Get an inside look at how Enzinger and Weiss's Soft Tissue Tumors approaches emerging entities — from GLI1-altered neoplasms and PATZ1-rearranged sarcomas to NFATC2 sarcomas and other newly recognized molecularly defined soft tissue tumors.
For more than 40 years, the most authoritative, comprehensive reference available on soft tissue pathology Order your copy today at elsevierhealth.com/9780443248757 From Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition Exclusive preview: Emerging Entities 1301 CHAPTER 36 Emerging Entities not SOX10) (Fig. 36.5B). The tumors are also variably posi- tive for smooth muscle actin, EMA, keratins, and CD99. 6,8,11,12 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 immunoreactiv- ity (Fig. 36.6) and GLI1 -rearranged tumors tending to show weaker, cytoplasmic staining. 13,14 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 diagno- sis. 6,15 Expression of p16 protein is also commonly present in GLI1 -amplified but not rearranged tumors. 9,13 MOLECULAR GENETIC FINDINGS 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 com- mon fusion partner is ACTB 15 ; 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. 16 Tumors harboring GLI1 amplification are less common and seem to behave more aggressively. 7 OUTCOME 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. 7 The natural history of GLI1 - rearranged tumors seems to be favorable, with disease pro- gression 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. 7 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 pro- gression, 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. 7 DIFFERENTIAL DIAGNOSIS 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., 6 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 Fig. 36.1 A GLI1 -rearranged tumor composed of tumor cells with a corded and nested growth pattern mim- icking a neuroendocrine tumor, as well as microcystic spaces. 1304 CHAPTER 36 Emerging Entities Other sites of disease have included the extremities, the head and neck, and the tongue. 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 mag- nification, 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 sar- coma) (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 pres- ent (Fig. 36.11). A A B B Fig. 36.4 GLI1 - rearranged tumor illustrating nested (A) and pseudopapillary (B) areas. 1309 CHAPTER 36 Emerging Entities lobules and nests. 30 The distinctive, polyphenotypic immuno- profile of these tumors also helps to greatly narrow down the differential diagnosis, with the obvious exceptions of rhabdo- myosarcoma and myoepithelioma. Morphologic evaluation is also the key to distinguishing EWSR1::PATZ1 sarcoma with expression of skeletal muscle markers from rhabdomyosarcoma, as the morphologic features of this tumor are quite different from those of alveolar rhab- domyosarcoma, embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, or MYOD1 - mutant spindle cell/sclerosing rhabdomyosarcoma (see Chapter 20) for details). Fusion-driven adult spindle cell rhabdomyosarcomas are also quite different, as they typically arise in bone, show high-grade spindle cell morphology and most often harbor FUS::TFCP2 fusions. 36 Morphologic evaluation is less helpful in the distinction of EWSR1::PATZ1 sarcoma from myoepithelial neoplasms, given the strikingly protean features of that tumor type (see Chapter 33) . 37–42 Unfortunately, immunohistochemical studies may not resolve this differential diagnosis, as almost all EWSR1::PATZ1 sarcomas demonstrate expression of myoepithelial markers (e.g., GFAP, SOX10, keratins). The expression of skeletal mus- cle markers points toward an EWSR1::PATZ1 sarcoma, as these markers are not positive in myoepithelial tumors. 37–42 NFATC2 SARCOMAS NFATC2 sarcoma was first described by Szuhai et al. in 2009 43 when they reported four “Ewing sarcomas” containing a A A B B Fig. 36.12 PATZ1 - rearranged tumors are “polyphenotypic, ” often with coexpression of GFAP (A), desmin (B), and MYOD1 Continued Fig. 36.8 PATZ1 - rearranged tumor. Tumor cells lining a microcyst, surrounded by bland, small, round cells. A A B B Fig. 36.9 PATZ1 - rearranged tumor. The tumor has a reticular (A) or a whorled growth pattern (B).
