Pleomorphic Sarcomas: The State of the Art (2018) PDF

P l e o m o r p h i c S a rc o m a s The State of the Art Sofia Daniela Carvalho, MDa,b, Daniel Pissaloux, PhDc, Amandine Crombé, MDd, Jean-Michel Coindre, MDb,e, François Le Loarer, MD, PhDa,e,* KEYWORDS  Sarcoma  Undifferentiated pleomorphic sarcoma  Genomic instability  Liposarcoma  Myxo...

P l e o m o r p h i c S a rc o m a s The State of the Art Sofia Daniela Carvalho, MDa,b, Daniel Pissaloux, PhDc, Amandine Crombé, MDd, Jean-Michel Coindre, MDb,e, François Le Loarer, MD, PhDa,e,* KEYWORDS  Sarcoma  Undifferentiated pleomorphic sarcoma  Genomic instability  Liposarcoma  Myxofibrosarcoma  Leiomyosarcoma  Rhabdomyosarcoma  Dedifferentiation Key points  Pleomorphic sarcomas encompass a group of mesenchymal malignancies associated with complex ge- netic features devoid of defining driver alterations.  They may display a broad array of histologic lineages including myogenic, lipogenic, neurogenic, or none.  They affect predominantly adult patients older than 50 years.  Morphologically, they display variable levels of pleomorphism, although pleomorphism is not always a feature of malignancy.  Prognostic stratification can be assessed with the 3-tier French grading system FNCLCC, taking into account morphologic features, mitotic activity, and tumor necrosis. ABSTRACT sarcomas but may provide theranostic and impor- T tant prognostic information in the future. his article focuses on pleomorphic sar- comas, which are malignant mesenchymal tumors with complex genetic background OVERVIEW at the root of their morphologic pleomorphism. They are poorly differentiated tumors that may Pleomorphic sarcomas refer to a heterogeneous retain different lines of differentiation, sometimes group of malignant mesenchymal tumors charac- correlating with clinicopathological or prognostic terized by morphologic pleomorphism, defined features. Accurate diagnosis in this group of tu- as having marked variations in the size and shape mors relies on adequate sampling due to their het- of tumor nuclei and/or cell shape, which is under- erogeneity and assessment with both microscopy lined by genetic instability. Pleomorphic sarcomas and large panels of immunohistochemistry. Mo- mostly affect patients older than 50 years and may lecular analyses have a limited role in their diag- display a wide array of histologic lineages, there- nosis as opposed to translocation-related fore a systematic immunohistochemical panel is Disclosure Statement: Dr. Loarer is supported by a grant from Le Fil d’Oriane. surgpath.theclinics.com a Department of Pathology, Hospital de Braga, Sete Fontes-Sao Victor, 4710-243 Braga, Portugal; b Department of Pathology, Institut Bergonié, 276 cours de l’Argonne, 33000, Bordeaux, France; c Department of Pathology, Centre Leon Berard, Promenade Lea Bullukian, 69376 Lyon, France; d Department of Radiology, Institut Bergonié, 276 cours de l’Argonne, 33000, Bordeaux, France; e University of Bordeaux, Talence, France * Corresponding author. E-mail address: [email protected] Surgical Pathology - (2018) -–- https://doi.org/10.1016/j.path.2018.10.004 1875-9181/18/Ó 2018 Elsevier Inc. All rights reserved. 2 Carvalho et al Box 1 Main types of pleomorphic sarcomas Lines of differentiation in pleomorphic sarcomas Lipogenic differentiation Dedifferentiated liposarcoma Pleomorphic liposarcoma Myogenic differentiation Leiomyosarcoma Pleomorphic rhabdomyosarcoma Neurogenic differentiation Malignant peripheral nerve sheath tumor Osteogenic differentiation Extraskeletal osteosarcoma Vascular differentiation Angiosarcoma Pleomorphic sarcomas as a result of dedifferentiation Dedifferentiated liposarcoma Dedifferentiated gastrointestinal stromal tumor (“sarcoma”) Dedifferentiated solitary fibrous tumor No lineage of differentiation as yet identified Undifferentiated pleomorphic sarcoma Unknown lineage of differentiation Myxofibrosarcoma used to support their classification (Box 1). The descriptive terms reflecting their heterogeneous most frequent subtypes of pleomorphic sarcomas features, and histotypes have been delineated include dedifferentiated liposarcomas, myxofibro- based on immunohistochemical and molecular sarcomas, and undifferentiated pleomorphic sar- studies.1 comas. From a molecular standpoint, their Nuclear pleomorphism refers to marked variation initiating oncogenic events are unknown, and the in both size and shape of tumor cell nuclei, with most recurrent alterations affect commonplace tu- frequent nuclear membrane irregularities, and nu- mor suppressor genes TP53, RB1, PTEN, and clear hyperchromasia, hints toward complex CDKN2A. The molecular classification of pleomor- underlying genetic features and genetic instability phic sarcomas mostly mirrors the histologic sub- in tumors as opposed to the bland nuclei, referred typing, except for myxofibrosarcomas, which are to as “monomorphism,” harbored by most molecularly similar to undifferentiated pleomor- translocation-related sarcomas. Pleomorphism is phic sarcomas. Pleomorphic sarcomas are strati- hardly a specific morphologic feature, as it is fied into 3 grades with histologic grading most often associated with high-grade advanced schemes, the most widely used being the French tumors, whatever their initial epithelial or mesen- sarcoma grading system (FNCLCC), which takes chymal lineage. In viscera, pleomorphic sarcomas into account the type of differentiation, necrosis, remain a diagnosis of exclusion after a sarcomatoid and mitotic activity. carcinoma is ruled out on microscopy and immuno- histochemistry. Conversely, the presence of pleo- morphism in a tumor, although worrisome, does MORPHOLOGIC PLEOMORPHISM AND not equal to malignancy with the notable example DIAGNOSTIC APPROACH OF PLEOMORPHIC of pleomorphic lipomas (Box 2). SARCOMAS Additionally, pleomorphism may occur as a marker of dedifferentiation in a specific type of Pleomorphic sarcomas have been historically sarcoma (see Box 1), such as dedifferentiated defined based on their morphologic features using liposarcomas, solitary fibrous tumors or  Pleomorphic Sarcomas 3 Box 2 Benign and locally aggressive mesenchymal tumors associated with pleomorphism Benign Fibrous histiocytoma (so-called atypical variant) Tenosynovial giant cell tumor Pleomorphic lipoma Schwannoma (“ancient” schwannoma) Atypical neurofibroma Intermediate (locally aggressive and rarely metastasizing) malignancy Pleomorphic dermal sarcoma Atypical fibroxanthoma Pleomorphic hyalinizing angiectatic tumor Myxoinflammatory fibroblastic sarcoma gastrointestinal stromal tumors (GISTs).2–4 In this sarcomatoid carcinomas from pleomorphic sar- situation, microscopic assessment may help iden- comas and the artificial boundaries of these en- tify the presence of a