where are we now with pleomorphic sarcoma

REVIEW

Classification of pleomorphic sarcomas: where are we now?

A P Dei TosDepartment of Pathology, Hospital of Treviso, Treviso, Italy

Dei Tos A P

(2006) Histopathology 48, 51–62

Classification of pleomorphic sarcomas: where are we now?

Until a decade ago, so-called pleomorphic and storiformmalignant fibrous histiocytoma (MFH) represented themost frequently diagnosed sarcoma, accounting forapproximately 40% of adult mesenchymal malignan-cies. However, the latest World Health Organizationclassification of soft tissue tumours considers MFH asynonym for undifferentiated pleomorphic sarcoma.Historically, the term MFH was introduced in themedical literature in 1963 by Ozzello, O’Brien andStout, on the basis of the acquisition of phagocyticproperties observed in cultured fibroblasts. The exist-ence of MFH as a well-defined clinicopathological entitybecame rapidly very popular and by the mid 1980sMFH represented the most common sarcoma in adults.With the advent of electron microscopy, immuno-

histochemistry and molecular genetics, it became clearthat the so-called ‘facultative fibroblast’ theory had noscientific grounds and, in 1992, a milestone papereventually brought attention to the concept that MFHmerely represented a morphological pattern sharedby a wide variety of poorly differentiated malignantneoplasms, which include specific subtypes of pleomor-phic sarcomas. Currently, accurate subclassification ofpleomorphic sarcomas is mandatory as it enablesrecognition of non-sarcomatous lesions as well aspleomorphic neoplasms not associated with aggressivebehaviour. Furthermore, as myogenic differentiationpredicts aggressive clinical behaviour among pleomor-phic sarcomas, precise histotyping allows prognosticstratification of patients.

Keywords: MFH, pleomorphic sarcoma

Abbreviations: MFH, malignant fibrous histiocytoma; MPNST, malignant peripheral nerve sheath tumours

Introduction

The evolution of the classification of pleomorphicsarcomas represents a prototype of the conceptualadvances generated by the integration of immuno-phenotyping and conventional morphology. Until littlemore than a decade ago, so-called pleomorphic andstoriform malignant fibrous histiocytoma (MFH) repre-sented the most frequently diagnosed sarcoma,accounting for approximately 40% of adult mesenchy-mal malignancies. The latest World Health Organiza-tion (WHO) classification of soft tissue tumours hasclearly indicated that MFH, at best, represents a

synonym for undifferentiated pleomorphic sarcomas,denying the status of a distinct clinicopathologicalentity.1 This means that whoever wishes to remainloyal to the old terminology should be aware that MFHhas become a diagnosis of exclusion for high-gradepleomorphic sarcomas showing no line of differenti-ation. However, the consensus achieved in the contextof the new WHO classification of soft tissue tumoursrepresents only the end of a long, as well as com-plex, conceptual evolution it is worthwhile briefly toreconstruct.

Historically, the term MFH was introduced in themedical literature in the early 1960s by Ozzello,O’Brien and Stout. These authors, who are amongthe founders of modern surgical pathology, wereimpressed by the acquisition of phagocytic propertiesobserved in cultured fibroblasts.2,3 Therefore, based on

Address for correspondence: Angelo P Dei Tos MD, Department of

Pathology, Hospital of Treviso, Piazza Ospedale 1, 31100 Treviso,

Italy. e-mail: [email protected]

� 2006 Blackwell Publishing Limited.

Histopathology 2006, 48, 51–62. DOI: 10.1111/j.1365-2559.2005.02289.x

the combination of morphology and tissue cultureanalysis, they suggested that this group of soft tissuesarcomas, showing a pleomorphic phenotype and astoriform or cartwheel-like growth pattern, would bederived from histiocytes.2 As a result, the findingsgenerated by an ‘ancillary technique’ overcame theobservations of conventional morphology, leading tothe creation of a novel nosological category. Theexistence of MFH as a well-defined clinicopathologicalentity became rapidly very popular and, by the mid1980s, pleomorphic and storiform MFH representedthe most common sarcoma in adults.4–6 However, inthe same way that an ancillary technique to someextent created MFH, ancillary techniques significantlycontributed to its demolition. In fact, with the adventof electron microscopy, immunohistochemistry andmolecular genetics, it became clear that the so-called‘facultative fibroblast’ theory had no scientificgrounds.7 In 1992 a milestone paper eventuallybrought attention to the concept that MFH representedmerely a morphological pattern shared by a widevariety of poorly differentiated malignant neoplasms.8

