, fairly nonspecific and tends to include some combination of CD56 and S100 protein expression (but not SOX10) ( Fig. 36.5B ). The tumors are also variably positive for smooth muscle actin, EMA, keratins, and CD99. ^{, , ,} Immunohistochemistry (IHC) for GLI1 protein, although not widely available, has been shown to be a specific and sensitive marker for GLI1 -altered tumors with GLI1 -amplified tumors typically showing diffuse, strong nuclear immunoreactivity ( Fig. 36.6 ) and GLI1 -rearranged tumors tending to show weaker, cytoplasmic staining. ^, Because the GLI1 gene is located in close proximity to the MDM2 , CDK4 , DDIT3 , and STAT6 , GLI1 -altered tumors may be positive by IHC for these markers, occasionally serving as a helpful clue to this diagnosis. ^, Expression of p16 protein is also commonly present in GLI1 -amplified but not rearranged tumors. ^,

GLI1 -amplified tumor, positive for GLI1 protein by immunohistochemistry.

GLI1 encodes for a transcription factor that plays a role in the Hedgehog signaling pathway, and GLI1 alterations are present in a variety of tumors. For rearranged tumors, the most common fusion partner is ACTB ; other partners include MALAT1, PTCH1, MRTFA, APOD, DERA, SYT, NCOR2, HNRNPA1, TXNIP, NEAT, and PAMR1 . A GLI1::FOXO4 fusion has been reported in myxoid epithelioid tumors arising in the kidney, although the classification of these very rare tumors is unclear. Tumors harboring GLI1 amplification are less common and seem to behave more aggressively.

A recent comprehensive analysis of 83 GLI1 -altered neoplasms with clinical follow-up, including 58 GLI1 -rearranged and 28 GLI1 -amplifed tumors, by Saoud et al., greatly improved our understanding of these tumors. The natural history of GLI1 -rearranged tumors seems to be favorable, with disease progression in 20 reported patients (34%), including 6 with local recurrences, 7 with metastases, and 7 with both. The median progression-free survival of patients with GLI1 -rearranged tumors was 77 months; only a single patient was reported to have died from disease, with 12 patients reported to be alive with disease and 45 alive without disease. In contrast, patients with GLI1 -amplified tumors had a more rapidly progressive clinical course, with a median progression-free survival of only 25 months; 11 of 28 patients with follow-up showed disease progression, including 3 with local recurrences, 3 with metastases, 4 with both, and 1 with death from advanced local disease. The overall survival for patients with GLI1 -amplified tumors was significantly worse than for their GLI1 -rearranged counterparts. Patients with GLI1 -rearranged but not GLI1 -amplified tumors may also have multiple metastatic events separated by multiyear disease-free intervals. Multivariate analysis identified larger tumor size (>5 cm) and mitotic activity >4/10 HPF as adverse prognostic factors for GLI1 -rearranged tumors; only elevated mitotic activity was significant for GLI1 -amplified tumors.

Recognition of GLI1 -altered tumors may be quite challenging, as these neoplasms have somewhat nonspecific morphologic features, potentially overlapping with those of a wide variety of round cell, epithelioid, and even spindle cell tumors. As has been emphasized by Papke et al., GLI1 -altered tumors may simulate glomus tumors or other myopericytic neoplasms. Although they tend not to have the very regular appearance or well-defined cell borders of glomus tumors, they usually show lesser degrees of smooth muscle actin expression and lack the caldesmon and diffuse pericellular collagen IV expression seen in true glomus tumors. Similarly, although the morphologic features of GLI1 -altered tumors may overlap with a variety of round cell malignant neoplasms, they lack characteristic immunohistochemical findings such as strong expression of markers such as CD99 (Ewing sarcoma), desmin (rhabdomyosarcoma), nuclear WT1 ( CIC- rearranged sarcomas), SOX10 (small cell melanoma), or keratins (carcinomas). Coexpression of S100 protein and smooth muscle actin in GLI1 -altered tumors may raise the question of a myoepithelial neoplasm; however, keratins, SOX10 and GFAP are absent. As noted above, finding MDM2, CDK4, DDIT3, or STAT6 expression by IHC in a round cell or glomoid tumor may also point toward a GLI1 -amplified tumor, if such markers are evaluated. Unlike perineuriomas or dermatofibrosarcomas, GLI1 -altered tumors with spindle cell morphology tend to lack EMA or CD34 expression. Ultimately, however, the diagnosis of GLI1 -altered tumors requires a high index of suspicion, GLI1 immunohistochemistry (if available), and appropriate molecular genetic testing for both fusion events and gene amplification.

Finally, GLI1 -altered soft tissue tumors should be distinguished from distinctive gastrointestinal tumors harboring GLI1 rearrangements, gastroblastomas and plexiform fibromyxomas. Gastroblastoma is a biphasic tumor that arises in the stomach and is characterized by MALAT1::GLI1 fusion or less often ACTB::GLI1 fusion. ^, They are morphologically different from GLI1 -rearranged tumors and are composed of spindle cells and nests of epithelial cells that stain for keratins. Plexiform fibromyxoma also arises in the stomach and, unlike GLI1 -rearranged tumors of soft tissue, has a plexiform growth pattern composed of bland spindled cells in a highly vascular background. They typically have MALAT1::GLI1 fusion.