coexisting nonpleomorphic tities in some settings. Aside from these tumor component within tumor bulk, pointing toward suppressors, and rare cases with DNA mismatch the proper diagnosis, although the “dedifferenti- repair defects, pleomorphic sarcomas have rela- ated” (anaplastic) pleomorphic component dic- tively low mutation burden and display mainly tates the prognosis. age-related types of mutations.6 Instead, pleo- For all reasons stated previously, the morphic sarcomas are characterized by copy microscopic assessment of a pleomorphic tumor number alterations (CNAs) that are thought to is systematically completed with a thorough drive tumorigenesis genomic studies have delin- immunohistochemical panel seeking for an over- eated 3 distinct molecular subgroups based on looked histologic lineage, all the more if the tumor the patterns of genomic events, including (1) sar- is not located in soft tissue. comas with arm and whole chromosome alter- An immunohistochemical panel supporting the ations, (2) sarcomas with amplicons, and (3) diagnosis when facing a pleomorphic proliferation sarcomas with segmental alterations.7 However, should at least include epithelial markers (AE1/E3, this genomic subclassification has no practical EMA, for instance), CD34, S100 protein, h-caldes- interest. In contrast, the degree of genomic mon, and desmin. Additional markers may be complexity present in mesenchymal tumors may added depending on the location or the clinico- well have both diagnostic and prognostic pathological features, such as HMGA2/MDM2 significance. (retroperitoneal mass lipogenic component), The concept of genomic complexity refers to CD117/DOG1 (in gastrointestinal tract or prior his- rearranged genomic profiles with CNAs inter- tory of GIST). spersed across tumor genomes. The level of ge- netic complexity can be quantified with the MOLECULAR FEATURES OF PLEOMORPHIC “genomic index,” calculated with the square num- SARCOMAS ber of CNAs divided by the number of chromo- somes involved.7 Overall, the higher the From a molecular standpoint, pleomorphic sar- genomic index, the higher the probability of ma- comas are genetically complex with no identified lignancy and aggressiveness of the tumor. The initiating genetic alteration. Although they are genomic index can therefore be used as a marker considered of mesenchymal origin, pleomorphic of malignancy when dealing with pleomorphic tu- sarcomas share with epithelial tumors the mors of uncertain malignant potential based on frequent inactivation of tumor suppressor genes the sole morphologic findings, such as uterine/ TP53, RB1, and CDKN2A (p16).5 This molecular prostatic leiomyosarcomas versus smooth mus- overlap suggests the critical nature of these path- cle tumor of uncertain malignant potential ways in tumorigenesis, and mirrors the chal- (STUMP)/atypical leiomyoma.8 Furthermore, lenges pathologists may have to distinguish genomic complexity in sarcomas correlates with 4 Carvalho et al prognosis: the CINSARC (Complexity INdex in Table 1 SARComas) signature can stratify patients with French Grading System for Sarcomas with sarcoma into 2 prognostic groups, as opposed updated criteria to the 3-tier histologic grading.7,9 This signature incorporates the levels of expression of a set of Three-Tier French Grading System for Sarcomas 67 genes that are mostly involved in the mainte- (FNCLCC Grading)12–14 nance of chromosome integrity and mitotic con- 1-Tumor Score 1 normal-like trol. Interestingly, the level of nuclear differentiation tissue, low-grade pleomorphism in sarcomas correlates with the cytological features underlying genomic complexity of the tumor.6 Score 2 certain Additionally, the Genomic Grade Index, a signa- histologic diagnosis ture of 108 genes initially identified in early- based on stage breast cancers, has been shown to predict morphology, low- outcomes in patients with resected sarcomas, grade cytologic features outperforming the CINSARC signature in this Score 3 synovial setting.10 sarcoma, clear cell, It is notable that next-generation sequencing epithelioid, alveolar, studies have also highlighted the presence of undifferentiated gene fusions in a subset of pleomorphic sar- sarcomas; high- comas such as TRIO rearrangements, which grade cytologic most probably represent passenger transloca- features tions as opposed to the translocations underlying 2-Mitotic activity (10 Score 1 0–9 mitotic monomorphic sarcomas, such as synovial high-power fields figures or Ki-67 sarcomas.11 assessed with a field positive in 0%–9% of 0.174 mm2) and/ Score 2 10–19 mitotic PROGNOSIS AND GRADING OF or Ki-67 staining on figures or Ki-67 core needle biopsy positive in PLEOMORPHIC SARCOMAS 10%–29% Pleomorphic sarcomas can be stratified with the Score 3 >19 mitotic figures or Ki-67 3-tier histologic grading system of the French positive in 30% sarcoma group.12–14 It takes into account 3 pa- 3-Tumor necrosis Score 1 absent, note rameters, including differentiation, mitotic activ- that in core needle ity, and necrosis (Table 1). Some investigators biopsies, the score is have advocated reliance on Ki67 staining rather upgraded to 1 if than mitotic count on core needle biopsy speci- necrosis is present mens due to tumor heterogeneity and poor inter- on MRI observer agreement in the counting of mitotic Score 2 50% of tumor rhabdomyosarcomas, has been associated with surface worse prognosis.16–19 Final grade: grade 1 (2–3), grade 2 (score 4–5), grade 3 (score 6–8). GROSS EXAMINATION OF PLEOMORPHIC Data from Refs.12–14 SARCOMAS Most pleomorphic sarcomas do not display spe- may be only focally present. We recommend cific gross features, save for dedifferentiated sampling of a complete section of the tumor liposarcomas, which may include both well- mass along its greatest axis to assess all sarcoma differentiated (fatty) and dedifferentiated compo- surgical specimens, with or without prior neoadju- nents (Fig. 1). Macroscopic features reflect the vant chemotherapy or radiation therapy.20 Addi- high-grade nature of these tumors with presence tional sampling will focus on the assessment of of necrosis and hemorrhage. margins, including areas of interest based on Gross examination should be performed gross examination and indications provided by following the general recommendations for sar- the surgeons. The presence of a fascia/aponeu- comas. In surgical specimens, a thorough sam- rosis should be mentioned in the report and its pling should be performed to ensure the histologic status reported to adjust adjuvant identification of lines of differentiation, which therapy.  