The careful analysis of a series of 159 ‘MFHs’ retrievedfrom the files of a single institution demonstrated that63% of the cases could be reclassified (with the supportof immunohistochemistry and ⁄ or electron microscopy)as specific types of pleomorphic sarcoma, and 12.6%as non-mesenchymal malignancies. Of the 42 cases(approximately half of which consisting of smallbiopsies) with no demonstrable line of differentiation,only a small fraction (13% of the total) were morpho-logically compatible with the MFH ‘category’. Almost30 years since its creation, pleomorphic MFH appearedto be a heterogeneous group of unrelated lesions. Sucha reappraisal generated sharp debate. However, evenmost recent gene profiling studies have further con-firmed the validity of this conceptual shift, since MFHsdo not form a discrete cluster.9–11

The main discussion nowadays, almost 15 yearssince that publication, focuses on whether accuratesubclassification of pleomorphic sarcomas is worth-while or not from the prognostic and therapeuticpoints of view. First of all, separation of true sarcomasfrom carcinomas, melanomas, and lymphomas show-ing sarcomatoid, pleomorphic morphology is of para-mount importance if the difference in prognosis and,more importantly, in therapy is considered. Presentlysuch differential diagnoses are mainly based on anaccurate and careful histopathological examination,accompanied by an immunohistochemical work-upthat includes a panel of differentiation markers.Second, it has also become evident that the presenceof myogenic differentiation among high-grade pleo-

morphic sarcomas identifies a group of tumourscharacterized by particularly poor prognosis.12 Thisfinding has been further confirmed by other studies,underlining beyond any doubt the clinical relevanceof pleomorphic sarcoma histotyping.13,14 During thelast decade, mostly as a consequence of more accuratephenotyping, the percentage of pleomorphic unclassi-fiable sarcomas that would fit in the former categoryof MFH has dropped dramatically.15 The aims of thisreview are to summarize the main clinicopathologicalfeatures of pleomorphic sarcoma subtypes, as well asto analyse a group of lesions featuring pleomorphicmorphology not associated with aggressive clinicalbehaviour.

Undifferentiated pleomorphic sarcoma,not otherwise specified (ex-pleomorphicand storiform MFH)

The 2002 WHO classification recognizes the exist-ence of an undifferentiated, unclassifiable category ofpleomorphic sarcoma, and defines it as a group ofpleomorphic high-grade sarcomas in which anyattempt to disclose their line of differentiation hasfailed.1 It has to be underlined that this is a diagnosis ofexclusion following thorough sampling and judicioususe of ancillary techniques. Most of these cases in thepast have contributed to the category of storiform andpleomorphic MFH. Currently, undifferentiated pleo-morphic sarcoma accounts for no more than 5% ofsarcomas occurring in adults. The term MFH as apossible synonym for undifferentiated pleomorphicsarcoma was maintained in the current WHO classifi-cation in order to have the opportunity to summarizethe conceptual evolution (discussed above) to bothpathologists and clinicians, but the term will probablydisappear in future classifications.

Undifferentiated pleomorphic sarcomas tend to occurin the extremities (most often lower limbs) of elderlypatients (peak age is in the 6th and 7th decades). Theypresent as deep-seated, progressively enlarging masses.Sometimes rapid growth is observed which may beassociated with local pain. About 5% of patients exhibitdistant metastases (mostly to the lungs) at presenta-tion. Microscopically these lesions tend to be veryheterogeneous; however, all share marked pleomor-phism, often with bizarre giant cells, admixed withspindle cells and a variable (from many to none)number of foamy histiocytes (Figure 1). Immunohisto-chemical analysis is disappointing as it usually dem-onstrates an ‘only vimentin’ phenotype. The presenceof scattered smooth muscle actin (SMA)-positive cells

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� 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.

should not be taken as evidence of myogenic differen-tiation.

