CHAPTER 3

So-called Fibrohistiocytic Tumours

Over the past 10 years, the concept of fibrohistiocytic differenti-ation has been challenged and is now regarded as a poorlydefined morphological descriptor of histiocytic differentiation.Pleomorphic malignant fibrous histiocytoma (MFH) was previ-ously regarded as a distinct tumour type representing the mostcommon adult soft tissue sarcoma. Today, this term is synony-mous with undifferentiated pleomorphic sarcoma, which hasbecome a diagnosis of exclusion accounting for less than 5% ofadult sarcomas. Similarly, the morphological features formerlyregarded as characteristic of the giant cell and inflammatoryvariants of MFH are shared by a variety of other, specific tumourtypes. Myxofibrosarcoma (formerly known as myxoid MFH) andso-called angiomatoid MFH remain as distinctive and discreteentities (see Chapters 2 and 9).

Cutaneous fibrous histiocytomas, dermatofibrosarcoma protu-berans (best classified as a fibroblastic neoplasm) and atypicalfibroxanthoma are described separately in the Skin volume.Since the localized and diffuse forms of giant cell tumour of ten-don sheath have more in common with the descriptive categoryof fibrohistiocytic lesions than with true synovium, they are fornow included in this chapter.

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Giant cell tumour of tendon sheath N. de St. Aubain SomerhausenP. Dal Cin

The term giant cell tumour of tendonsheath encompasses a family of lesionsmost often arising from the synovium ofjoints, bursae and tendon sheath {1027}.These tumours are usually dividedaccording to their site (intra- or extra-articular) and growth pattern (localizedor diffuse) into several subtypes, whichdiffer in their clinical features and biolo-gical behaviour.

DefinitionThe localized type of giant cell tumour oftendon sheath is a circumscribed prolif-eration of synovial-like mononuclearcells, accompanied by a variable num-ber of multinucleate osteoclast-like cells,foam cells, siderophages and inflamma-tory cells, most commonly occurring inthe digits.

ICD-O code 9252/0

SynonymsTenosynovial giant cell tumour, localizedtype, nodular tenosynovitis.

EpidemiologyThe localized form is frequent and themost common subset of giant cell tu-mours. Tumours may occur at any agebut usually between 30 and 50 years,with a 2:1 female predominance {2163}.

Sites of involvementLocalized giant cell tumours occur pre-dominantly in the hand where they prob-ably represent the most common neo-plasm. Approximately 85% of thetumours occur in the fingers, in closeproximity to the synovium of the tendonsheath or interphalangeal joint. Thelesions may infrequently erode or infil-trate the nearby bone {2160}, or rarelyinvolve the skin.Other sites include the wrist, ankle / foot,knee, and very rarely the elbow and thehip {1492,2163}.

Clinical featuresThe most common presenting symptomis that of a painless swelling. Thetumours develop gradually over a longperiod and a preoperative duration ofseveral years is often mentioned .Antecedent trauma is reported in a vari-able number of cases (from 1 to 50%){1492,2163}.Radiological studies usually demon-strate a well circumscribed soft tissuemass, with occasional degenerativechanges of the adjacent joint or erosionof the adjacent bone {1046}.

AetiologyTenosynovial giant cell tumours initiallywere regarded as an inflammatory

process based on animal models, thecommon history of trauma, the predilec-tion for the first three fingers of the righthand {1492} and one X-inactivation study suggesting polyclonality {2295}.However, the finding of aneuploidy insome cases {7}, the demonstration ofclonal chromosomal abnormalities{1774}, and the fact that these lesionsare capable of autonomous growthstrongly support a neoplastic origin.

MacroscopyGrossly, most localized giant celltumours are small (between 0.5 and 4cm), although lesions of greater size maybe found in large joints. Tumours are wellcircumscribed and typically lobulated,white to grey with yellowish and brownareas.

HistopathologyTumours are lobulated, well circum-scribed and at least partially covered bya fibrous capsule. Their microscopicappearance is variable, depending onthe proportion of mononuclear cells,multinucleate giant cells, foamymacrophages, siderophages and theamount of stroma. Osteoclast-like cells,which contain a variable number ofnuclei (from 3-4 to more than 50), areusually readily apparent but may be

110 Fibrohistiocytic tumours

BAFig. 3.01 Giant cell tumour of tendon sheath. A Typical admixture of histiocytoid cells, foamy cells and lymphocytes. In this case, giant cells are scanty. B Typical mononu-clear histiocytoid cells with variably prominent eosinophilic cytoplasm and scattered osteoclastic giant cells.

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inconspicuous in highly cellular tumours.Most mononuclear cells are small, roundto spindle-shaped. They are character-ized by pale cytoplasm and round orreniform, often grooved nuclei. They areaccompanied by larger epithelioid cellswith glassy cytoplasm and roundedvesicular nuclei. Xanthoma cells are fre-quent, tend to aggregate locally near theperiphery of nodules and may be associ-ated with cholesterol clefts.Haemosiderin deposits are virtuallyalways identified. The stroma shows vari-able degrees of hyalinization and mayoccasionally have an osteoid-likeappearance. Cleft-like spaces are lessfrequent than in the diffuse form {2163}.Mitotic activity usually averages 3 to 5mitoses per 10 HPF but may reach up to20/10 HPF {2295}. Focal necrosis israrely seen.

ImmunophenotypeImmunohistochemically, mononuclearcells are positive for CD68. Some cellsmay also express muscle-specific actin

(HHF35). A subset of desmin-positivedendritic cells is reported in up to 50% ofcases {705}. Multinucleate giant cells express CD68,CD45 and markers such as tartrateresistant acid phosphatase {449,1590}.

UltrastructureUltrustructural studies have revealed anheterogeneous cell population com-posed of a majority of histiocyte-likecells, accompanied by fibroblast-likecells, intermediate cells, foam cells andmultinucleate giant cells {35,2163}.