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1300 GLI1 - ALTERED NEOPLASMS GLI1 - altered malignant neoplasms are an emerging group of tumors characterized by predominantly epithelioid morphology and GLI1 gene alterations, including gene fusions and amplifi- cations. 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. 1 Fusion events involving the GLI1 gene are also seen in two distinctive tumors of the gas- trointestinal tract, plexiform fibromyxoma ( MALAT1::GLI1 ) 2,3 and gastroblastoma ( MALAT1::GLI1 and ACTB::GLI1 ) 4,5 (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”. 6 CLINICAL FINDINGS These are rare tumors, with 108 reported cases, including 80 tumors with GLI1 - rearrangement and 28 tumors with GLI1 amplification. 7 They have a wide age range, with median patient ages of 38 and 46 years, for rearranged and amplified tumors, respectively. 7,8 The gender distribution appears to be approxi- mately 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. 6–10 Clinically, they are usually painless, slowly growing tumors. Gross and Microscopic Findings Grossly, the tumors are solid and cystic and sometimes hemor- rhagic. 8 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 evalu- ation 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 neuroendo- crine tumor. 6,7 Less often, the tumors are composed of spindled cells or a mixture of cell types. 7 A variety of architectural pat- terns 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, remi- niscent of a perineurial tumor or dermatofibrosarcoma protu- berans. 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. 7 IMMUNOHISTOCHEMICAL FINDINGS 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 36 Emerging Entities O U T L I N E GLI1 - Altered Neoplasms, 1300 PATZ1 -Rearranged Sarcoma, 1303 NFATC2 Sarcomas, 1309 EWSR1/FUS::POU2AF3 ( COLCA2 ) Sarcoma, 1311 Sarcomas Harboring Fusions of the NUTM1 Gene with Max (MYC-Associated Factor X) Dimerization (MAD) Family Genes ( MGA, MXD4, MXD1, MXI1 ), 1312 KMT2A -Rearranged Sarcoma, 1316 PRRX::NCOAx Fibroblastic Tumors, 1318 Superficial Neurocristic FET::ETS Fusion Tumor, 1321 Pseudoendocrine Sarcoma, 1324 Spindle Cell Tumors with Kinase Gene Fusions, 1328 1300 GLI1 - ALTERED NEOPLASMS GLI1 - altered malignant neoplasms are an emerging group of tumors characterized by predominantly epithelioid morphology and GLI1 gene alterations, including gene fusions and amplifi- cations. 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. 1 Fusion events involving the GLI1 gene are also seen in two distinctive tumors of the gas- trointestinal tract, plexiform fibromyxoma ( MALAT1::GLI1 ) 2,3 and gastroblastoma ( MALAT1::GLI1 and ACTB::GLI1 ) 4,5 (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”. 6 CLINICAL FINDINGS These are rare tumors, with 108 reported cases, including 80 tumors with GLI1 - rearrangement and 28 tumors with GLI1 amplification. 7 They have a wide age range, with median patient ages of 38 and 46 years, for rearranged and amplified tumors, respectively. 7,8 The gender distribution appears to be approxi- mately 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. 6–10 Clinically, they are usually painless, slowly growing tumors. Gross and Microscopic Findings Grossly, the tumors are solid and cystic and sometimes hemor- rhagic. 8 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 evalu- ation 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 neuroendo- crine tumor. 6,7 Less often, the tumors are composed of spindled cells or a mixture of cell types. 7 A variety of architectural pat- terns 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, remi- niscent of a perineurial tumor or dermatofibrosarcoma protu- berans. 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. 7 IMMUNOHISTOCHEMICAL FINDINGS 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 36 Emerging Entities O U T L I N E GLI1 - Altered Neoplasms, 1300 PATZ1 -Rearranged Sarcoma, 1303 NFATC2 Sarcomas, 1309 EWSR1/FUS::POU2AF3 ( COLCA2 ) Sarcoma, 1311 Sarcomas Harboring Fusions of the NUTM1 Gene with Max (MYC-Associated Factor X) Dimerization (MAD) Family Genes ( MGA, MXD4, MXD1, MXI1 ), 1312 KMT2A -Rearranged Sarcoma, 1316 PRRX::NCOAx Fibroblastic Tumors, 1318 Superficial Neurocristic FET::ETS Fusion Tumor, 1321 Pseudoendocrine Sarcoma, 1324 Spindle Cell Tumors with Kinase Gene Fusions, 1328 GLI1 - ALTERED NEOPLASMS GLI1 - altered malignant neoplasms are an emerging group of tumors characterized by predominantly epithelioid morphology and GLI1 gene alterations, including gene fusions and amplifi- cations. 