Myxofibrosarcoma (ex-myxoid MFH)

Myxoid MFH has been, for decades, the preferredsynonym of myxofibrosarcoma,16,17 based on thepresence of pleomorphic MFH-like morphology inhigh-grade examples. The current WHO classificationadopted the term myxofibrosarcoma, first proposed byAngervall17 to underline the fibroblastic nature (andnot fibrohistiocytic) of this spectrum of myxoid mesen-chymal neoplasia.1,18 Myxofibrosarcoma is one of thecommonest sarcomas in elderly patients. The vastmajority of these lesions arise in the limbs and limbgirdles, while occurrence in the trunk, head and neckand acral sites is much rarer. Approximately two-thirdstend to be superficially located and present as multi-nodular masses. As already mentioned, myxofibro-sarcoma shows a broad spectrum of cellularity andpleomorphism. At the low-grade end of the spectrum,neoplastic cells exhibit elongated or stellate morphol-ogy associated with atypical, hyperchromatic nuclei. Avariable number of pseudolipoblasts (vacuolated neo-plastic cells containing mucin vacuoles instead of fat) ispresent. Neoplastic cells are invariably set in a variableamount of myxoid stroma containing characteristicthin-walled, archiform blood vessels (Figure 2a). High-grade lesions exhibit morphological overlap with so-called MFH in showing, at least focally, a hypercellularproliferation of spindle and pleomorphic cells. Areas oflower grade are often present (Figure 2b). Intermedi-ate-grade lesions simply exhibit cellularity and nuclearatypia intermediate between the low- and high-grade

ends of the spectrum. Immunohistochemistry does notplay a significant role as neoplastic cells most oftenexpress only vimentin and, focally, SMA. Local recur-rences are observed in approximately half of thepatients and is related to histological grade. Themetastatic rate of high-grade myxofibrosarcoma rangesbetween 30 and 35% and therefore appears lower thanthat observed in other subtypes of pleomorphic sarc-oma.12 In contrast to local recurrences, metastaticspread is more reliably predicted by grading to theextent that low-grade myxofibrosarcoma almost nevermetastasizes.18

Pleomorphic sarcoma showing myogenicdifferentiation

Both leiomyosarcoma and rhabdomyosarcoma candisplay a pleomorphic phenotype. The recognition ofpleomorphic leiomyosarcoma and rhabdomyosarcoma

Figure 1. Undifferentiated pleomorphic sarcoma ex-malignant

fibrous histiocytoma. A mitotically active pleomorphic spindle cell

proliferation is seen (haematoxylin and eosin).

a

b

Figure 2. Myxofibrosarcoma represents a spectrum of lesions ranging

from low-grade (a) to high-grade sarcoma (b) (haematoxylin and

eosin).

Pleomorphic sarcomas 53


on histological grounds alone may be challenging;however, the presence of large, spindled or polygonal,deeply eosinophilic cytoplasm should raise the suspi-cion of myogenic differentiation. In this context,immunohistochemical and ⁄ or ultrastructural studiesplay an important role.19–21

Pleomorphic leiomyosarcoma tends to occur inmiddle-aged or older patients and forms a significantsubset of retroperitoneal sarcomas. It is also the mostfrequent sarcoma arising from large blood vessels,while it is somewhat less common in the limbs.Pleomorphic rhabdomyosarcoma occurs most exclu-sively in the deep soft tissue of the lower limbs. Peakincidence is in the sixth decade. Pleomorphic rhabdo-myosarcoma is extremely rare in childhood; the vastmajority of sarcomas displaying features of pleomor-phic rhabdomyosarcoma in children actually repre-

sent examples of embryonal rhabdomyosarcoma withanaplastic features.22 Neoplastic cells in pleomor-phic rhabdomyosarcoma tend to exhibit more strik-ing cytoplasmic eosinophilia and more extremevariation in cell size than pleomorphic leiomyosarcoma(Figure 3a,b). Presence of better differentiated areascomposed of fascicles of spindle cells featuring fibrillaryeosinophilic cytoplasm represent a useful diagnosticclue in favour of leiomyosarcoma (Figure 3c,d). Ultra-structural analysis may demonstrate sarcomericdifferentiation by showing Z-band material, myosin–ribosome complexes, or alternating thin (actin) andthick (myosin) filaments in a characteristic hexagonalpattern. Reactivity to desmin and to actin isoforms is‘not helpful’ per se in distinction among them. Thereexists a trend for rhabdomyosarcoma to display adesmin+ ⁄ SMA– phenotype, but exceptions are more

Figure 3. Pleomorphic rhabdomyosarcoma is characterized by a pleomorphic homogeneously eosinophilic cell population (a,b). Pleomorphic

leiomyosarcoma exhibits less striking cytoplasmic eosinophilia (c). The presence of better differentiated areas showing more uniform spindle cells

with a fascicular pattern represents a useful diagnostic clue (d). (Haematoxylin and eosin.)

