Immunohistochemistry of Epithelioid Soft Tissue Sarcomas ... · Immunohistochemistry of Epithelioid Soft Tissue Sarcomas, Literature Review Based on Case Studies Megha Joshi 1*, Philip

Ó Journal of Krishna Institute of Medical Sciences University

JKIMSU, Vol. 1, No. 2, July-Dec. 2012

MINI REVIEW ARTICLE

Immunohistochemistry of Epithelioid Soft Tissue Sarcomas,Literature Review Based on Case StudiesMegha Joshi1*, Philip S. Nawrocki2, Madison R. Ballard2

1Department of Pathology, Lawrence General Hospital, Lawrence, MA 018422St George�s Medical School, Grenada, West Indies

Abstract:

Neoplasms with epithelioid histology may bediagnostically challenging. Immunohistochemistry (IHC) can aid in confirming thedifferential diagnosis of mesotheliomas,melanomas, lymphomas, and soft tissuesarcomas, all tumors that can present with anepithelioid histology. Immunohistochemistrycan also assist in confirming the type ofsarcomas. Using cases diagnosed in acommunity hospital setting over a ten yearperiod, the use of IHC in sarcomas will beillustrated.

Introduction:

Epithelioid neoplasms tend to have bland/non-specific histological features, which can makediagnosis especially challenging. Cells vary inmorphology based on tumor location, butcharacteristically appear as a monomorphicproliferation of cuboidal to polygonal cells withextensive eosinophilic cytoplasm thusresembles somewhat epithelial cells.Morphology of specific epithelioid tumors willbe discussed later for each example.In addition to mistaking epithelioid neoplasmsfor more common epithelial neoplasticprocesses, pathologists may mistake their blandappearance and a heavy epithelioid cellinfiltrate for more common granulomatouspathologies or microbial infections [1- 2].

Clinical history and special stains for particularorganisms can help in such situations andinfectious processes such as Mycobacteriumavium infections and leprosy can thus be ruledout.Soft tissue sarcomas have presented withdifferent morphologic features includingepithelioid histology. Most patients willpresent at a community hospital setting with amass lesion. The mass is often mistaken for anon-sarcomatous lesion, as sarcomas arefortunately extremely rare. In 2011, accordingto the National Cancer Institute, only 10,980people in the United States will be diagnosedwith a sarcoma. These estimates have been madebased on data supporting the fact that theincidence of soft tissue sarcomas has beenstable over the last 30 years [3]. Sincesarcomas can be overlooked it is imperative thatpathologist retain soft tissue sarcomas as adifferential diagnosis until they can be ruled outwith certainty.Examination of histological features alone canleave the pathologist with an extensive list ofdifferential diagnoses. Fortunately, epithelioidneoplasms, and soft tissue sarcomas oftenexpress characteristic patterns of markers thatcan be used to identify such tumors. Thus, theuse of immunohistochemistry is oftenessential in the formulation of a definitivediagnosis.

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The examples presented are from a surgicalpathology practice at a 200 bed communityhospital in the US. In many cases, only ahematoxylin and eosin stain was performed inthe initial diagnostic work ups with furthercharacterization obtained through consultativeimmunohistochemistry. These cases aresupplemented with information regardingimmunohistochemical markers gathered froma thorough literature review.

Case 1: Epithelioid Melanoma :