Pleomorphic Sarcomas 5 Fig. 1. Gross specimen of a dedifferentiated liposar- coma. Yellow differenti- ated fatty areas adjacent to solid, fleshy areas with necrosis. PLEOMORPHIC LIPOSARCOMA spectrum of undifferentiated pleomorphic sarcoma (UPS), including fascicular, epithelioid, or myxoid Pleomorphic liposarcoma is the rarest subtype of histologic patterns.22–25 Rare cases with extensive liposarcoma, and is defined by the coexistence lipogenic differentiation have been reported24 of undifferentiated sarcomatous areas admixed (Fig. 2B–D). The vascular network may even be with a variable amount of pleomorphic prominently staghorn/pericytic.24 Heterologous lipoblasts.21,22 osteoid, chondroid, or striated muscle differentia- tion can be rarely observed,24 and in practice, their CLINICAL FEATURES presence should be mentioned in the report, as the presence of another line of mesenchymal differenti- Pleomorphic liposarcomas affect most commonly ation may suggest the differential diagnosis of the elderly, with a peak incidence in the sixth mesenchymoma. decade and a slight predominance in men. They show marked predilection for deep soft tissues of the extremities, particularly the thigh and limb gir- IMMUNOHISTOCHEMICAL FEATURES dles, but can be found in a wide variety of sites,23,24 Immunohistochemistry helps in excluding any line of with the exception of the retroperitoneum in which differentiation in the setting of a pleomorphic spindle the primary diagnosis to consider, if not the only proliferation. Lipoblasts can be highlighted with one, is a dedifferentiated liposarcoma. S100 protein staining or adipophilin, as proposed They do not have specific radiological features, by a few groups.26 Smooth muscle actin and but MRI may evidence necrosis or edema, in keep- CD34 are focally expressed in half of cases. Other ing with their high-grade features. markers that can be positive at least focally are HMGA2, desmin, pankeratin, and EMA, the last 2 MICROSCOPIC FEATURES in almost half of the epithelioid cases.23–25,27 Stain- By definition, pleomorphic liposarcomas are ing for MDM2 and CDK4 is typically negative.28 composed of areas of undifferentiated pleomorphic sarcoma admixed with pleomorphic lipoblasts. This MOLECULAR PATHOLOGY lipogenic component may vary greatly in abun- dance. Pleomorphic lipoblasts correspond to multi- Pleomorphic liposarcomas are not associated with vacuolated or univacuolated tumor cells with MDM2 amplification.29 Molecular studies have pleomorphic scalloped nuclei (Fig. 2A). The nonlipo- highlighted they are close to UPS at the genomic genic component may cover the wide morphologic level.30 6 Carvalho et al Fig. 2. Pleomorphic lipo- sarcoma. (A) Pleomor- phic lipoblasts. Different histologic patterns may be seen in these tumors with (B) spindle cell, DIFFERENTIAL DIAGNOSIS suspicion of malignancy. However, pleomorphic cells are never lipogenic. Pleomorphic cells are The differential diagnosis of pleomorphic liposar- mostly multinucleated “floret cells” and may comas is broad, including both other adipocytic coexist with a spindled monomorphic component and nonadipocytic neoplasms. (Fig. 3A, B). Pleomorphic lipoma presents typi- Dedifferentiated liposarcoma (DD-LPS) is the cally as a well-circumscribed subcutaneous most important differential diagnosis to consider, mass, smaller than 6 cm. This lesion shows especially in retroperitoneal location. The dediffer- diffuse expression of CD34, and is associated entiated component may indeed display pleomor- with RB1 inactivation at proteic level and hetero- phic lipoblasts, corresponding to persistence or zygous deletion of 13q spanning RB1 locus at reactivation of lipogenic differentiation, which is genomic level (Fig. 3C). repressed during the dedifferentiation process.31 The epithelioid subtype of pleomorphic liposar- The coexistence of a well-differentiated adipocytic coma may be misinterpreted as primary or meta- component in the tumor hints toward the diagnosis static carcinoma, in particular renal cell of DD-LPS,32 and the identification of MDM2 carcinoma and adrenal cortical carcinoma, in amplification is confirmatory of this diagnosis.32 which neoplastic cells can be similar to lipoblasts. A subset of spindle cell/pleomorphic lipoma Renal cell carcinoma has diffuse expression of displays a striking level of pleomorphism, raising  Pleomorphic Sarcomas 7 Fig. 2. (continued). (C) xanthomatous, (D) or myxoid morphologies (hematoxylin-eosin [H&E], original magnification, [B, D] 10; [A, C] 20). keratins and EMA, in addition to being positive for PROGNOSIS PAX8, and the renal cell carcinoma antibody. In a series of epithelioid pleomorphic liposarcomas, Pleomorphic liposarcomas are aggressive neo- EMA was absent in all cases.25 plasms with both local recurrence and metastatic rates ranging from 30% to 50%. Five-year survival rate is estimated to 60%. Metastases occur pri- marily in the lungs and pleura. Clinical and histo- Pitfalls logic factors linked with worse prognosis are PLEOMORPHIC LIPOSARCOMA nonextremity location, size, and mitotic index.23,24 ! Pleomorphic lipoblasts may be very scarce LEIOMYOSARCOMA AND PLEOMORPHIC and not readily identified. SARCOMAS WITH PARTIAL MYOGENIC ! Epithelioid pattern and rare expression of PHENOTYPE keratins may be misleading and raise suspi- cion of carcinoma. Leiomyosarcomas (LMSs) are sarcomas display- ing smooth muscle differentiation. They may be ! Myxoid stromal changes, for example, in myx- poorly differentiated with overt pleomorphism ofibrosarcoma may cause cytoplasmic vacuo- in fewer than 10% of cases, most commonly lation, which may resemble lipogenic admixed with classic areas of LMS33–35 differentiation but S100 protein is not ex- pressed by tumor cells. (Fig. 4A–E). In this setting, the smooth muscle dif- ferentiation may be overlooked on microscopic 8 Carvalho et al Fig. 3. Spindle/pleomor- phic cell lipoma. (A) Flor- etlike multinucleate cells in a background of thick collagen fibers and adi- pocytes. (B) Cells present pleomorphic, hyperchro- matic nuclei (H&E, orig- inal magnification, [A] 10; [B] 20). (C) aCGH profile showing hetero- zygous deletion of RB1 and TP53 compatible with a pleomorphic cell lipoma. examination. Expression of smooth muscle actin, or with diffuse expression of only 1 marker in markers (h-caldesmon AND smooth muscle actin the absence of all others. Tumors presenting par- or desmin or transgelin) should be positive in the tial myogenic phenotype may have a higher meta- well-differentiated component or partially retained static potential than UPS but lower than bona fide in pleomorphic areas to render this diagnosis33,34 LMS.36 From a molecular standpoint, pleomorphic (Fig. 4F–H). sarcomas with partial myogenic phenotype are Studies highlighted a subclass of pleomorphic close to, if not indistinguishable from, UPS at the sarcoma with incomplete myogenic phenotype, genomic level,7,36–38 therefore this terminology