54 A P Dei Tos


than occasional. Immunoreactivity for h-caldesmonis preferentially seen in leiomyosarcoma, while fastmyosin is seen only in rhabdomyosarcoma. Nowadays,the demonstration of nuclear positivity for myogenin (anuclear transcription factor involved in the commit-ment of primitive mesenchymal cells to striated muscledifferentiation) is currently accepted as unquestionabledemonstration of rhabdomyoblastic differentiation.23

Importantly, in contrast with what is usually observedin alveolar rhabdomyosarcoma, myogenin positivityis most often limited to a small fraction of neoplasticcells in pleomorphic rhabdomyosarcoma. Expression ofmyoglobin is also considered of diagnostic value in thiscontext. It has to be remembered that heterologousstriated muscle differentiation is rarely observed inother high-grade neoplasms, in particular malignantperipheral nerve sheath tumours (MPNSTs) (so-calledmalignant triton tumour) and in a small fraction ofdedifferentiated liposarcomas. From the clinical stand-point both pleomorphic leiomyosarcoma and rhabdo-myosarcoma behave as high-grade sarcomas and areassociated with the poorest outcome among high-gradepleomorphic sarcomas, showing a 5-year metastaticrate ranging between 60 and 70% in leiomyosarcomaand between 90 and 100% in rhabdomyosarcoma.19,21

Pleomorphic liposarcoma

Pleomorphic liposarcoma is a high-grade pleomorphicsarcoma showing histological evidence of adipocyticdifferentiation and represents the rarest variant ofliposarcoma.24,25 The main diagnostic clue to defineadipocytic differentiation in a pleomorphic sarcoma isthe presence of lipoblasts, and their identification oftenrequires careful histopathological examination of anoptimally sampled neoplasm. Pleomorphic liposarc-oma represents the rarest of lipomatous malignancies,accounting for no more than 5% of all liposarcomas. Itoccurs in patients usually in or after the sixth decade oflife. It slightly predominates in the male sex, and thelower extremity, particularly the thigh, is the mostfrequent location, followed by the upper extremity andretroperitoneum. Rare cases of pleomorphic liposarc-omas have also been reported in the skin; however,in these rare cases clinical outcome appears mostlybenign, complete removal being usually curative.26

Lipoblasts are frequently large and show irregular,hyperchromatic, scalloped nuclei, prominent nuclei, setin a multivacuolated cytoplasm. Vacuoles are sharplypunched out. Nuclear pseudoinclusions and multinu-cleation are frequent findings. Most cases tend to fitinto one of three main morphological subsets: approxi-mately two-thirds are represented by a non-distinctive

high-grade pleomorphic ⁄ spindle cell sarcoma withscattered lipoblasts or sheets of lipoblasts (Figure 4a),in less than one-third a high-grade pleomorphicsarcoma with epithelioid areas27 and scattered lipo-blasts is seen (Figure 4b), and a smaller group of casesoverlaps morphologically with intermediate- to high-grade myxofibrosarcoma except for the presence oflipoblasts (Figure 4c). More rarely, pleomorphic lipo-sarcoma in entirely composed of pleomorphic, multi-vacuolated lipoblasts (Figure 4d). These neoplasms areusually rich in mitotic figures, mostly atypical, andnecrosis can be extensive. In those cases in which fewlipoblasts are present, S100 protein may prove helpfulin highlighting their presence.28 Pleomorphic lipo-sarcoma is a high-grade sarcoma associated withrelatively poor survival figures. The metastatic rate isbetween 30 and 50% and overall mortality rangesbetween 40 and 50%.