GeneticsCytogenetic aberrations have beendescribed in 11 giant cell tumours of ten-don sheath. A near- or pseudodiploidkaryotype was seen in all cases, mostlywith simple structural changes {1910}. The short arm of chromosome 1 is fre-quently involved, with a clustering ofbreakpoints to the region p11-p13 in 7/11cases. A recurrent t(1;2)(p11;q35-36)has been identified, but several other

translocation partners have beendescribed, including 3q21, 5q31, and11q11. In addition, two cases without1p11-13 rearrangement had transloca-tions involving 16q24, thus possibly rep-resenting an alternative primary cytoge-netic change. Numerical changes seemto be rare. In particular, it should benoted that gain of chromosomes 5 and 7,which is common in the diffuse type giantcell tumour {1477}, has not beendescribed in the localized form {1910}.

Prognostic factorsLocalized giant cell tumour is a benignlesion with a capacity for local recur-rence. Local excision is the treatment ofchoice. 4 to 30 % of cases recur {1504,1757,1774} but these recurrence areusually non-destructive and are con-trolled by surgical reexcision. It has beensuggested that recurrences developmost often in highly cellular tumours orlesions with a high mitotic count{1757,2298}.

BAFig. 3.03 Giant cell tumour of tendon sheath. A Localized giant cell tumours of tendons sheath are usually CD68 positive. B Some cases of both localized and diffuse type contain numerous desmin-positive mononuclearcells, sometimes with dendritic cytoplasmic porcesses.

Fig. 3.04 Giant cell tumour of tendon sheath. Partialkaryotype showing the characteristic t(1;2)(p13;q37)translocation. Arrows indicate breakpoints.

B CAFig. 3.02 Giant cell tumour of tendon sheath. A Most cases show focal collections of xanthoma cells, while others (B) show extensive stromal hyalinization. C Small, his-tiocyte-like cells with occasional nuclear grooves and larger cells with vesicular nuclei and abundant eosinophilic cytoplasm, frequently with a rim of haemosiderin.

Giant cell tumour of tendon sheath 111

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112 Fibrohistiocytic tumours

DefinitionDiffuse-type giant cell tumour is adestructive proliferation of synovial-likemononuclear cells, admixed with multi-nucleate giant cells, foam cells,siderophages and inflammatory cells.The extraarticular form is defined by thepresence of an infiltrative soft tissuemass, with or without involvement of theadjacent joint. The very uncommon malignant giant celltumour of tendon sheath is defined bythe coexistence of a benign giant celltumour with overtly malignant areas or bythe recurrence of a typical giant celltumour as a sarcoma.

ICD-O code 9251/0

SynonymsPigmented villonodular synovitis, pig-mented villonodular tenosynovitis.

EpidemiologyDiffuse-type giant cell tumours tend toaffect younger patients than their local-ized counterpart. The age of patientsvaries widely but most lesions affectyoung adults, under the age of 40. Thereis a slight female predominance {1523,1984,2164}.

Sites of involvementIntraarticular lesions affect predominant-ly the knee (75% of cases), followed bythe hip (15%), ankle, elbow and shoul-der. Rare cases are reported in the tem-

poromandibular and spinal facet joints{782,1899}. Extraarticular tumours mostcommonly involve the knee region, thighand foot. Uncommon locations includethe finger, wrist, groin, elbow and toe {87,1984,2164}.Most extraarticular tumours are locatedin periarticular soft tissues but theselesions can be purely intramuscular orpredominantly subcutaneous {2164}.

Clinical featuresPatients complain of pain, tenderness,swelling or limitation of motion.Haemorrhagic joint effusions are com-mon. The symptoms are usually of rela-tively long duration (often several years). Radiographically, most tumours presentas ill defined peri-articular masses, fre-quently associated with degenerativejoint disease and cystic lesions in theadjacent bone {542}. On magnetic reso-nance imaging, giant cell tumours showdecreased signal intensity in both T1-and T2-weighted images {1036}.

AetiologyAlthough these lesions have beenregarded as reactive, the presence ofclonal abnormalities {1910} and thecapacity for autonomous growth are nowwidely regarded as evidence for a neo-plastic origin.

MacroscopyDiffuse-type giant cell tumours are usual-ly large (often more than 5 cm), firm or

sponge-like. The typical villous pattern ofpigmented villonodular synovitis is usual-ly lacking in extraarticular tumours. Thelatter have a multinodular appearanceand a variegated colour, with alternationof white, yellowish and brownish areas.

HistopathologyMost tumours are infiltrative and grow asdiffuse, expansile sheets. Their cellularityis variable: compact areas alternate withpale, loose, discohesive zones. Cleft-likespaces are common and appear eitheras artefactual tears or as synovial-linedspaces. Blood-filled pseudoalveolarspaces are seen in approximately 10% ofcases.In comparison with the localized form,osteoclastic giant cells are less commonand may be absent or extremely rare inup to 20% of cases. They are irregularlydistributed throughout the lesions andare more easily found around haemor-rhagic foci. The mononuclear component comprisestwo types of cells: small histiocyte-likecells, which represent the main cellularcomponent, and larger cells. Histiocyte-like cells are ovoid or spindle-shaped,with palely eosinophilic cytoplasm. Theirnuclei are small, ovoid or angulated, con-tain fine chromatin, small nucleoli andfrequently display longitudinal grooves.Larger cells are rounded or sometimesshow dendritic cytoplasmic processes.Their cytoplasm is abundant, pale todeeply eosinophilic, often contains a

N. de St. Aubain SomerhausenP. Dal CinDiffuse-type giant cell tumour

BAFig. 3.05 A Villous appearance of an intra-articular diffuse-type giant cell tumour. B Low magnification of a com-pletely extra-articular tumour showing infiltration of the muscular and adipose tissue.

Fig. 3.06 Diffuse-type giant cell tumour with promi-nent inflammatory component and numerous largedendritic cells with abundant cytoplasm.