is defined as tumors harboring morphologic features not widely used in clinical practice. Some investi- reminiscent of myogenic differentiation but with gators use the term dedifferentiated LMS to refer only focal expression of myogenic markers h-cal- to LMS in which morphologically and phenotypi- desmon, transgelin, calponin, and smooth muscle cally typical areas of LMS coexist along with  Pleomorphic Sarcomas 9 pleomorphic areas negative for smooth muscle PROGNOSIS markers.33,39 LMS has a more aggressive clinical course than pleomorphic sarcomas without myogenic differ- MOLECULAR PATHOLOGY entiation.16,18,34 Reported metastasis and mortal- ity rate are of 48% to 89% and 50% to 65%, LMSs represent a molecularly distinct subgroup of respectively, with a median survival of 9 to pleomorphic sarcomas enriched in myogenic fac- 17 months. Lung is the most common site of tors.6 Two subgroups of soft tissue LMS can be metastasis.33,34 delineated, including a group with PTEN/AKT pathway deregulation and a second group PLEOMORPHIC RHABDOMYOSARCOMA expressing hypomethylated and inflammation sig- natures.6 LMS genomes contain mainly losses and Pleomorphic rhabdomyosarcomas are high- deletions (Fig. 4I) but rare amplifications with the grade pleomorphic sarcomas showing an exception of MYOCD amplicons.40 Of note, soft isolated rhabdomyosarcomatous phenotype tissue LMS can be distinguished from uterine without any other line of differentiation. They LMS at the transcriptomic and methylation levels; are the most common subtype of rhabdomyosar- these 2 tumor types belonging to distinct clusters.6 coma in adults.21 Array-comparative genomic hybridization (aCGH) may be useful to distinguish benign smooth mus- CLINICAL FEATURES cle proliferation from leiomyosarcoma, as homo- zygous deletions of RB1 and/or TP53 are not Pleomorphic rhabdomyosarcomas arise predomi- present in benign smooth muscle lesions and the nantly in the lower extremities of elderly men, most overall genomic complexity is higher in malignant commonly in the sixth to seventh decades of lesions.36 life.43,44 Cases occurring in pediatric patients may be associated with Li-Fraumeni syndrome45 DIFFERENTIAL DIAGNOSIS MICROSCOPIC FEATURES LMSs may focally express keratins and/or These tumors are mainly composed of a pleomor- EMA41 and are therefore misdiagnosed as phic high-grade “UPS-like” proliferation. Some carcinomas. cases may contain scattered large atypical cells Myogenin or myoD1 staining should be per- with abundant polygonal and eosinophilic cyto- formed when dealing with a pleomorphic tumor plasm, reminiscent of rhabdomyoblasts. These expressing desmin to rule out a pleomorphic rhab- cells are frequently multinucleated, harboring ve- domyosarcoma. Morphologically, they character- sicular nuclei with prominent nucleoli (Fig. 5A, B). istically have large polygonal and pleomorphic High mitotic count and extensive necrosis are cells. GISTs express h-caldesmon in 80% of cases frequent, in keeping with their high-grade and desmin in fewer than 1%42 but not transge- features.43 lin.35 Expression of CD117 may be lost in dediffer- entiated GIST. IMMUNOHISTOCHEMICAL FEATURES Desmin expression is multifocal in most cases, restricted to the scattered polygonal cells, but may be diffuse (Fig. 5C). By definition, they ex- Pitfalls press at least 1 skeletal muscle–specific marker; LEIOMYOSARCOMA for example, MyoD1 and/or myf4/myogenin at the nuclear level (Fig. 5D). The expression of 1 of these 2 markers is required for unequivocal ! h-caldesmon can be expressed in GIST and de- diagnosis.43,46 Variable smooth muscle actin differentiated GISTs may be negative for and focal keratin AE1/AE3 and EMA positivity CD117. also can be observed.43,44 MDM2 nuclear label- ! Sarcoma with partial myogenic phenotype ing without MDM2 amplification has been are defined as spindled tumors reminiscent reported.44 of LMS displaying focal or isolated expression of 1 myogenic marker. MOLECULAR PATHOLOGY ! LMSs might display an epithelioid pattern and express keratins. No large series are available regarding this histo- type. They are not associated with MDM2 10 Carvalho et al Fig. 4. Leiomyosarcoma. (A) Intersecting fascicles of spindle cells with eosinophilic cytoplasm and (B) tapered end nuclei (C) admix with pleomorphic spindle, multinucleated bizarre cells, and rarely  Pleomorphic Sarcomas 11 Fig. 4. (continued). (D) epithelioid cells. (E) Multinucleated cells can be prominent in this group of tumors. (F) Diffuse and 12 Carvalho et al Fig. 4. (continued). (G) focal expression of h-cal- desmon. (H) A subset of leiomyosarcomas are positive for EMA (H&E, original magnification, [F] 10; [A, C–E, G, H] 20; [B] 40). (I) aCGH analyses of a smooth muscle neoplasm showing a complex genomic profile contain- ing numerous deletions in chromosomes 10, 16, 1p, and 6q, consistent with the diagnosis of leiomyosarcoma. Dele- tions in chromosomes 13 and 17 are also a frequent finding in LMS but were absent in this case. Homozygous dele- tion in DMD was also present. This profile is highly suggestive of leiomyosarcoma. amplification44 and their genomic profiles are Pitfalls indistinguishable from those of UPS (unpublished PLEOMORPHIC RHABDOMYOSARCOMA data). DIFFERENTIAL DIAGNOSIS ! Desmin expression is mostly focal, restricted to polygonal/epithelioid tumor cells. On small biopsy specimens, the rhabdomyosar- ! Rhabdomyosarcoma may represent the heter- comatous component may represent a heterolo- ologous component of a complex high-grade gous component part of a complex tumor, such tumor that may be overlooked on a core nee- as a sarcomatoid carcinoma, a malignant periph- dle biopsy. eral nerve sheath tumor (also known as Triton ! Rhabdomyosarcoma might express MDM2 tumor), dedifferentiated liposarcoma, or a malig- without underlying amplification. nant mesenchymoma.  