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. 1 Fusion events involving the GLI1 gene are also seen in two distinctive tumors of the gas- trointestinal tract, plexiform fibromyxoma ( MALAT1::GLI1 ) 2,3 and gastroblastoma ( MALAT1::GLI1 and ACTB::GLI1 ) 4,5 (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”. 6 CLINICAL FINDINGS These are rare tumors, with 108 reported cases, including 80 tumors with GLI1 - rearrangement and 28 tumors with GLI1 amplification. 7 They have a wide age range, with median patient ages of 38 and 46 years, for rearranged and amplified tumors, respectively. 7,8 The gender distribution appears to be approxi- mately 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. 6–10 Clinically, they are usually painless, slowly growing tumors. Gross and Microscopic Findings Grossly, the tumors are solid and cystic and sometimes hemor- rhagic. 8 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 evalu- ation 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 neuroendo- crine tumor. 6,7 Less often, the tumors are composed of spindled cells or a mixture of cell types. 7 A variety of architectural pat- terns 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, remi- niscent of a perineurial tumor or dermatofibrosarcoma protu- berans. 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. 7 IMMUNOHISTOCHEMICAL FINDINGS 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 36 Emerging Entities O U T L I N E GLI1 - Altered Neoplasms, 1300 PATZ1 -Rearranged Sarcoma, 1303 NFATC2 Sarcomas, 1309 EWSR1/FUS::POU2AF3 ( COLCA2 ) Sarcoma, 1311 Sarcomas Harboring Fusions of the NUTM1 Gene with Max (MYC-Associated Factor X) Dimerization (MAD) Family Genes ( MGA, MXD4, MXD1, MXI1 ), 1312 KMT2A -Rearranged Sarcoma, 1316 PRRX::NCOAx Fibroblastic Tumors, 1318 Superficial Neurocristic FET::ETS Fusion Tumor, 1321 Pseudoendocrine Sarcoma, 1324 Spindle Cell Tumors with Kinase Gene Fusions, 1328
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1301 CHAPTER 36 Emerging Entities not SOX10) (Fig. 36.5B). The tumors are also variably posi- tive for smooth muscle actin, EMA, keratins, and CD99. 6,8,11,12 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 immunoreactiv- ity (Fig. 36.6) and GLI1 - rearranged tumors tending to show weaker, cytoplasmic staining. 13,14 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 diagno- sis. 6,15 Expression of p16 protein is also commonly present in GLI1 - amplified but not rearranged tumors. 9,13 MOLECULAR GENETIC FINDINGS 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 com- mon fusion partner is ACTB 15 ; 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. 16 Tumors harboring GLI1 amplification are less common and seem to behave more aggressively. 7 OUTCOME 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. 7 The natural history of GLI1 - rearranged tumors seems to be favorable, with disease pro- gression 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. 7 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 pro- gression, 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. 7 DIFFERENTIAL DIAGNOSIS 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., 6 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 Fig. 36.1 A GLI1 - rearranged tumor composed of tumor cells with a corded and nested growth pattern mim- icking a neuroendocrine tumor, as well as microcystic spaces.
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1302 CHAPTER 36 Emerging Entities A A B B Fig. 36.2 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). 1302 CHAPTER 36 Emerging Entities A A B B Fig. 36.2 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). 1302 CHAPTER 36 Emerging Entities A A B B Fig. 36.2 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).