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peripheral rim of hemosiderin granulesand occasionally shows a paranucleareosinophilic filamentous inclusion. Nucleiare characterized by reniform or lobulat-ed shape, thick nuclear membranes,vesicular chromatin and eosinophilicnuclei. The occasional predominance ofthese larger cells may obscure the typi-cal features of giant cell tumour and leadto a diagnosis of sarcoma. Sheets offoam cells are frequently observed, usu-ally in the periphery of lesions and vari-able amounts of haemosiderin are identi-fied in most cases. Giant cell tumoursmay also contain a significant lymphocyt-ic infiltrate. The stroma shows variabledegrees of fibrosis and may appearhyalinized, although this is usually lessmarked than in the localized form. Mitoses are usually identifiable andmitotic activity of more than 5 per 10 HPFis not uncommon {1984,2164,2239}. There have been several reports of typi-cal giant cell tumours recurring as a his-tologically malignant neoplasms and afew series included primary histological-ly malignant tumours of the tendonsheath resembling giant cell tumours{187,637,1555,1941,1984}. These neo-plasms tended to show significantlyincreased mitotic rate (more than 20mitoses / 10 HPF), necrosis, enlargednuclei with nucleoli, spindling of mononu-cleated cells, the presence of abundanteosinophilic cytoplasm in histiocyte-likecells, and stromal myxoid change,although none of these features could beused in isolation as a criterion for malig-nancy {187,637,1984}. In addition, two cases with banal histol-ogy which developed metastatic disease(in the lungs or lymph nodes) have beenreported to date {1984,2239}.

Immunophenotype The immunohistochemical and ultra-structural features of diffuse-type giantcell tumour are similar to those of thelocalized form. Mononuclear cells arepositive for CD68 and other macrophagemarkers. Desmin stain highlights a popu-lation of cells with dendritic features in 35to 40% of cases; these frequently corre-spond to the larger eosinophilic cells.Giant cells are positive for CD68 andCD45 {705,1590,1984}.

GeneticsChromosomal aberrations have beendescribed in 17 cases, all with a near- or

pseudodiploid karyotype. Rearrange-ments of the 1p11-13 region have beendetected in eight of them, one had at(1;2)(p22;q35-37), and one had involve-ment of band 16q24, suggesting a closecytogenetic relationship with the local-

ized form of giant cell tumour {1910}.One difference, however, between thesetwo entities, is that trisomies for chromo-somes 5 and 7, usually as the sole anom-alies, have been detected only in diffuse-type giant cell tumours {1477}. The sig-

Fig. 3.07 Diffuse-type giant cell tumour. A Pseudosynovial or 'pseudoglandular' spaces, surrounded by clustersof xanthoma cells. B Pseudoalveolar spaces are commonly seen in diffuse-type giant cell tumours.

A

B

BAFig. 3.08 Diffuse-type giant cell tumour. A Typical mononuclear histiocytoid cells, some of which have promi-nent eosinophilic cytoplasm. B Note frequent nuclear grooves in the histiocytoid cells. Some tumour cells havemore prominent eosinophilic cytoplasm with haemosiderin granules.

113Diffuse-type giant cell tumour

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Deep benign fibrous histiocytoma J.M. Coindre

DefinitionA benign fibrous histiocytoma, whichdevelops entirely within subcutaneoustissue, deep soft tissues or in parenchy-mal organs.

ICD-O code 8830/0

EpidemiologyDeeply located fibrous histiocytomas arerare. Based on the only published series,they represent less than 1% of fibrohisti-ocytic tumours {673}. Their exact fre-quency is difficult to determine because

some cases published as deep fibroushistiocytomas may represent solitaryfibrous tumours {673,706}. They maydevelop at any age, but most affectadults over 25 years old, with a predom-inance in males.

Sites of involvementThe lower limb and the head and neckregion are the most common sites. Mostcases develop in subcutaneous tissue,but a few cases have been reported inmuscle, mesentery, trachea and kidney{673,869,1147,1843}.

nificance of trisomy 5 and 7 for tumourdevelopment in this context is question-able because the same aneuploidies arefrequent also in synovial samples frompatients with various forms of reactivesynovial lesion {1429}.

Prognostic factors Recurrences are common, often multipleand may severely compromise joint func-

tion. The recurrence rate has been esti-mated between 18 and 46 % for intraar-ticular lesions and between 33 and 50%of cases for extraarticular tumours {1899,1984,2164,2239}. The risk of recurrencedoes not seem to be correlated with anyhistological parameter other than posi-tive excision margins. Therefore, diffuse-type giant cell tumours should be regard-ed as locally aggressive but nonmetasta-

sizing neoplasms and wide excision isthe treatment of choice. Although the number of cases is limited,malignant giant cell tumours of tendonsheath showing obvious sarcomatousareas are potentially aggressive and maygive rise to pulmonary metastasis {187,1555,1941,1984}.

Fig. 3.10 Deep benign fibrous histiocytoma tends tobe more circumscribed than the cutaneous form andpseudo-encapsulated.

114 Fibrohistiocytic tumours

BAFig. 3.09 Malignant diffuse-type giant cell tumour. Although there is usually at least focal morphological overlap with usual giant cell tumour (A), closer examinationreveals increased cellularity and predominance of atypical large cells with prominent nucleoli (B).

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Clinical featuresMost lesions present as a painless andslowly enlarging mass.

MacroscopyContrary to the cutaneous form, deeplesions tend to be well circumscribedand pseudo-encapsulated with occa-sional areas of haemorrhage. Mostlesions are 4 cm or more when resected.

HistopathologyDeep fibrous histiocytomas usually showa prominent storiform pattern, sometimescombined with haemangiopericytoma-like areas. Contrary to conventional cutaneouslesions, most lesions show monomor-

phism and usually lack secondary ele-ments such as foamy cells and giantcells but usually show scattered lympho-cytes. Thus, they more closely resmblethe cellular variant of cutaneous fibroushistiocytoma. The tumour cells are cyto-logically bland and generally spindle-shaped with elongated or plump vesicu-lar nuclei and eosinophilic, ill definedcytoplasm. There is no nuclear pleomor-phism or hyperchromasia, and mitoses,although commonly present, are usuallyless than 5 per 10 high power fields. Thestroma may show myxoid change orhyalinization and rarely osteoclast-likegiant cells or metaplastic ossification{673,1973}. Small foci of necrosis maybe present.

ImmunophenotypeImmunohistochemistry shows similarresults as in cutaneous lesions with neg-ativity for epithelial markers, desmin andS100 protein. Alpha smooth muscle actinmay be positive in some parts of thelesion. CD34 is usually (but not always)negative, but, if positive, solitary fibroustumour should be considered.