Pleomorphic Sarcomas 13 Fig. 5. Pleomorphic rhab- domyosarcoma. (A) Scat- tered large eosinophilic cells (B) with vesicular nuclei and prominent nucleoli, in a back- ground with UPS-like morphology. PROGNOSIS and the identification of this higher-grade “differ- entiated” component is required to render the Pleomorphic rhabdomyosarcoma portends a diagnosis. This dedifferentiation process has worse prognosis than other pleomorphic sar- been best described in liposarcomas, solitary comas. Tumors have a relapse rate of 53.8% fibrous tumors, and GISTs. and more than 80% metastasize within 5 years. Median survival at local and metastatic stage are 12.8 months and 7.1 months, respectively. DEDIFFERENTIATED LIPOSARCOMA Older patients have higher risk of adverse outcome.44,47 Dedifferentiated liposarcomas (DD-LPSs) are ma- lignant adipocytic tumors underlined by MDM2 amplification with coexistent lipogenic and nonli- PLEOMORPHIC SARCOMAS AS A RESULT OF pogenic differentiated components. They develop DEDIFFERENTIATION from a known well-differentiated liposarcoma or de novo. Dedifferentiation occurs in up to 10% of Dedifferentiation, or anaplastic change, refers to well-differentiated liposarcomas.2 tumor progression involving the transformation of a low-grade sarcoma to a higher-grade CLINICAL FEATURES sarcoma.2–4,39,48 The dedifferentiated component mainly displays a pleomorphic morphology, DD-LPS affects predominantly adults older than distinct from the low-grade component,49 50 years but not exclusively. Retroperitoneum is 14 Carvalho et al Fig. 5. (continued). (C) Diffuse desmin expres- sion and (D) focal positiv- ity for myogenin (H&E, original magnification, [A, C] 10; [D] 20; [B] 40). the most frequent location. Other common sites dedifferentiated component with the presence of include extremities, trunk, and scrotum/spermatic pleomorphic lipoblasts resembling a pleomorphic cord.2,50 liposarcoma.32,54 Their radiological features are diagnostic with coexistent fatty and nonfatty solid components within the tumor bulk (Fig. 6). IMMUNOHISTOCHEMICAL FEATURES MICROSCOPIC FEATURES DD-LPSs display diffuse nuclear expression of HMGA2 and MDM2 in 67% and 85% of cases, The lipogenic “well-differentiated” and nonlipo- respectively27,28,32 (Fig. 7H, I). MDM2 amp- genic components often display abrupt transition lification should be demonstrated by fluores- (Fig. 7A, B). The dedifferentiated component is cence in situ hybridization (FISH) (Fig. 7J), highly plastic, and spans a wide morphologic especially if MDM2 is only focally expressed or spectrum from low-grade to high-grade pleomor- the location of the tumor is other than retroperi- phic sarcomas2,22,51–53 (Fig. 7C–G). Rarely, the toneum.55 Eleven percent of DD-LPSs show nu- lipogenic differentiation may persist in the clear STAT6 staining, as the STAT6 locus is  Pleomorphic Sarcomas 15 Fig. 6. Imaging features in a retroperitoneal dedifferentiated liposarcoma. Imaging distinguished 2 distinct com- ponents in this tumor. Computed tomography with iodine contrast-agent intravenous injection, acquisition at portal phase, axial (B,C) and coronal view (A). The levels of the axial slices are reported in white dashed lines on the coronal view. Well-differentiated areas typically show very low attenuation consistent with fat (white asterisks) whereas dedifferentiated areas (white arrows) display higher, tissular attenuation and enhancement af- ter contrast-agent injection. located close to MDM2 and may be Pitfalls coamplified.56,57 DEDIFFERENTIATED LIPOSARCOMA MOLECULAR PATHOLOGY ! DD-LPSs span a wide morphologic spectrum DD-LPSs are defined by the amplification of and may mimic many sarcoma histotypes. the MDM2 oncogene.50 Most DD-LPSs harbor additional genetic alterations that turn off ! DD-LPS may express STAT6, leading to poten- tially misinterpretation as fat-forming SFT. pathways involved in lipogenesis, such as peroxisome proliferator-activated receptor ! MDM2 staining is not entirely specific for DD- gamma signaling through JUN and ASK ampli- LPS and should be correlated with genetic fications31 or VGLL3, DDIT3, and CEBPA6,58 status (presence of amplification). (Fig. 7K). DIFFERENTIAL DIAGNOSIS PROGNOSIS Any mesenchymal pleomorphic tumor devel- DD-LPSs have lower metastatic potential than oping in the retroperitoneum should be consid- other pleomorphic sarcomas, but are associated ered as DD-LPS until proven otherwise.59 An with important morbidity, especially retroperitoneal immunohistochemical screening with HMGA2 or tumors.64 Local recurrence occurs in 40% to 80% CDK4 and MDM2 should at least be performed of cases. Distant metastases account for 19% of to test this hypothesis and, as MDM2 immuno- cases and disease-related mortality is of 42%.65 histochemistry has a sensitivity of 85% for the The histologic grade of the dedifferentiated diagnosis of DD-LPS, although not being entirely component correlates with survival.64,66 specific,28,60,61 positive cases should be Both smooth muscle and rhabdomyoblastic dif- confirmed with FISH testing for MDM2 ferentiation (Fig. 9) correlate with aggressive clin- amplification. ical behavior in DD-LPS.53,66 MPNST can occasionally show extensive pleo- morphism and, in 60% of cases, display MDM2 staining. However, amplification of MDM2 is DEDIFFERENTIATED GASTROINTESTINAL absent.62 STROMAL TUMOR As a great mimicker, DD-LPS can have solitary fibrous tumor (SFT)-like features, show diffuse GIST is the most common primary mesenchymal tu- expression of CD34, and may even overexpress mor in the gastrointestinal tract, deriving from the STAT6.63 In these cases, search for MDM2 ampli- interstitial cell of Cajal. They may behave in a benign fication is mandatory, as it is not observed in or malignant manner.21 Dedifferentiation in GIST is SFTs56,57 (Fig. 8). extremely uncommon, being mainly secondary to 16 Carvalho et al Fig. 7. Dedifferentiated liposarcoma. (A) Sharp transition between (B) well-differentiated com- ponent and (C) dediffer- entiated component is highly variable with ex- amples of spindled,  Pleomorphic Sarcomas 17 Fig. 7. (continued). (D) epithelioid, (E) myxoid, (F) UPS-like, 18 Carvalho et al Fig. 7. (continued). (G) and meningothelial-like appearances. (H) HMGA2 staining in both compo- nents (I) and MDM2 expression in the dedif- ferentiated component (H&E, original magnifica- tion, [A] 2,5; [B, G, H] 10; [C–F, I] 20).  Pleomorphic Sarcomas 19 Fig. 7. (continued). (J) FISH screening showing strong amplification of MDM2 forming clusters (probes targeting MDM2 locus and chromosome 12 centromere are labeled in green and red, respectively). (K) aCGH analyses of a dedif- ferentiated liposarcoma with characteristic ampli- fication of MDM2, CDK4 and JUN. DD-LPS typically display amplicons in their genome. chronic imatinib therapy and secondary resistance a morphologically classic area of GIST and to therapy, but may develop de novo.3 a high-grade anaplastic/pleomorphic prolifera- tion (Fig. 10A, B). The dedifferentiated compo- MICROSCOPIC FEATURES nent is highly variable with reports of angiosarcomatous,3 epithelioid/rhabdoid, rhab- Dedifferentiated GIST (DD-GIST) displays 2 domyosarcomatous, and chondrosarcomatous components in abrupt transition, including differentiation.67 Fig. 8. Fat-forming SFT. Hemangiopericytomalike vessels and adipocytic component (H&E, orig- inal magnification, 10). 