86 year old female has presented with bleed-ing and a urethral lesion

This case shows overlying urothelialepithelium, with an invasive tumor infiltratingsub epithelial tissue in broad sheets. Thepattern of invasion is unusual for an urothelialcarcinoma. On higher magnification, the tumorcells show abundant cytoplasm, central nucleiand prominent nucleoli. Though the tumormimics an epithelial malignancy, it is indeed amelanoma. The difficulty in diagnosis is due tothe unusual location of the melanoma, and thefact that it is a non-pigmented melanoma. Aprior history of a melanoma at this site, madethe diagnosis easier in this instance.Although melanomas are not most commonlyfound in the urethra, melanoma of thegenitourinary tract is most likely found in theurethra [4-5]. Melanoma of the genitourinarytract is rare and accounts for less then 1% ofall melanomas [6]. Not much is known aboutthe cause or pathogenesis of melanoma of theurethra; however, epidemiological studies haveshown that these lesions are more common inblack women between the ages of 50 and 70.The clinical presentation is nonspecific andconsists of dysuria or hematuria due to theirpresence in the distal urethra. Other sites ofmelanoma in the genitourinary tract include theglans penis and labia which may progress to adistal urethra melanoma. Interestingly onexamination not all melanomas may producemelanin and the cells may be papillary orspindled making diagnosis difficult [5]. Theprognosis for malignant melanomas is poor evenin cases where the lesion is localized as in thecase of urethral melanoma seen in a communityhospital [7].Histologically, melanomas can be classified asepithelioid and/or spindled in appearance. Cells

Fig. 1: Urothelium with an underlying tumorinfiltrating large sheets. H&E; 10X.

Fig. 2: Higher power showing cells with abun-dant cytoplasm. H&E; 40X.

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tend to be large and round with abundant/eosinophilic cytoplasm, features that oftenmimic poorly differentiated malignantneoplasms [8-9] and make diagnosis challenging.To make a diagnosis, most physicians utilizeimmunohistochemistry [10] in melanomasoccurring in unusual sites, such as internalorgans and viscera.A conventional panel of S100 antibody andHMB45 antibody is often used in the clinicalsetting to identify malignant melanoma [8, 11].Recently, however, several other markers havebeen identified that may have equal or greatersensitivity and specificity. One recent studyfound that an immunohistochemical panel

consisting of Melan-A and microphthalmiatranscription factor (MiTF) had a sensitivity andspecificity of 95% and 100%, respectively,while a panel consisting of S100 protein andHMB45 had a sensitivity of 80% and aspecificity of 100% [8]. MiTF is indicative ofmelanin synthesis [12-13] and can be used todetermine the amount of intraepidermalmelanocytes [10]. These results are promising;however, a larger scale study is needed. WT1is expressed in 88% of epithelioid melanomasand 100% of spindled cell and desmoplasticmelanomas [11]. However, WT1 is alsoexpressed in several other neoplasms limitingits specificity, and does not have the ability to

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Table 1: Immunostaining in Epithelioid Melanomas and Common Differential Diagnoses

IHC Profile GIST [29]Epithelioid

Melanoma [8-11,28,10, 60]

S100

S100áS100â

HMB-45 (epidermal)HMB-45 (dermal)

HMB-45Diffuse HMB-45

Melan-AA-103

TyrosinaseMiTF

WT1CyclinD1

p21CD117 (c-kit)

Other Diagnostic Clues

-

+/-+/-

+

BenignMelanocytic

Nevi [26,25,10]

Spindled CellMelanoma

[8,11]

Spitz Nevi(28,10)

+

+

++

++

+- (84%)

- (73%)

High Ki-67 pro-liferative index

+

-

+

+

+ (74%)

+ (91%)

++

-+

-

+

++

+

Low Ki-67 pro-liferative index

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distinguish between epithelioid and spindle cellmelanomas. CXCR4 is a marker that isbelieved to be involved in angiogenesis andmetastasis of cutaneous melanoma, and wasrecently found to be predictive of epithelioidtype uveal melanoma, indicating a worseprognosis relative to the non-epithelioid type[14]. It is unknown whether these results canbe extrapolated to cutaneous melanoma andused as a similar prognostic marker.Distinction of skin lesions based onmorphology and clinical findings remains achallenge. Immunohistochemistry may assistthis differentiation in some circumstances;however, specific markers for manypathological entities have yet to be discovered.A summary of common immunohistochemicalmarkers expressed in epithelioid melanoma, aswell as common differential diagnoses, isdisplayed below in Table 1.Current work is being done to develop theoptimal set of immunohistochemical markersto diagnoses melanoma. It has been suggestedby Preito and Shea that the use of a �pan-melanocytic cocktail� containing HMB-45,anti-MART1, anti-tyrosinase, is widely used;however, a different mixture containinganti-MART1 and anti-Ki-67 may more easilyillustrate the amount of melanocytesundergoing mitosis [10]. Other markers ofincreasing clinical value include the following:NKI-C3 [12], p16 [13], galectin-3 [15], Cox-2[16], TRP [17], surviving [18], andclaudin-1[19].Melanoma can be differentiated from a nevususing HBM-45 and Ki-67. This is due to thefact that these markers are usually present within the epidermis and periepithelial dermis so