The current WHO classification of soft tissue and bone tumors includes two entities in this category; PATZ1 -rearrranged sarcomas, which have only been reported in soft tissue locations, and NFATC2 -rearrranged sarcomas, which almost always arises in bone, with only rare soft tissue cases. More recently, a small number of sarcomas with fusion involving EWSR1 and POU2AF3 have been reported.

PATZ1 -rearranged sarcoma is a recently described soft tissue tumor with variable morphology and a polyphenotypic immunohistochemical profile. This tumor was first described by Mastrangelo et al. in their report of an unusual chest-wall mass in a 16-year-old boy. An expression profiling study of 184 round cell sarcomas by Watson et al. identified five EWSR1::PATZ1 -fused tumors, displaying a gene expression profile different from that of other tumors.

Gross and Microscopic Findings

Grossly, the tumors have measured from 0.7 to 18 cm. They are well-circumscribed with tan–yellow or gray–white cut surfaces with or without areas of necrosis. At low-power magnification, PATZ1 sarcomas often have a very characteristic appearance, with a well-formed fibrous capsule, peripheral lymphoid aggregates, and small “mushroom-like” tumor cell protrusions through the capsule into surrounding connective tissue ( Fig. 36.7 ). Diffusely infiltrative growth is uncommon. A distinctly lobulated growth pattern, with intervening thick, fibrous septa is frequently present, as are pseudoalveolar or microcystic spaces ( Fig. 36.8 ). Thick-walled, hyalinized vessels are typically seen, a feature suggesting relatively slow growth. PATZ1 sarcomas are usually moderately cellular, and consist of an admixture of short spindled cells, smaller round cells, and somewhat epithelioid cells, growing in solid, fascicular, trabecular, reticular, or whorled growth patterns ( Fig. 36.9 ). A zone of accentuated cellularity is often present adjacent to the microcystic spaces. Although these tumors were originally identified in a study of apparently undifferentiated “round cell” sarcomas, they actually tend to be quite bland, and do not display the high cellularity or primitive appearance of true round cell sarcomas (e.g., Ewing sarcoma, CIC -rearranged sarcoma) ( Fig. 36.10 ). Mitotic activity is typically low and tumor cell necrosis is infrequent, although it may be present. Rarely, small clusters of differentiating rhabdomyoblasts may be present ( Fig. 36.11 ).

Low-power view of a PATZ1 -rearranged tumor, demonstrating encapsulation, thick fibrous septae, and microcystic spaces.

PATZ1 -rearranged tumor. Tumor cells lining a microcyst, surrounded by bland, small, round cells.

PATZ1 -rearranged tumor. The tumor has a reticular (A) or a whorled growth pattern (B).

PATZ1- rearranged tumor with greater cytologic atypia.

Although expression of skeletal muscle markers is common in PATZ1 -rearranged tumors, overt skeletal muscle differentiation in the form of rhabdomyoblasts is rare.

Immunohistochemical Findings

PATZ1 -rearranged sarcomas are polyphenotypic lesions, usually showing in part a myoepithelial phenotype, with coexpression of keratins, S100 protein, SOX10, and GFAP ( Fig. 36.12A ), as well as skeletal muscle differentiation, in the form of variable expression of desmin, myogenin, MYOD1, and/or PAX7 ( Fig. 36.12B and C ). Other markers present in subsets of cases include CD99 (weak, patchy), synaptophysin, and neuron-specific enolase (NSE). In combination with the distinctive morphology of these tumors, this peculiar immunoprofile (in particular, expression of skeletal muscle markers) is an excellent clue to this diagnosis.

PATZ1 -rearranged tumors are “polyphenotypic,” often with coexpression of GFAP (A), desmin (B), and MYOD1(C).

NFATC2 sarcoma was first described by Szuhai et al. in 2009 when they reported four “Ewing sarcomas” containing a variant translocation. Since then, fewer than 100 cases have been reported. In the largest study of 1024 EWSR1 fusion positive tumors, Seligson et al. found 14 EWSR1::NFATC2 tumors (1.4%). These tumors were found to be genetically different from Ewing sarcoma and demonstrated upregulation of the mTOR pathway. Additional methylation analysis has supported this with the NFATC2 tumors sharing a different signature from Ewing sarcoma and other EWSR1 -rearranged tumors.

They have a wide age range and are more common in males. NTATC2 -rearranged tumors predominantly arise in bone, with only rare cases arising in soft tissues.

Grossly, the tumors are solid, tan-pink, and fleshy. Histologically, these tumors can have a variety of different patterns, and can be impossible to diagnose by light microscopy alone. They can display features similar to sclerosing epithelioid fibrosarcoma or KMT2A -rearranged sarcoma, where the tumor cells are ovoid or round and are embedded in an extracellular collagenous matrix ( Fig. 36.13 ). They can also have features similar to a myoepithelial tumor, where they form cords, nests, or tubular structures and are embedded in a hyalinized matrix ( Fig. 36.14 ). Sometimes, they can have the features of a malignant round cell sarcoma, being composed of sheets of undifferentiated malignant cells ( Fig. 36.15 ). Within the bone, they demonstrate an infiltrative growth pattern. Mitotic figures are easily found, and necrosis may be present.

This NFATC2 -rearranged sarcoma is composed of round to oval cells embedded in an extracellular collagenous matrix.

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