20 Carvalho et al Fig. 9. Dedifferentiated liposarcoma with myo genic differentiation. (A) Spindle cell proliferation with eosinophilic cyto- plasm somewhat re- miniscent of myogenic differentiation. Expres- sion of MDM2 (B), desmin IMMUNOHISTOCHEMICAL FEATURES metastasize (“malignant SFT”).21 They may rarely undergo dedifferentiation. Dedifferentiated SFTs The dedifferentiated components lose expression (DD-SFTs) are mostly diagnosed de novo,4,68 but of CD117 and CD343 and may express variable dedifferentiation can occur at the time of markers depending on the line of differentiation67 recurrence.68 (Fig. 10C–E). MOLECULAR PATHOLOGY MICROSCOPIC FEATURES Despite differences in the immunophenotype, both DD-SFT shows a conventional SFT component conventional and dedifferentiated components admixed to a dedifferentiated component have the same KIT, BRAF, and TP53 mutational with high-grade and pleomorphic features profile.3,67 DD-GIST may be wild-type, but the cor- (Fig. 11).4,68,69 The dedifferentiated component responding conventional area is wild-type as well may even exhibit pseudorosettes4 or heterologous in these cases.3 rhabdomyosarcomatous, osteosarcomatous, or chondrosarcomatous differentiation.68,70 DEDIFFERENTIATED SOLITARY FIBROUS TUMOR IMMUNOHISTOCHEMICAL FEATURES SFT is a fibroblastic mesenchymal tumor of inter- The dedifferentiated component loses expression mediate malignancy defined by intrachromosomic of CD34 in half of the cases4,68 and has decreased NAB2-STAT6 fusions. SFT may remain local or or absent expression of STAT6.71  Pleomorphic Sarcomas 21 Fig. 9. (continued). (C) and myogenin (D) Myogenic differentiation correlates with adverse outcome in DD-LPS (H&E, original magnifica- tion, [A, B] 25, [C] 10, [D] 10). MOLECULAR PATHOLOGY of cases, affecting primarily lung but also brain, liver, and bone.68 In the risk stratification model SFTs are underlined by recurrent NAB2-STAT6 fu- study by Demicco and colleagues,73 all 3 included sions.72 Interestingly, DD-SFTs retain the fusion in cases of dedifferentiated SFT, which were the dedifferentiated component, although the accounted as high-risk tumors, metastasized. expression of STAT6 is dramatically decreased at the proteic level.71 DD-SFTs display unstable genomic profile with MYXOFIBROSARCOMA CNAs, contrasting with the simple diploid profiles Myxofibrosarcoma is a clinicopathological entity of conventional SFT. CNAs include constant loss arising in limbs and trunk of the elderly associ- of chromosome 13 and in 16q.4,71 Malignant ated with a longitudinal spreading of malignant SFTs harbor genomic profiles of intermediate cells along fascial planes. They span a wide complexity between benign SFT and DD-SFT morphologic spectrum with variable levels of with gains of whole chromosomes and loss of myxoid stromal changes, cellularity, and chromosome 13. pleomorphism.21 PROGNOSIS CLINICAL FEATURES Dedifferentiation in SFT portends a worse prog- Myxofibrosarcoma (MFS) is one of the most nosis with a high risk of metastasis in up to 50% common sarcomas in the elderly individuals, 22 Fig. 10. Dedifferentiated GIST. (A) Primary lesion displayed an epithelioid pattern. (B) After 2 years of adjuvant therapy with KIT inhibitor, pa- tient developed a recur- rence. Tumor mass contained a high-grade dedifferentiated compo- nent. (C) Diffuse expres- sion of CD117 was retained but not DOG1  Pleomorphic Sarcomas 23 Fig. 10. (continued). (D). (E) The dedifferentiated component expressed desmin and myogenin (not shown), in keeping with a rhabdomyosar- comatous differentiation (H&E, original magnifica- tion, [C] 10; [A–E] 20). with a peak at the sixth to eighth decades. There MICROSCOPIC FEATURES is a slight predominance in men. Tumors commonly present as a slow-growing subcu- MFSs are composed of nodules (Fig. 13A) of pleo- taneous mass in limbs and limb girdles.74 They morphic cells embedded in a myxoid stroma develop within muscles and in close vicinity (conventionally representing at least 20% of tumor with fascia. surface), richly vascularized with typical curvilinear capillaries74 (Fig. 13B). RADIOLOGICAL AND GROSS FEATURES Like UPS, MFS is a tumor with no specific line of differentiation, and it can be a challenge to MRIs reveal ill-defined tumors with peritumoral discriminate between the 2 entities, particularly infiltration, beyond apparent tumor borders. This as myxoid changes may occur in UPS. Attempts infiltration is referred to as “tail sign” when located at setting a quantitative threshold of myxoid along fascia and is correlated with the presence of changes necessary to reach a diagnosis of MFS satellite tumor cells. Radiologists must inform the have proposed values from 10% to 50% of the tu- surgeon of these findings to include the tissue mor surface.74 Retrospective clinical studies have with peritumoral enhancement within the surgical evidenced improved outcomes with as low as 5% margins (Fig. 12). of myxoid changes, although clinical outcomes are At gross examination, MFS presents as a myx- even better with myxoid changes beyond 70%.75 oid multinodulated mass. Pragmatically, we render the diagnosis of MFS 24 Carvalho et al Fig. 11. Dedifferentiated SFT. (A) Well-differen- tiated component with monotonous prolifera- tion of cells with round uniform nuclei and few scattered pleomorphic cells. (B) Pleomorphic areas with high mitotic activity (H&E, original magnification, [A, B] 20) STAT6 expression was focally and weakly expressed in the dedif- ferentiated component (not shown). without quantifying precisely the amount of myx- IMMUNOHISTOCHEMICAL FEATURES oid changes, but by taking into account the clinical setting (mass of limb or trunk) and presence of the S100 protein is negative, whereas CD34 highlights typical vascular network within the myxoid stroma. the vascular network. MDM2 can be focally MFSs may display variable levels of cellularity, expressed by immunohistochemistry.28 atypia, and proliferation (Fig. 13C–E). Lower grade lesions may progress to higher grade at time of MOLECULAR PATHOLOGY recurrence. Tumor cells are stellate to ovoid with hyperchromatic nuclei74 (Fig. 13F). Cytoplasmic Clustering analysis has highlighted the vicinity of vacuolation may occur due to the myxoid stroma, MFS and UPS. These entities may be part of a giving to tumor cells a pseudolipoblastic appear- phenotypic spectrum of tumors sharing a common ance (Fig. 17B). MFSs also may display a focal histogenesis, although further studies are required or diffuse epithelioid appearance.76 to confirm this concept.6 They do not harbor  Pleomorphic Sarcomas 25 Fig. 12. MRI findings in MFS. Myxofibrosarcoma of the internal face of the left ankle. T2-weighted imaging with coronal (A) and axial (B) views, axial T1-weighted imaging (C) and axial T1-weighted imaging with suppression of fat signal and after a gadolinium chelates intravenous injection (D). The tumor is ill-defined with presence of peritumoral infiltration (white arrows, bright signal and contrast enhancement), spreading beyond apparent tu- mor borders. Myxoid component (white arrowhead) displays bright fluidlike signal on T2-weighted imaging, low signal on T1-weighted and enhancement after contrast-agent injection. specific genetic hits that would be defining or deregulated pathways. One subgroup, defined represent therapeutic targets.77,78 On methylation by MDM2 amplification and alteration of chromatin profiling, 3 molecular subgroups of MFS can be modifiers, is associated with excellent outcome delineated, each defined by different sets of (no disease-related death).79 These data further 26 Carvalho et al Fig. 13. Myxofibrosarco- ma. (A) Multinodular ar- chitecture, (B) abundant myxoid stroma with abundant curvilinear blood vessels character- istic of MFS.  