Other sarcomas with a possible pleomorphicphenotype

The two additional distinct sarcoma subtypes that canrarely exhibit a pleomorphic morphology are represen-ted by extraskeletal osteosarcoma and MPNSTs.

Extraskeletal osteosarcoma is a rare lesion thatoccurs most frequently in the limbs of elderly patients.The main diagnostic clue is the presence of malignantosteoid produced by neoplastic cells (Figure 5). The cellpopulation exhibits a variable morphology whichincludes spindle cell, round cell, epithelioid and pleo-morphic variants. Extraskeletal osteosarcoma is a veryaggressive neoplasm with a 5-year overall survival rateof 25%.29,30

MPNST accounts for approximately 5% of all sarc-omas and in half of the cases is associated with the NF1syndrome (von Recklinghausen’s disease). Two-thirdsarise from neurofibromas (more often plexiform neuro-fibromas in the context of NF1 syndrome), while one-third are unrelated to pre-existing neural lesions.31

Association with a pre-existing schwannoma, ganglio-neuroma and pheochromocytoma represents a veryuncommon occurrence. Typically, MPNST is a spindlecell, fascicular neoplasm characterized by taperingnuclei and variation in cellularity associated withperivascular accentuation. Immunopositivity for S100protein is observed in 40–50% of cases and mostoften involves no more than one-third of neoplasticcells. Heterologous (epithelial, rhabdomyoblastic,chondro ⁄ osteoblastic, angiosarcomatous) differenti-ation is observed in approximately 15% of cases.32 Asmentioned, a minority of cases may exhibit striking



pleomorphic morphology (Figure 6). MPNST is anaggressive neoplasm with an overall 5-year survivalrate of 35% which is unrelated to histological grade.33

Pleomorphic mesenchymal lesions not to beconfused with high-grade pleomorphicsarcomas

Pleomorphism is not per se an unquestionable indicatorof extreme biological aggression. There exist, in fact,neoplasms such as dedifferentiated liposarcoma andatypical fibroxanthoma that, despite featuring all thehistological hallmarks of pleomorphic mesenchymalmalignancies, behave much less aggressively thanexpected. Furthermore, pleomorphism is also presentin completely benign lesions, good examples being the

cytological atypia of degenerative ⁄ regressive naturecommonly found in so-called ‘ancient’ neurilemmomasor in symplastic (bizarre) leiomyoma of the uterus. Adegenerative mechanism may also explain the cyto-logical atypia observed typically in the rare lesiondescriptively termed pleomorphic hyalinizing angiect-atic tumour.

Dedifferentiated liposarcoma

Dedifferentiated liposarcoma represents both a mor-phologically and biologically fascinating lesion, inwhich transition from well-differentiated liposarcomato non-lipogenic sarcoma is observed (Figure 7a,b).First described by Evans in 1979,34 who co-opted theterm from David Dahlin’s description of tumour

Figure 4. Pleomorphic liposarcoma can present as a high-grade pleomorphic ⁄ spindle cell sarcoma with scattered lipoblasts (a) or sheets of

lipoblasts; as a high-grade pleomorphic sarcoma with epithelioid areas and lipoblasts (b); as a lesion morphologically mimicking intermediate to

high-grade myxofibrosarcoma except for the presence of lipoblasts (c); as high-grade sarcoma almost entirely composed of pleomorphic,

multivacuolated lipoblasts (d). (Haematoxylin and eosin.)

56 A P Dei Tos


progression in chondrosarcoma,35 dedifferentiation inwell-differentiated liposarcoma tends to occur morefrequently in the primary tumour (90%) but can alsobe observed in recurrences (10%). The transitionusually occurs in an abrupt fashion, but in some casescan be more gradual and, exceptionally, low-grade andhigh-grade areas appear to be intermingled. Dediffer-entiated areas exhibit a variable histological picture butmost frequently it overlaps with undifferentiated pleo-morphic sarcoma (ex-MFH) or myxofibrosarcoma (ex-myxoid MFH). Recently it has also been proposed thatdedifferentiated liposarcoma should be further classifiedinto low-grade and high-grade subtypes.36,37 Dediffer-entiated liposarcoma may exhibit heterologous differ-entiation in about 5–10% of cases which apparently

does not affect the clinical outcome. Most often the line ofheterologous differentiation is myogenic or osteo ⁄chondrosarcomatous, but angiosarcomatous elementshave also been reported. Recently, a peculiar ‘neural-like’ or ‘meningothelial-like’ whorling pattern of dedif-ferentiation has been described, but both immuno-histochemistry and electron microscopy failedto elucidate the line of differentiation in theselesions.38,39 This pattern is often associated withossification.