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1303 CHAPTER 36 Emerging Entities 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 immu- nohistochemical 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, ker- atins, 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 distin- guished from distinctive gastrointestinal tumors harboring GLI1 rearrangements, gastroblastomas 4 and plexiform fibro- myxomas. 3 Gastroblastoma is a biphasic tumor that arises in the stomach and is characterized by MALAT1::GLI1 fusion or less often ACTB::GLI1 fusion. 4,5 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. 3 SARCOMAS WITH EWSR1 ::NON- ETS FUSIONS ( EWSR1::PATZ1, EWSR1::NFATC2 AND EWSR1::POU2AF3 ) The current WHO classification of soft tissue and bone tumors includes two entities in this category; PATZ1 - rearrranged sar- comas, 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. 17 More recently, a small number of sarcomas with fusion involving EWSR1 and POU2AF3 have been reported. 18–20 PATZ1 -REARRANGED SARCOMA PATZ1 - rearranged sarcoma is a recently described soft tis- sue 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. 21 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. 22 Clinical Findings Fewer than 50 cases have been reported, occurring in 30 men and 16 women, ranging from 1 to 81 years of age (median 47 years). 21–31 They have been reported to arise in a variety of soft tissue locations, most commonly the chest wall and abdomen. Fig. 36.3 A GLI1- amplified tumor arising in the tongue. The tumor has reticulated growth pattern with extra- cellular myxoid matrix.
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1304 CHAPTER 36 Emerging Entities Other sites of disease have included the extremities, the head and neck, and the tongue. 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 mag- nification, 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 sar- coma) (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 pres- ent (Fig. 36.11). A A B B Fig. 36.4 GLI1 - rearranged tumor illustrating nested (A) and pseudopapillary (B) areas.
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1305 CHAPTER 36 Emerging Entities 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 expres- sion of desmin, myogenin, MYOD1, and/or PAX7 30 (Fig. 36.12B and C). Other markers present in subsets of cases include CD99 (weak, patchy), synaptophysin, and neuron-specific enolase (NSE). 26 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. Molecular Genetic Findings All cases reported to date have harbored EWSR1::PATZ1 gene fusion. 21–31 EWSR1 exon 8: PATZ1 exon 1 is by far the most common fusion subtype, followed by EWSR1 exon 9: PATZ1 exon 1 and EWSR1 exon 7: PATZ1 exon 1. 30 The PATZ1 gene, a member of the BTB-ZF (broad- complex, tram-track and bric-a-brac - zinc finger) gene fam- ily, is involved in chromatin remodeling and transcriptional control. 32 EWSR1 and PATZ1 are closely located on chromo- some 22 and are normally transcribed in opposite directions. As the EWSR1::PATZ1 fusion is thought to be the result of a cryptic paracentric inversion, 24 Fluorescence in situ hybrid- ization (FISH) studies for EWSR1 rearrangement are often falsely negative. 26 In our own practices, we identify this fusion event with NGS. EWSR1::PATZ1 fusion is not specific to these rare sarcomas, and has also been reported in very rare thyroid-like follicular renal cell carcinoma and a distinct group of central nervous system tumors. 33,34 A A B Fig. 36.5 GLI1- rearranged tumor composed of non-pleomorphic round cells (A) that express S100 protein (B).
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1306 CHAPTER 36 Emerging Entities Outcome Owing to its rarity and recent recognition long-term follow-up on these tumors is limited, and their natural history remains incompletely understood. Initially, EWSR1::PATZ1 sarcomas were believed to represent highly aggressive, “Ewing-like” sar- comas, with documented metastatic disease in 9 of 11 (82%) patients with clinical follow-up in the first few studies of this entity. 21–24,26 However, as is often the case in the initial reports of new entities defined by molecular genetic events, clinical fol- low-up was not available for nearly half of the reported patients, raising the distinct possibility of overreporting of clinically malignant tumors. The more recent, larger study by Dehner et al. suggests that the prognosis of patients with EWSR1::PATZ1 sarcomas may be more favorable than was initially thought, with 12 of 16 patients with follow- up being disease-free at the time of last clinical contact. 30 These investigators suggested that patients with EWSR1::PATZ1 sarcomas might fall into two subgroups; those with metastases either at presentation or very shortly thereafter, and those in whom metastatic disease either occurs significantly Fig. 36.6 GLI1 - amplified tumor, positive for GLI1 protein by immunohistochemistry. Fig. 36.7 Low- power view of a PATZ1 - rearranged tumor, demonstrating encapsulation, thick fibrous septae, and microcystic spaces.