Prognostic factorsDeep fibrous histiocytoma may recurlocally {673}, particularly if incompletelyexcised. No metastasis has been report-ed so far.

BAFig. 3.11 Deep benign fibrous histiocytoma. A A monomorphic storiform pattern is usually seen. B Branching pericytoma-like vessels are common.

115Deep benign fibrous histiocytoma

BAFig. 3.12 Deep benign fibrous histiocytoma. A These lesions show less cytologic polymorphism than their dermal counterparts. B Staining for CD34 is most often nega-tive.

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116 Fibrohistiocytic tumours

DefinitionPlexiform fibrohistiocytic tumour (PFT) isa mesenchymal neoplasm of children,adolescents, and young adults, charac-terized by fibrohistiocytic cytomorpholo-gy, and a multinodular growth pattern. Itrarely metastasizes.

ICD-O code 8835/1

EpidemiologyPFT preferentially affects young individuals;mean age at presentation is approximately14.5 years {603,1782}. The tumour occurs

more often in female than in male patients,with reported female-to-male ratios rangingfrom 2.5:1 {603} to 6:1 {1782}. PFT has notbeen reported to occur with greater fre-quency in any particular race.

Sites of involvementPFT involves the upper extremities inapproximately 65% of cases {603,1782},with the hands and wrists being affectedin about 45% of cases {1782}. The lowerextremities are involved in approximately27% of cases {1782}. PFT rarely occursin the head and neck region.

Clinical featuresPFT usually presents as a small, poorlydemarcated, painless dermal or subcu-taneous mass that slowly enlarges formonths to years {603,1782}. It is clinical-ly characterized by slow growth, frequentlocal recurrence, and rare regional lym-phatic and systemic metastasis {603,1782}.

MacroscopyPFT is usually a multinodular, firm, poorlycircumscribed dermal or subcutaneousmass that rarely exceeds 3 cm.

HistopathologyPFT is composed of small nodules orelongated cellular clusters that are inter-connected in a characteristic plexiformarrangement. Three distinct cell typesare present in variable amounts:mononuclear histiocyte-like cells, spindlefibroblast-like cells, and multinucleategiant cells. The nodules and clusters areinterconnected by spindle cells situatedat the periphery of the nodules. Threehistologic subtypes are recognized: afibrohistiocytic subtype composed main-ly of nodules of mononuclear histiocyte-like cells and multinucleated giant cells,a fibroblastic subtype composed mainlyof elongated clusters and short fasciclesof fibroblast-like cells, and a mixed sub-type composed of both patterns in equalproportion. Cellular atypia and pleomor-phism are minimal, mitotic count fre-quently is low, and necrosis is absent.Vascular invasion is observed in 10-20%of cases. The nodules and clusters aresituated in subcutaneous tissue anddeep dermis, but extension into skeletalmuscle can occur. In pulmonary metas-tases, PFT presents as small fibrohistio-cytic nodules in subpleural and peribron-chiolar locations.

ImmunophenotypePFT displays immunoreactivity forvimentin, CD68 (KP1), and smooth mus-cle actin {62,783,962,1782,2340}. CD68immunoreactivity is mainly displayed bymultinucleated giant cells and mononu-

A.G. NascimentoP. Dal CinPlexiform fibrohistiocytic tumour

Fig. 3.13 A Plexiform fibrohistiocytic tumour is composed of a mixture of small nodules and elongated fas-cicles that interconnect with each other, forming a characteristic plexiform arrangement. B The fibroblasticsubtype is composed mainly of elongated clusters and short fascicles of fibroblastlike cells, creating a pictureresembling fibromatosis. Scattered multinucleated giant cells are present.

A

B

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117Plexiform fibrohistiocytic tumour

clear histiocyte-like cells {1782,2340};the fibroblast-like cells stain only rarelywith CD68. However, the fibroblast-likecells and occasional histiocytelike cellsstain for smooth muscle actin {62,783,962,2340}.

UltrastructurePFT cells have features of myofibroblastsand histiocyte-like cells {62,783,962},such as abundance of lysosomes, promi-nent filopodia, and bundles of thin cytofil-aments along the cytoplasmic mem-brane {62}.

GeneticsOnly two plexiform fibrohistiocytictumours with clonal chromosome aberra-tions have been reported, and no sharedchromosome abnormalities were found{1767,1974}.

Prognostic factorsPFT has been associated with a localrecurrence rate ranging from 12.5%{1782} to 37.5% {603}, a regional lymphnode metastatic rate of 3/61 cases withfollow-up {603,1782} and a systemic(lungs only, to date) metastatic rate of3/61 cases {603}. Such significantmetastatic rates likely reflect the bias ofconsultation practice. No clinicopatho-logic or genetic factors seem to influencethe prognosis of patients with PFT {603,1782}.

Fig. 3.14 The fibrohistiocytic subtype of plexiform fibrohistiocytic tumour is characterized by nodules ofmononuclear histiocyte-like cells and multinucleated giant cells.

BAFig. 3.15 Plexiform fibrohistiocytic tumour. A Vascular invasion is occasionally present in 10-20% of cases. BSmall, peribronchiolar tumoural nodule in pulmonary metastasis of plexiform fibrohistiocytic tumour.

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DefinitionGiant cell tumour of soft tissue (GCT-ST)is a primary soft tissue neoplasm that isclinically and histologically similar togiant cell tumour of bone; it very rarelymetastasizes.

ICD-O code 9251/1

SynonymsOsteoclastoma of soft tissue, giant celltumour of low malignant potential.

EpidemiologyGCT-ST occurs predominantly in the fifthdecade of life but can affect patientsranging in age from 5 to 89 years. GCT-ST affects both sexes in equal numbers.GCT-ST does not occur with greater fre-quency in any particular race {702,1591,1608}.

Sites of involvementGCT-ST usually occurs in superficial softtissues of the upper and lower extremi-ties (70% of tumours). Less frequentlyaffected are the trunk (20%) and headand neck region (7%) {702,1591,1608}.