Surprisingly, the biological behaviour of dedifferen-tiated liposarcoma tends to be much less aggressivethan that of other types of high-grade pleomorphicsarcomas.40 At variance with well-differentiated lipo-sarcoma, dedifferentiation is associated with a 15–20%metastatic rate. However, long-term survival rates forretroperitoneal dedifferentiated liposarcoma are notsignificantly worse than that observed in ordinarywell-differentiated liposarcoma occurring at the same

Figure 5. The most important diagnostic clue in a pleomorphic

extraskeletal osteosarcoma is represented by the presence of

neoplastic osteoid (haematoxylin and eosin).

Figure 6. Malignant peripheral nerve sheath tumours may rarely

exhibit cytological pleomorphism (haematoxylin and eosin).

Figure 7. Dedifferentiated liposarcoma is characterized by the

transition from well-differentiated liposarcoma (a) to non-lipogenic

sarcoma (b) (haematoxylin and eosin).



site, mortality being principally related to repeateddestructive local recurrences rather than to metastaticspread. The fact the dedifferentiated liposarcoma canrecur as an entirely well-differentiated liposarcoma alsorepresents a morphological indicator of the uniquebiological behaviour of this liposarcoma subtype. Gen-etics as well as molecular pathology have recentlyprovided data that, at least in part, may account for thediscrepancy observed between morphology and bio-logical aggressiveness. Interestingly, in contrast to thecomplex karyotypic aberrations observed in pleomor-phic sarcomas, dedifferentiated liposarcoma usuallyretains the same basic cytogenetic anomalies as well-differentiated liposarcoma, represented by the presenceof ring and ⁄ or giant marker chromosomes,41 althoughthere are often superimposed additional aberrations.42

A significant increase in the level of both MDM2overexpression and amplification in the high-gradeareas has been observed, which may account for thetumour progression in this subset of sarcomas.43,44

However, while high-grade pleomorphic sarcomasoften contain concomitant aberrations of both MDM2and TP53 (which correlate with poor outcome),45 indedifferentiated liposarcoma TP53 integrity is almostalways observed.43 Dedifferentiated liposarcoma there-fore appears to be just one more step along thespectrum of well-differentiated adipocytic neoplasia,showing only an increased dosage of the same mole-cular targets involved in the molecular pathogenesisof well-differentiated liposarcoma.

Atypical fibroxanthoma

Atypical fibroxanthomas also represent a biologicallyfascinating lesion that, despite extreme pleomorphism,is characterized by most often benign clinical beha-viour.46,47 For many years, this distinct lesion hasoften been regarded as the superficial, cutaneous non-metastasizing variant of so-called MFH. Currently, as aconsequence of the described conceptual evolution,atypical fibroxanthoma is no longer considered afibrohistiocytic lesion. With the advent of new tech-niques, especially immunohistochemistry, atypicalfibroxanthoma has become the prototypic diagnosis ofexclusion, main differential diagnoses being represen-ted by malignant melanoma, spindle cell (sarcomatoid)carcinoma and leiomyosarcoma. Even if classic atypicalfibroxanthoma is a pleomorphic lesion, a more mono-morphic variant has been recognized as part of thespectrum of atypical fibroxanthoma and has beencalled spindle-cell non-pleomorphic atypical fibro-xanthoma.48 Given the distinctive p53 mutations, aswell as ultraviolet (UV) photoproducts, identified in

these lesions, it seems increasingly that atypical fibro-xanthoma is best regarded as a UV-induced prolifer-ation of dermal fibroblasts.49,50

Atypical fibroxanthoma presents as a solitary, poly-poid, ulcerated lesion in sun-damaged skin, especiallyof the head and neck and less commonly on the dorsumof the hands, of elderly patients. A clinical history ofrapid growth is most often reported. Those casesreported in the past to occur in non-actinically dam-aged skin in the limbs of young adults probablyrepresent examples of atypical benign fibrous histio-cytoma.