Pleomorphic Sarcomas 27 Fig. 13. (continued). (C– E) MFS may display vari- able cellularity from low to solid UPS-like areas (F) Pleomorphic elon- gated cells with hy- perchromatic atypical nuclei. Mitotic figures may be scant in low- grade MFS. aCGH may be helpful in this setting, evidencing complex ge- netic profiles similar to those of UPS (H&E, orig- inal magnification, [A] 0.5; [B] 5; [C–E] 20; [F] 40). 28 Carvalho et al fuel the hypothesis that MDM2-amplified pleomor- antibodies of poor specificity, thereby the differen- phic sarcomas in limbs or trunk represent dediffer- tial relies on the clinical vignette, morphologic entiated liposarcomas rather than MFS or UPS.79 clues, and the use of molecular tools. The 2 other subgroups are defined by high- Myxoinflammatory fibroblastic sarcomas are frequency of TP53 alterations and homozygous mesenchymal tumors of intermediate malignancy deletions of CDKN2A, respectively. The latter (locally aggressive) arising in the extremities (typi- group harbors the worse overall survival.78 In this cally acral location in hands and feet) of middle- study, no correlation was performed between the aged adults. This tumor has a multinodular archi- histologic grading and the molecular classifica- tecture composed of larger atypical cells with tions. Notably, the deregulated pathways include viral-like vesicular nuclei (Fig. 14) embedded in a commonplace tumor suppressor genes, namely myxoid stroma, admixed with a prominent inflam- RB1 axis, TP53, and RAS-PI3K axis.78 matory infiltrate of histiocytes and lymphocytes. Emperipolesis of inflammatory elements may be DIFFERENTIAL DIAGNOSIS present. The diagnosis can be confirmed by the identification of TGFBR3-MGEA5 translocations For most of the differential diagnosis of MFS, im- by FISH, reverse-transcriptase polymerase chain munostaining will be of limited interest with reaction, or aCGH.80 Alternatively, translocations Fig. 14. Myxoinflammat- ory fibroblastic sarcoma. (A) Large atypical cells with large nucleoli within a myxoid and in- flammatory background. (B) “Virocyte”-like cells and emperipolesis of in- flammatory cells seeming engulfed in the cyto- plasm of tumor cells (H&E, original magnifica- tion, [A] 20; [B] 40). (C) aCGH profile of a myxoinflammatory fibro- blastic sarcoma show- ing breakpoint within TGFBR3 locus and ampli- fication of VGLL3. This sarcoma is commonly associated with unbal- anced translocation, which can be evidenced by aCGH.  Pleomorphic Sarcomas 29 may involve BRAF in TGFBR3 non-rearranged chondrosarcoma (Fig. 16), and myxoid liposar- cases81 or remain unidentified in a subset of coma (Fig. 17A). However, although they can be cases. hypercellular or show degenerative atypia, pleo- Pleomorphic liposarcoma may display focal to morphism is absent. The differential diagnosis of extensive myxoid changes. Careful sampling and cellular myxoma versus myxofibrosarcoma may identification of pleomorphic lipoblasts will secure sometimes be difficult with the sole morphology. the diagnosis This differential can be supported by aCGH, as Additional tumors with prominent myxoid higher genetic complexity and oncogene amplifi- stroma may enter the differential, including cation or homozygous deletions of tumor suppres- myxoma (Fig. 15), extraskeletal myxoid sor genes RB1 and TP53 are absent in myxomas. Fig. 15. Myxoma. (A) Extensive myxoid stroma with rare capillaries. Var- iable cellularity may be seen, especially in recur- rent myxomas. (B) Tumor cell nuclei may display irregular contours and be hyperchromatic but do not display overt pleomorphism (H&E, original magnification, [A] 10; [B] 20). (C) aCGH profile showing CNAs (gains of whole chromosomes) consistent but not specific of myx- oma. aCGH may be helpful in recurrent myx- oma on core needle biopsy to rule out myxofibrosarcoma. 30 Carvalho et al low-grade MFS almost never metastasizes, Pitfalls whereas intermediate-grade and high-grade neo- MYXOFIBROSARCOMA plasms may develop metastases in approximately 20% to 35% of cases.16,74 The overall 5-year sur- vival rate is 70%.82 ! Low-grade lesions with intermediate cellu- Apart from classic clinical predictors (tumor larity and limited pleomorphism may raise the differential diagnosis of myxoma. size, histologic grade, and margin status), the per- centage of myxoid component correlates with ! Artifacts of vacuolation may be interpreted as disease-specific survival and recurrence-free sur- lipoblasts, raising suspicion for pleomorphic vival: more than 5% of the myxoid component cor- liposarcoma. relates with better outcome.75 ! MDM2 may be overexpressed by MFS but MDM2 amplification is absent. UNDIFFERENTIATED PLEOMORPHIC SARCOMA PROGNOSIS UPSs are pleomorphic tumors devoid of line of dif- ferentiation,21 accounting for 15% to 20% of soft MFS displays a longitudinal mode of spreading, tissue sarcomas.16 and can infiltrate microscopically far beyond what is grossly apparent, warranting careful surgi- CLINICAL FEATURES cal resection. MFSs are characterized by high local recurrence rates of 50% to 60%. Metastatic UPSs mostly arise in deep soft tissue of limbs and potential is reliably predicted by histologic grade: trunk, and predominantly affect male adults older Fig. 16. Extraskeletal myxoid chondrosarcoma. (A) Prominent myxoid stroma and neoplastic cells arranged in a cord- like pattern. (B) Small, ovoid and hyperchro- matic neoplastic cells, without pleomorphism (H&E, original magnifica- tion, [A] 10; [B] 20).  