Clinical featuresThe tumours present as painless growingmasses {1591,1608}, with an averageduration of symptoms of 6 months{1608}. As in giant cell tumour of bonewith soft tissue implants {397}, peripher-al mineralization is exceedingly frequent

in GCT-ST, yielding a characteristic radi-ographic appearance.

AetiologyNo aetiologic factors have been identi-fied, but GCT-ST has occurred rarely inpatients with Paget disease of bone{758} or after trauma {1608}.

MacroscopyIn the 3 major series of patients withGCT-ST reported to date {702,1591,1608}, tumours ranged in size from 0.7 to10 cm (mean, 3 cm). Seventy percent ofthe tumours involved subcutaneous adi-pose tissue or dermis; only 30% were sit-uated below the superficial fascia. GCT-ST presents as a well circumscribed,mostly solid, nodular mass with a fleshy,red-brown or gray cut surface. Grittyregions of mineralized bone frequentlyare present at the periphery of thetumours {1591}.

HistopathologyAt low magnification, approximately 85%of GCT-STs display a multinodular archi-tecture, with the nodules ranging in sizefrom microscopic dimensions to 15 mm{1608}. The cellular nodules are separat-ed by fibroconnective tissue septa ofvarying thickness and containinghaemosiderin-laden macrophages{1591}. The nodules are composed of amixture of round to oval cells that aremononuclear and osteoclastlike giantcells that are multinucleated, with bothcell types immersed in a richly vascu-larised stroma. The nuclei in the multinu-cleate cells are similar to the nuclei in themononuclear cells.Mitotic activity generally is present inevery GCT-ST; typical mitoses range from1 to 30 figures per 10 high-power fields{702,1591,1608}. Atypia, pleomorphism,and tumoural giant cells are absent, andnecrosis is found rarely {702,1591,1608}. Metaplastic bone formation ispresent in approximately 50% of thetumours; frequently it is in the form of aperipheral shell of woven bone.

Secondary cystic changes and the for-mation of blood-filled lakes, changes thatare similar to aneurysmal bone cysticchanges, are present in approximately30% of tumours. Unquestionable foci ofvascular invasion are part of the histolog-ical picture in about 30% of tumours{702,1608}. Additional histological fea-tures include stromal haemorrhage(50%) and regressive changes in theform of marked stromal fibrosis and clus-ters of foamy macrophages (70%).

ImmunophenotypeGCT-STs display immunoreactivity forvimentin, CD68, and smooth muscleactin {702,1591,1608}. CD68 stronglymarks the multinucleated giant cells; themononuclear cells show focal stainingonly. Smooth muscle actin stains a fewmononuclear cells and does not markthe multinucleated giant cells. Rarely,tumours react focally with antibodiesagainst keratin and S100 protein {1608}.

Prognostic factorsIn patients with clinical follow-up rangingfrom 34 to 45 months, GCT-ST was asso-ciated with a local recurrence rate of12% and very rare metastasis and death{702,1591,1608}. Incomplete surgicalexcision is apparently followed by localrecurrence {702}. No clinicopathologicfactors are currently predictive ofmetastatic behaviour associated withGCT-ST {702,1591,1608}.

A.G. NascimentoGiant cell tumour of soft tissue

118 Fibrohistiocytic tumours

Fig. 3.17 Cellular nodules in giant cell tumour of softtissue contain a mixture of round / oval mononuclearand multinucleate osteoclast-like giant cells.

Fig. 3.16 Giant cell tumour of soft tissue, presentingas well circumscribed, mostly solid nodule with afleshy, red-brown or grey cut surface.

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BAFig. 3.18 A A multinodular growth pattern is present in approximately 85% of giant cell tumours of soft tissues. B Typical nodule with peripheral accumulation of osteo-clast-like giant cells.

BAFig. 3.19 A Secondary cystic changes, similar to aneurysmal bone cystic changes, occur in approximately 30% of giant cell tumours of soft tissue. B Metaplastic bone,frequently in the form of a peripheral shell of woven bone, is present in approximately 50% of giant cell tumours of soft tissue.

119Giant cell tumour of soft tissues

BAFig. 3.20 A Clusters of foam macrophages reflecting regressive change in a giant cell tumour of soft tissue. B CD68 marks the multinucleate, osteoclastlike giant cells anda few of the mononuclear cells in giant cell tumours of soft tissue.

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DefinitionThe term pleomorphic malignant fibroushistiocytoma is now reserved for a smallgroup of undifferentiated pleomorphicsarcomas. Both terms may be used syn-onymously. Current technology does notshow a definable line of differentiation.

ICD-O code 8830/3

SynonymsFibroxanthosarcoma {1088}; malignantfibrous histiocytoma, storiform or fibrob-lastic type; malignant fibrous xanthoma.

Historical annotationFor many years, pleomorphic malignantfibrous histiocytoma (MFH) has beenregarded as the prototypical form of MFHand the most common soft tissue sarco-ma in adults {599,2233,2237}. Originallydefined, based on morphology and tis-sue culture analysis, as a pleomorphicspindle cell malignant neoplasm show-ing fibroblastic and facultative histiocyticdifferentiation, it is now widely acceptedthat the morphologic pattern known asso-called pleomorphic MFH may beshared by a wide variety of poorly differ-entiated malignant neoplasms {675}. It isalso now agreed that these tumoursshow no evidence of true histiocytic dif-ferentiation. This diagnostic term is nowreserved (by those who still use it) for themuch smaller group of pleomorphic sar-comas which, by current technology,show no definable line of differentiation{2243}. As a consequence, the apparentincidence of pleomorphic MFH has fallensharply over the past 10 years and it ispossible that this term may disappearaltogether at such time as criteria for thediagnosis of pleomorphic sarcomasshowing fibroblastic or myofibroblasticdifferentiation can be reproduciblydefined.

EpidemiologyThe group of pleomorphic (MFH-like)sarcomas collectively represent the mostcommon types of sarcoma in patientsover age 40. The overall incidence

among adults approximates to 1-2 casesper 100,000 patients annually and theincidence increases with age {861}.Most undifferentiated high grade sarco-mas occur in patients over age 40 withpeak incidence in the 6th and 7thdecades. Rare examples may beencountered in adolescents and youngadults. There is a male predominance ofapproximately 1.2:1.