Histologically, all atypical fibroxanthomas arecentred in the dermis, quite often surrounded by anepidermal collarette. Growth tends to be expansile withonly limited infiltration. Actinic degeneration of elasticfibres in the surrounding dermis is a prominent feature.Ulceration is present in most cases, making evaluationfor the presence of epidermal dysplasia or junctionalactivity often difficult or even impossible. Classicalatypical fibroxanthoma is composed of highly pleomor-phic histiocyte-like cells and bizarre giant cells inter-spersed with a variable number of spindle-shaped cellsand inflammatory cells. Mitotic activity is usually veryhigh and is associated with the presence of atypicalmitotic figures (Figure 8). The spindle cell (non-pleo-morphic) variant of atypical fibroxanthoma is com-posed of fascicles of eosinophilic spindle cells withvesicular nuclei and one or multiple eosinophilicnucleoli. Mitotic figures, which are often atypical, arecommon but cytological pleomorphism is focal or evenabsent in this subset of cases. Importantly, subcuta-neous or deeper invasion, necrosis or vascular orperineurial invasion should not be accepted as features

Figure 8. Atypical fibroxanthoma is represented by a dermal

pleomorphic cell proliferation, usually associated with heavy

actinic damage (haematoxylin and eosin).

58 A P Dei Tos


of atypical fibroxanthoma, although there may befocal, very superficial invasion into fat. Immunohisto-chemistry is essential for confirming the diagnosis ofatypical fibroxanthoma. Vimentin is diffusely positivein all cases and a few are positive focally for SMA,suggestive of fibroblastic or myofibroblastic differenti-ation. Immunostains for keratins, S100 protein anddesmin are always negative, and play a main role inruling out the main three differential diagnoses,namely, spindle cell (sarcomatoid) squamous cell car-cinoma, spindle cell melanoma and leiomyosarcoma.

Behaviour is usually benign and complete excision isgenerally curative. Local recurrence is uncommon andshould prompt re-analysis of the initial diagnosis.Those lesions reported in the past as metastatic atypicalfibroxanthoma51 were characterized by deep infiltrativegrowth and, taking into account the limited or absentimmunohistochemical work-up at that time, mostprobably represented examples of other high-gradesarcomas or non-mesenchymal malignancies, such asmelanoma and squamous cell carcinoma.

Pleomorphic hyalinizing angiectatic tumour

Described in 1996,52 pleomorphic hyalinizing angiect-atic tumour is a very uncommon non-encapsulatedmesenchymal lesion that occurs mostly in lowerextremity subcutaneous tissue of middle-aged patientswith no sex predilection. Histologically, this lesionpresents as a proliferation of spindle and ⁄ or pleomor-phic cells associated with ectatic thin-walled vesselssurrounded by prominent eosinophilic fibrin ⁄ collagendeposition (Figure 9). Most often, the lesion has

infiltrative borders; intratumoral haemosiderin depositsmay be prominent and organized intravascular thro-mbi are commonly observed. The spindle and pleomor-phic cells possess bizarre hyperchromatic, pleomorphicnuclei with frequent intranuclear pseudoinclusions.Mitoses are rare (usually absent or less than 1 per 50high-power fields) and, when dealing with a mitoticallymore active lesion, a true pleomorphic sarcoma shouldbe first considered. Chronic inflammatory cells can befound in or surrounding the lesion, as well as intra-tumoral aggregates of mast cells. The spindle ⁄ pleo-morphic cells in pleomorphic hyalinizing angiectatictumour are negative for S100 protein and vascularmarkers (CD31, factor VIII) but half of the tumours inthe original series and in a subsequent report53 wereCD34+.

Because of the cellular pleomorphism, the haemor-rhagic changes, and the occasional presence of prom-inent cytoplasmic intranuclear inclusions, the lesionmay be confused with a high-grade pleomorphicsarcoma, although one should be alerted by thecontrast between the extremely low mitotic rate andthe marked pleomorphism of the lesion. The peculiararrangement of vessels with heavy perivascular fibrindeposition is another clue to the diagnosis. Pleomor-phic hyalinizing angiectatic tumour is also likely tobe confused with benign lesions, especially ancientschwannoma, melanotic schwannoma (in cases withheavy intratumoral haemosiderin) or a long-standinghaemangioma. The lack of immunoreactivity for S100protein and vascular markers allows distinction fromthese latter.