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 Fig. 36.8 PATZ1 - rearranged tumor. Tumor cells lining a microcyst, surrounded by bland, small, round cells. A A B B Fig. 36.9 PATZ1 - rearranged tumor. The tumor has a reticular (A) or a whorled growth pattern (B).
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1308 CHAPTER 36 Emerging Entities later or perhaps not at all. Histological, immunohistochem- ical and molecular genetic features, including the presence of secondary genetic alterations such as CDKN2A/B muta- tions, do not seem associated with outcome in EWSR1::PATZ1 sarcomas. 24,26,30 Differential Diagnosis The differential diagnosis of EWSR1::PATZ1 sarcomas is poten- tially quite expansive, and includes a variety of round cell sarcomas, rhabdomyosarcomas, myoepithelial tumors, and even solitary fibrous tumor or ossifying fibromyxoid tumor. 26,30,35 Recognition of the distinctive morphologic features of EWSR1::PATZ1 sarcomas is particularly helpful in resolving these differential diagnoses. As has been emphasized by Dehner et al., it is the combination of round, spindled and epithelioid cell types that is most characteristic of this entity, as well as its unique architectural features, in particular microcystic/pseudo- alveolar spaces and thick fibrous bands dividing the tumor into Fig. 36.10 PATZ1- rearranged tumor with greater cytologic atypia. Fig. 36.11 Although expression of skeletal muscle markers is common in PATZ1 - rearranged tumors, overt skeletal muscle differentiation in the form of rhabdomyoblasts is rare.
Order your copy of Enzinger and Weiss’s Soft Tissue Tumors, 8th Edition at elsevierhealth.com/9780443248757 1309 CHAPTER 36 Emerging Entities lobules and nests. 30 The distinctive, polyphenotypic immuno- profile of these tumors also helps to greatly narrow down the differential diagnosis, with the obvious exceptions of rhabdo- myosarcoma and myoepithelioma. Morphologic evaluation is also the key to distinguishing EWSR1::PATZ1 sarcoma with expression of skeletal muscle markers from rhabdomyosarcoma, as the morphologic features of this tumor are quite different from those of alveolar rhab- domyosarcoma, embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, or MYOD1 -mutant spindle cell/sclerosing rhabdomyosarcoma (see Chapter 20) for details). Fusion-driven adult spindle cell rhabdomyosarcomas are also quite different, as they typically arise in bone, show high-grade spindle cell morphology and most often harbor FUS::TFCP2 fusions. 36 Morphologic evaluation is less helpful in the distinction of EWSR1::PATZ1 sarcoma from myoepithelial neoplasms, given the strikingly protean features of that tumor type (see Chapter 33) . 37–42 Unfortunately, immunohistochemical studies may not resolve this differential diagnosis, as almost all EWSR1::PATZ1 sarcomas demonstrate expression of myoepithelial markers (e.g., GFAP, SOX10, keratins). The expression of skeletal mus- cle markers points toward an EWSR1::PATZ1 sarcoma, as these markers are not positive in myoepithelial tumors. 37–42 NFATC2 SARCOMAS NFATC2 sarcoma was first described by Szuhai et al. in 2009 43 when they reported four “Ewing sarcomas” containing a A A B B Fig. 36.12 PATZ1 - rearranged tumors are “polyphenotypic, ” often with coexpression of GFAP (A), desmin (B), and MYOD1 Continued