Sites of involvementMost undifferentiated high grade pleo-morphic sarcomas occur in the extremi-ties (especially the lower limb) and lessoften the trunk. The majority of casesarise in deep (subfascial) soft tissue,while less than 10% are primarily subcu-taneous. A notable exception amongpleomorphic sarcomas is dedifferentiat-ed liposarcoma (see p. 38) which is mostcommon in the retroperitoneum.

Clinical featuresUndifferentiated high grade pleomorphicsarcomas are typically large deep-seat-ed tumours which show progressive,often rapid enlargement. Only thosewhich grow very rapidly tend to bepainful. Around 5% of patients havemetastases at presentation, most often tolung. Although little is known about aeti-ology of these lesions, a subset of pleo-morphic sarcomas (<2-3%) arise at thesite of prior radiation therapy {1224} andvery rare cases arise at the site of chron-ic ulceration or scarring.

MacroscopyMost undifferentiated high grade pleo-morphic sarcomas are well circum-scribed, expansile masses which mayappear pseudoencapsulated. Tumoursize varies and, to some extent, dependson location with subcutaneous lesionsoften measuring <5 cm, while retroperi-toneal tumours often exceed 20 cm. Mosttumours measure between 5 and 15 cmin maximum diameter. Cut surface is vari-able and may include pale fibrous orfleshy areas, admixed with zones ofnecrosis, haemorrhage or myxoid

change. Aside from an adjacent well-dif-ferentiated component in dedifferentiat-ed liposarcoma, there are no distinctivemacroscopic features which correlatereliably with line of differentiation.

HistopathologyUndifferentiated high grade sarcoma is adiagnosis of exclusion following thoroughsampling and judicious use of ancillarydiagnostic techniques. Tumours in thegeneral category of high grade pleomor-phic (MFH-like) sarcomas are very het-erogeneous in appearance and also incellularity, since some cases have anextensive fibrous stroma. These tumourshave in common marked cytological andnuclear pleomorphism, often with bizarretumour giant cells, admixed with spindlecells and often rounded histiocyte-likecells (which may have foamy cytoplasm)in varying proportion {675}. A storiformgrowth pattern and stromal chronicinflammatory cells are common. Thespindle cell component most oftenappears fibroblastic, myofibroblastic orsmooth muscle-like. Tumours showingmyogenic differentiation (pleomorphicleiomyosarcoma or rhabdomyosarco-ma), as well as carcinoma andmelanoma with MFH-like morphology,often have more copious eosinophiliccytoplasm and prominent large polygo-nal cells. The presence of fascicularspindle cell areas may suggest smoothmuscle or nerve sheath differentiation(which needs to be proved immunohisto-chemically or ultrastructurally). Thorough

C.D.M. FletcherE. van den BergW.M. Molenaar

Pleomorphic malignant fibrous histiocytoma / Undifferentiated highgrade pleomorphic sarcoma

Fig. 3.21 Undifferentiated high grade pleomorphicsarcomas are typically deep-seated and large, witha variable cut surface; this case shows fleshy solidareas, necrosis and cystic change.

120 Fibrohistiocytic tumours

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sampling is critical in all cases to checkfor the presence of lipoblasts or ‘malig-nant’ osteoid.

ImmunohistochemistryThe widespread introduction of immuno-histochemistry has been one of the majorfactors in demolition of the MFH concept.Most high grade pleomorphic sarcomasshow a definable line of differentiation,foremost among which are the pleomor-phic variants of leiomyosarcoma, liposar-coma, rhabdomyosarcoma and myxofi-brosarcoma, after carcinomas,melanomas and lymphomas have beenexcluded {675}. Immunohistochemistrywas critical in helping to separate the lat-ter non-mesenchymal malignancies.Controversy exists as to the extent ofimmunopositivity required for a givenantigen to define a specific line of differ-entiation but diagnostic criteria have

been proposed for the different pleomor-phic sarcomas and these appear to bereproducible {683,1425}. The presenceof just rare cells showing positivity forepithelial or myogenic antigens mostoften has little significance and does not,of itself, exclude this diagnosis. It is nowaccepted that histiocytic antigens (suchas alpha-1-antitrypsin, alpha-1-antichy-motrypsin, lysozyme and CD68) play nouseful role in the diagnosis of pleomor-phic sarcomas.

UltrastructureElectron microscopic findings dependupon the specific type of tumour givingrise to the pleomorphic MFH pattern.Inevitably almost all tumours in this cate-gory are poorly differentiated so only aminority of tumour cells may show ultra-structural features of a specific lineage.Many tumour cells show relatively undif-

ferentiated, non-specific fibroblast-like orhistiocyte-like features.

Genetics The genetic aspects of malignant fibroushistiocytomas (MFH) are difficult to eval-uate because of the shifting diagnosticcriteria used throughout the years.Bearing these shortcomings in mind,cytogenetic aberrations have beendetected in more than 50 cases pub-lished as storiform or pleomorphic MFHor MFH NOS {1477}. Only a few cases ofgiant cell or inflammatory MFH havebeen investigated. In general, the kary-otypes tend to be highly complex, withextensive intratumoral heterogenity andchromosome numbers in the triploid ortetraploid range in the majority of cases{1317,1477,1486,1635,1957}. Also near-haploid karyotypes have been reportedin a few cases {92}. No specific structur-

BAFig. 3.22 Undifferentiated high grade pleomorphic sarcoma. A Note the variable cellularity and striking cytological pleomorphism. This tumour proved to be a malignantperipheral nerve sheath tumour. B In other areas this lesion turned out to be pleomorphic liposarcoma with prominent lipoblasts.

121Pleomorphic malignant fibrous histiocytoma / Undifferentiated high grade pleomorphic sarcoma

BAFig. 3.23 Undifferentiated high grade pleomorphic sarcoma. A Note the anaplastic cytomorphology in this unclassified sarcoma. B Many tumour cells show a promi-nent eosinophilic cytoplasm and this case proved to be pleomorphic leiomyosarcoma.