MFH and MFHs: is there anything left?

Following the creation of the prototypical form of MFH,the storiform-pleomorphic variant, other MFH variantswere generated: namely myxoid MFH,16 inflammatoryMFH,54 giant cell MFH55 and angiomatoid MFH.56 Dothey still exist as distinct clinicopathological entities?Unavoidably, the fall of the progenitor affected itsprogeny. As mentioned above, myxoid MFH has beennow renamed ‘myxofibrosarcoma’ to underline thefibroblastic line of differentiation of this neoplasm.Inflammatory MFH was defined as a malignant neo-plasm, most frequently occurring in the retroperitone-um, composed of a spindle cell and pleomorphic cellproliferation, containing numerous xanthomatous cellsand ⁄ or acute and chronic inflammatory cells. Xantho-matous cells may appear cytologically either benign ormalignant. It is now agreed that inflammatory MFHrepresents a heterogeneous group of unrelated lesions.Many of the cases diagnosed as such in the past

Figure 9. Pleomorphic hyalinizing angiectatic tumour histologically

presents as a proliferation of spindle and ⁄ or pleomorphic cells

associated with ectatic thin-walled vessels surrounded by prominent

eosinophilic fibrin ⁄ collagen deposition (haematoxylin and eosin).



actually represented lymphomas of both Hodgkin andnon-Hodgkin types, leiomyosarcomas and sarcomatoidcarcinomas. More importantly, recent molecular ana-lysis of the 12q13-14 chromosome region of a largeseries of retroperitoneal ‘inflammatory MFH’ reachedthe conclusion that a significant subset of these casesactually represent examples of dedifferentiated lipo-sarcoma.57 The inflammatory areas may sometimes beso abundant that the adipocytic component can beeasily overlooked. Careful sampling and microscopicexamination are mandatory before a diagnosis ofundifferentiated inflammatory pleomorphic sarcoma(ex-inflammatory MFH) is rendered.

Giant cell MFH also represents a wastebasket cate-gory which includes specific sarcoma types, such asleiomyosarcoma with osteoclastic giant cells, giant celltumour of soft tissue58–60 and examples of extraskeletalosteosarcoma. It is worth considering that this concepthad been anticipated in 1971 by Salm and Sissons;61

however, because of the widespread use of the MFHterminology, their observation had to wait threedecades before being fully recognized.

The last ‘MFH’ category is represented by angiomatoidMFH, which characteristically affects much youngerpatients than other ‘MFH’ variants. Currently, this entityis no longer considered a frankly malignant neoplasm(metastatic rate is lower than 2% of cases and meta-stases usually involve regional lymph nodes). Desminimmunopositivity has been observed in approximately40% of cases, perhaps supporting a myogenic pheno-type; however, epithelial membrane antigen is alsopositive in 40% of cases. The ultimate line of differenti-ation remains to be elucidated.62,63 Angiomatoid (M)FHno longer belongs to the fibrohistiocytic category and iscurrently classified within the lesions of uncertaindifferentiation. Importantly, angiomatoid FH shouldnot be confused with aneurysmal FH, which representsa variant of benign dermal fibrous histiocytoma.

Conclusions

The conceptual evolution in the classification of pleo-morphic sarcomas represents a paradigm of howsurgical pathology in general has evolved throughthe last two decades. Until recently, subclassification ofthis heterogeneous group of mesenchymal malignan-cies was regarded by clinicians (and also by manypathologists) as a mere academic exercise. Nowadays,it has been unequivocally demonstrated that accuratehistological subtyping is clinically relevant. In fact, thisnot only allows recognition of non-sarcomatous lesionswith consequent planning of proper therapy, butalso permits identification of subsets of pleomorphic

sarcoma with especially unfavourable prognoses. Thismay allow stratification to more aggressive therapy orsuitable clinical trials. In consideration of the recentadvent of molecular therapies, it seems also likely thatthe accurate recognition of the different histotypes willrepresent a prerequisite for effective treatment of thisrare group of malignancies.

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where are we now with pleomorphic sarcoma

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