Pleomorphic Sarcomas 31 Fig. 17. Myxoid liposar- coma versus myxofibrosar- coma. (A) Lipoblasts in a myxoid liposarcoma compared with (B) pseu- dolipoblasts in myxofibro- sarcoma (H&E, original magnification, [A, B] 40). than 40 years, although they may occur at any age. verging on the formation of osteoid matrix. Tumor They may occasionally occur in the setting of prior cells are pleomorphic and may display a wide radiation therapy (being the most frequent histo- array of cytologic appearance: spindled, epithe- type of radiation-associated sarcomas83–85), or of lioid, or be multinucleated. The level of pleomor- tumor predisposition syndrome, such as Li- phism is variable, sometimes striking with Fraumeni syndrome. presence of giant pleomorphic cells (Fig. 19A–D). Radiological features are poorly specific, reflect- Malignant mesenchymomas refer to pleomor- ing their high-grade nature (Fig. 18). phic sarcomas harboring at least 2 different types of mesenchymal differentiation in the setting of a MICROSCOPIC FEATURES “UPS-like” proliferation.86 They are not singled out as a specific entity in the World Health Organi- Histologically, UPSs are morphologically hetero- zation (WHO) classification. geneous and by definition devoid of line of differ- entiation. They are pleomorphic tumors with IMMUNOHISTOCHEMICAL FEATURES high-grade features, commonly combining several architectural patterns, the most frequent presenta- The poorly specific morphologic features of UPS tion being a mixture of storiform and fascicular. warrant the systematic use of immunostaining to Their stroma may vary from myxoid to hyaline, rule out melanoma, sarcomatoid carcinoma, or 32 Carvalho et al Fig. 18. MRI findings in a UPS. Deep-seated UPS of the right thigh. Axial T2-weighted imaging (A); coronal T1-weighted imaging with suppression of fat signal before (B) and after (C) a gadolinium chelates contrast- agent injection; subtracted images (D 5 C–B). Necrotic area (asterisk) typically demonstrates high signal intensity on T2-weighted imaging and no enhancement after contrast-agent injection. Persistence of viable tumor compo- nent within tumor mass after neoadjuvant chemotherapy within tumor mass (high signal intensity on T1-weighted imaging, white arrow). identify a line of differentiation overlooked by the of several epithelial markers and p63 are required. microscopic examination (including AE1/E3, The differential is all the more challenging, as EMA, CD34, S100 or SOX10, h-caldesmon, des- UPSs may focally express cytokeratins. min/myoD1, MDM2). Their immunophenotype is Pleomorphic tumors located near large joints plastic and they may even focally express keratins, (knees) of the elderly should always raise suspi- EMA, or p63.87 Therefore, it is mandatory to inte- cion for a tenosynovial giant cell tumor, which grate the clinical context before rendering this may display degenerative atypia, although these diagnosis of exclusion. It is worth noting that lesions are classically not mitotic (Fig. 20). UPSs are commonly infiltrated by histiocytes/ In the retroperitoneum, UPS-like tumors are macrophages, which may result in difficulty in the dedifferentiated liposarcomas until proven interpretation of certain immunostains, including otherwise. CD31. Extraskeletal osteosarcoma can pose a particu- larly difficult differential diagnosis, as it resembles MOLECULAR PATHOLOGY UPS except for the presence of osteoid matrix (Fig. 21). The osteoid nature of a matrix may be Genomically, UPSs display complex genomic pro- difficult to assess in tumors with fibrohyaline files. Two molecular subtypes can be delineated: a stroma and SATB2 staining may help ascertain less rearranged group with CNAs of chromosome this suspicion, if strongly and diffusely arms, and a second, more genetically complex expressed.88 group, displaying whole chromosome gains and The presence of a myxoid component may losses.7 This molecular subclassification is of entertain the differential with MFS, which may be limited practical interest. Commonplace tumor difficult to ascertain on core needle biopsy. Pres- suppressor genes TP53, RB1, and PTEN are ence of a myxoid component as low as 5% may frequently inactivated in UPS, emphasizing path- be associated with better outcome75 but the cur- ways that are shared with many tumor types, rent WHO classification recommendation is to including epithelial ones (Fig. 19E). use a 20% threshold for the diagnosis of MFS.21 DIFFERENTIAL DIAGNOSIS PROGNOSIS Overall, it should be kept in mind that UPSs are a Local recurrence and metastatic rates in UPS diagnosis of exclusion, which should be made range between 20% and 30% and 30% and cautiously outside of soft tissue, especially in 35%, respectively.89 Both local recurrence and viscera, considering the phenotypic plasticity of distant metastasis often develop within 12 to high-grade undifferentiated tumors, whatever their 24 months after initial diagnosis. Metastatic sites epithelial or mesenchymal origin. include lung, bone, and liver. The reported 5-year Facing tumors developed in viscera, the diag- overall survival is 65% to 70%. Prognostic factors nosis of sarcomatoid carcinoma should always include tumor size, grade, and distant metastases be the first to be considered. Recognition of an at initial presentation. UPS arising in limbs or trunk intraepithelial dysplastic component and the use have improved 5-year metastases-free survival  Pleomorphic Sarcomas 33 Fig. 19. UPS. Morpho- logic spectrum of UPS, including (A) spindle, (B) epithelioid/rhabdoid, (C) osteoclastlike giant cells, and 34 Carvalho et al Fig. 19. (continued). (D) slightly myxoid stroma with no criteria for myxo- fibrosarcoma (H&E, orig- inal magnification, [A–D] 20). (E) aCGH profile of a high-grade UPS showing homozygous deletion of both RB1 and TP53 genes. rate of 83%.90,91 Reported survival in children is measures less than 2 to 3 cm, whereas PDS le- 70% to 75%,92,93 suggesting that UPS in this sions can be larger.95 age group may have a different tumorigenesis. Microscopic Features SUPERFICIAL PLEOMORPHIC SARCOMAS AFXs present as cutaneous nodules often associ- ated with epidermal ulceration. Epidermal collar- ATYPICAL FIBROXANTHOMA AND ette and marked solar elastosis in the adjacent PLEOMORPHIC DERMAL SARCOMA dermis are common (Fig. 22A, B). The most frequent morphologic pattern is an admixture of Atypical fibroxanthomas (AFXs) are cutaneous tu- pleomorphic epithelioid, spindled, and multinucle- mors of intermediate malignancy devoid of line of ated tumor cells in varying proportions (Fig. 22C, differentiation.21 Pleomorphic dermal sarcoma D), often admixed with a chronic inflammatory (PDS) refers to dermal-based pleomorphic tumors infiltrate. Nuclear pleomorphism is marked and indistinguishable from AFX but associated with in- there is brisk and atypical mitotic activity.94,96,98 vasion of deep subcutaneous tissue, tumor necro- However, AFXs are morphologically heteroge- sis, lymphovascular invasion, or perineurial neous, with reports of pseudoangiomatous, infiltration.94,95 These tumors are part of a disease osteoclastlike giant cells, clear cell, and granular spectrum with partial overlap, but PDSs are asso- cell patterns.94,98 ciated with a low metastatic potential as opposed By definition, all 3 criteria should be present to AFX.96,97 to render the diagnosis of AFX: (1)