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al or numerical aberrations haveemerged, but telomeric associations,ring chromosomes, and/or dicentricchromosomes are frequent. Such chro-mosomal abnormalities are, however,common also in other fibrohistiocyticlesions {1854}. Due to the presence ofnumerous marker chromosomes in mostcases, the distribution of genomic imbal-ances is impossible to asses reliablyfrom cytogenetic data. Genomic imbalances, as detected bycomparative genomic hybridization(CGH), frequently include loss of 2p24-pter and 2q32-qter, and chromosomes11, 13 and 16 {1219,1311,1651,1957,2094}, as well as gain of 7p15-pter, 7q32,and 1p31. Several proto-oncogenes mapping tochromosome region 12q13-15 appear toparticipate in the development of MFH-like pleomorphic sarcomas: SAS, MDM2,

CDK4, DDIT3 (a.k.a. CHOP), and HMGIC(a.k.a HMGA2) have all been reported tobe amplified in MFH {172,1772,1842}. Inan amplicon at 8p23.1 a candidate genedesignated MASL1 has been found{1842}.Alterations (mutations and/or deletions)of TP53, RB1 and CDKN2A have beensuggested to play a critical role in pleo-morphic sarcoma development {341,1772,1957,2097,2326}, but no clear rela-tionship with clinical outcome has yetbeen found. The significance of HRASmutations and their relationship withother genetic changes, such as TP53and MDM2 gene status, remain to beclarified {221,1790,2269}.

Prognostic factorsHigh grade pleomorphic sarcomas areaggressive with an overall 5-year survivalprobability of only 50-60% {861,2233}.

However, it has become clear that thereare prognostic subgroups among thelesions formerly categorised as pleomor-phic MFH {683}. For example, dediffer-entiated liposarcoma has a metastaticrate of only 15-20%, high grade myxofi-brosarcoma has a metastatic rate ofaround 30-35%, while pleomorphic myo-genic sarcomas (leiomyosarcoma orrhabdomyosarcoma) are especiallyaggressive with much more frequentmetastasis and shorter relapse-free sur-vival {1679}. The clinical and therapeuticbenefits of subclassifying pleomorphicsarcomas are only just beginning to beappreciated, hence the approach to sub-classification and grading of pleomor-phic sarcomas is likely to evolve.

122 Fibrohistiocytic tumours

Fig. 3.24 A Many pleomorphic sarcomas contain large bizarre cells with foamy cytoplasm, which in the past were mistakenly regarded as histiocytic in nature. BA storiform growth pattern is a common feature shared by many of these undifferentiated high grade pleomorphic sarcomas, irrespective of lineage. C The pres-ence of polygonal cells with prominent eosinophilic cytoplasm usually suggests myogenic, epithelial or less often melanocytic differentiation. This case proved tobe a pleomorphic rhabdomyosarcoma.

BA C

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DefinitionFormerly defined as a variant of malig-nant fibrous histiocytoma (MFH) withprominent osteoclastic giant cells, it isnow appreciated that this morphologicpattern may be shared by a variety oftumour types. The term giant cell MFH iscurrently reserved for undifferentiatedpleomorphic sarcomas with prominentosteoclastic giant cells.

ICD-O code 8830/3

SynonymsMalignant giant cell tumour of soft parts,malignant osteoclastoma, giant cell sarcoma.

Historical annotationAlthough formerly defined as a variant ofmalignant fibrous histiocytoma (MFH)with prominent osteoclastic giant cells{599} (and frequently known as malig-nant giant cell tumour of soft parts/tis-sues {61,848}) it is now appreciated thatthis morphologic pattern may be sharedby a variety of tumour types (mostnotably giant cell tumour of soft tissues,extraskeletal osteosarcoma, leiomyosar-coma and osteoclast-rich carcinoma){961}. It is difficult to define giant cellMFH as a discrete entity and this diagno-sis is gradually disappearing from com-mon usage in soft tissue pathology.

EpidemiologyAll of the lesions previously subsumedunder this heading are very uncommon.Arguably giant cell tumour of soft tissues(see page 118) is the most frequent.Almost all of the tumours which adopt thepattern known as so-called giant cellMFH occur in older adults with no sexpredilection. Rare examples of giant celltumour of soft tissue occur in childrenand adolescents.

Sites of involvementWith the exception of giant cell tumour ofsoft tissues (which shows a predilectionfor subcutaneous tissue) {702,1591,

1608}, most tumours in this general cate-gory occur in deep soft tissue of thelimbs or trunk. Organs in which giant cell-rich or osteoclastoma-like carcinomasare most common include pancreas, thy-roid, breast and kidney.

Clinical featuresMost tumours in this general categorypresent as an enlarging, painless, deep-seated mass without distinctive features.

MacroscopyWith the exception of giant cell tumour ofsoft tissues, most tumours in this generalcategory are high grade and thus tend tobe large tumours with haemorrhage andnecrosis. Tumour size is variable butsuperficially located examples are small-er than those in deep soft tissue.

HistopathologyThe features shared by tumours previ-

C.D.M. FletcherGiant cell malignant fibrous histiocytoma / Undifferentiated pleomorphic sarcoma with giant cells

Fig. 3.25 Giant cell MFH. Two tumours showing the pattern often labelled as giant cell MFH, being character-ized by atypical spindle-shaped and more epithelioid cells admixed with prominent osteoclastic giant cells. Theexample on top (A) proved to be anaplastic carcinoma of thyroid, while the lower one (B) was a soft tissueosteosarcoma.

A

B

123Pleomorphic malignant fibrous histiocytoma

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ously labelled as giant cell MFH includevariably pleomorphic ovoid-to-spindle-shaped cells and a prominent stromalosteoclastic giant cell reaction. In most(but not all) lesions the giant cell compo-nent lacks cytological features of malig-nancy, but some tumours diagnosed asgiant cell MFH were notable for the pres-ence of numerous bizarre multinucleatetumour giant cells. Aside from these similar (shared) fea-tures, morphology is largely determinedby the specific tumour type. Giant cell-rich soft tissue osteosarcoma (see page182) definitionally shows variably promi-nent ‘malignant’ osteoid being laid downby cytologically atypical cells {355}.Giant cell tumour of soft tissues (seepage 118) usually has a multinodulargrowth pattern and cytologically resem-bles giant cell tumour of bone {702,1591,1608}. Leiomyosarcoma withprominent osteoclastic giant cells has atleast small areas with conventionalsmooth muscle cytomorphology and afascicular growth pattern {1411}. Othersarcoma types may occasionally showprominent osteoclastic giant cells {1415}.

ImmunohistochemistryLeiomyosarcoma with prominent osteo-clastic giant cells usually shows positivi-ty for smooth muscle actin and desmin inthe fascicular spindle cell component.Unequivocal positivity for keratin is adiagnostic requirement for osteoclas-toma-like or giant cell-rich carcinoma,with the exception of those cases show-ing obvious morphologic transition tousual carcinoma.

Prognostic factorsUndifferentiated high grade sarcomaswith prominent osteoclastic giant cellsbehave similarly to other pleomorphic

sarcomas. Among neoplasms simulatinggiant cell MFH, extraskeletal osteosarco-ma and leiomyosarcoma are much moreaggressive than giant cell tumour of softtissues.

Fig. 3.28 Leiomyosarcoma mimicking so-called giantcell MFH. Note with prominent osteoclastic giantcells and the eosinophilic fascicular spindle cellcomponent..

Fig. 3.26 Giant cell MFH may resemble giant cell tumour of soft tissue, which has a multinodular growth pat-tern, was often formerly labelled as giant cell MFH.

124 Fibrohistiocytic tumours

Fig. 3.27 Giant cell-rich soft tissue osteosarcoma.This osteoclast-rich spindle cell malignant neoplasmcontains seams of osteoid produced by cytologicallymalignant cells.

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DefinitionA malignant neoplasm characterized bynumerous xanthomatous cells, morpho-logically both benign and malignant,admixed with atypical spindle cells andacute and chronic inflammatory cells.Originally regarded as a variant of so-called malignant fibrous histiocytoma(MFH), differentiation in these tumours ispoorly understood and their morphologymay be shared by both mesenchymaland epithelial neoplasms. The terminflammatory MFH is now reserved forundifferentiated pleomorphic sarcomaswith a prominent histiocytic and inflam-matory infiltrate.

ICD-O code 8830/3

SynonymsXanthomatous MFH, malignant fibrousxanthoma, xanthosarcoma.

EpidemiologyThis is the rarest and the least document-ed type of MFH, with only two publishedseries of 7 and 8 cases {1096,1198} anda few case reports. There is no apparentgender predominance, and patients areusually more than 40 years old.

Sites of involvementThe most common site is the retroperi-toneum but intra-abdominal and deepsoft tissue locations have also beenobserved.

Clinical featuresIn addition to symptoms and imagingfeatures of a large retroperitoneal tumour,inflammatory MFH may be associatedwith fever, weight loss, leukocytosis,eosinophilia, and leukaemoid reaction.Analysis of tumour extracts and immuno-histochemistry suggested that produc-tion of specific cytokines by tumour cellsis responsible for the systemic symptoms{1401,2076}.

AetiologyThere is no aetiology known for inflam-matory MFH, but one post-radiation casehas been reported {735}.

MacroscopyThis tumour is usually large and oftendisplays a yellow colour due to large col-lections of xanthoma cells.

HistopathologyInflammatory MFH is characterized by

sheets of benign xanthoma cells withnumerous inflammatory cells includingneutrophils, eosinophils and a minorcomponent of lymphocytes and plasmacells. Some cases show only a few or noxanthoma cells but are predominantlycomposed of neutrophils and eosino-phils. There are scattered atypical largecells, with one or more irregular, hyper-chromatic nuclei with prominent nucleoli.These cells may be rare and difficult tofind and occasionally resemble Reed-Sternberg cells. Occasionally atypicalcells are xanthomatized and typicallydisplay phagocytosis of neutrophils.These cells may be set in a hyalinizedcollagenous background. In most cases,there are typical areas of pleomorphicMFH-like sarcoma with spindle and pleo-morphic cells arranged in a haphazardgrowth pattern. Like pleomorphic MFH,inflammatory MFH is a diagnosis ofexclusion and could represent an inflam-matory dedifferentiated componentshared by different neoplasms such ascarcinomas, lymphomas, leiomyosarco-mas, inflammatory myofibroblastictumours and liposarcomas {956,961}.Among these, dedifferentiated liposarco-ma is the most common simulant.

J.M. CoindreInflammatory malignant fibrous histiocytoma / Undifferentiated pleomorphic sarcoma with prominentinflammation

BAFig. 3.29 Inflammatory malignant fibrous histiocytoma. A Pleomorphic spindle cells are associated with numerous inflammatory cells. B The atypical cells may be sug-gestive of a lymphoid neoplasm.

125Inflammatory malignant fibrous histiocytoma

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Therefore inflammatory MFH areas mayoften be associated with areas of morespecific tumours which should be care-fully looked for.

ImmunophenotypeImmunohistochemistry is useful for show-ing a specific line of differentiation suchas epithelial, lymphoid or smooth muscu-lar. In the other cases, the neoplasticcells express vimentin, occasionallyCD68, but are negative for CD15, CD20,CD30, CD43 and CD45 {1096}.

UltrastructureThe tumour cells do not differ ultrastruc-turally from tumour cells of pleomorphicMFH.

GeneticsGenetic analysis may be particularly use-ful for identifying a possible dedifferenti-ated liposarcoma or other simulants suchas anaplastic large cell lymphoma.

Prognostic factorsFrom a review of the literature {961} anda small series {1198}, it appears that two-thirds of patients died of their tumour withpersistent or recurrent disease. Aboutone fourth of patients developed distantmetastasis. As in other retroperitonealsarcomas, this poor prognosis is proba-bly related to the extent of the tumourand its inaccessibility to proper surgeryat the time of the diagnosis.

126 Fibrohistiocytic tumours

Fig. 3.30 Inflammatory malignant fibrous histiocytoma. A Note the striking cytophagocytosis. B PleomorphicMFH-like areas with collagenous stroma are common.

A

B

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