if the stain remains located to these areas andthere are more Ki-67 positive cells at the topof the lesion than at the bottom, the lesion ismost likely a nevus. After determining that thelesion is a nevus, it must be deduced as towhether it is a Spitz nevus or a blue nevus. Spitznevi generally stain diffusely for HMB-45 butdo not stain Ki-67. Blue nevi mimic thepresentation of malignant blue nevi howeverthey can be differentiated by gp100 which isfocal in malignant lesions but diffuse in abenign lesion. How invasive the lesion is canalso be determined using these markers as themore invasive lesions have higher rates ofproliferations and differentiation. Desmoplasticmelanoma can be distinguished from adesmoplastic nevus using MART1 which is notusually present in melanomas but S100protein most likely would be present. S100 canalso be used to gauge invasion however it shouldnot be confused with scar tissue [20-21]. Theamount of S100 positivity in scars is lower thanthat seen in desmoplastic melanomas and scarsdo not express p75 [22]. The presence ofLentigo Maligna or melanoma in situ can stainpositively for anti-MART1 and HMB-45 in aconverging pattern as opposed to pigmentedactinic keratosis which has a less confluentpattern. The usefulness of anti-MART1,however, has been challenged due to itsability to detect melanocyte dendrites and thusmimic a converging pattern of labeling whichmay be misleading [23]. This confusion canbe avoided by staining with HMB-45[24] oranti- MiTF [10].Of note, Spindled cell melanoma alsoexhibits WT1 and S100 positivity, but isroutinely negative for HMB45.

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Benign melanocytic nevi are commonlypositive for all markers of melanogenesis(MelanA, Tyrosinase, MiTF, and HMB45);however, the staining pattern for HMB45differs from malignant melanoma. In benignnevi, HMB45 stains strongly in the epidermisbut show a loss of HMB45 expression withprogressive descent into the dermis [25]. Somecases have shown aberrant dermal expressionof HMB45, however, making distinctiondifficult. One case series showed that ásubunit of S100 is commonly expressed in thejunctional nests of dysplastic junctional nevi,however á subunit expression does not occurin benign nevi [26]. The authors theorized thatá subunit expression relates to verticalprogression of malignant melanomas.Proliferative index (Ki-67) is another usefultool that helps the clinician to differentiatebetween benign and malignant lesions [27].Normally, no more than 1% of cells will testpositive for Ki-67; however, in melanomas, themean proliferative fraction is greater than 10%of the lesion [10].Spitz nevus is another melanocytic lesion that

is difficult to distinguish from malignantmelanoma. One case series has reported themost significant difference beingoverexpression of cyclin D1 and p21 in Spitznevi compared with non-spitzoid melanomas(74 vs. 16% and 91 vs. 27%, respectively) [28].Some Spitz nevi lesions may also staincompletely for HMB-45 [10]. Morphology andclinical findings may be needed in conjunctionwith immunohistochemical findings to make anaccurate diagnosis.Stage IV melanoma has a 26-58% probabilityof metastasizing to the gastrointestinal tract,where it can mimic epithelioid gastrointestinalstromal tumor (GIST) [8, 29]. EpithelioidGISTs can be positive for Melan-A, favoring adiagnosis of metastatic melanoma, however,Melan-A reactive cases have been found to benegative for S100 and positive for CD117 [29],confirming the diagnosis of GIST.

Case 2: Malignant Mesothelioma:

Patient has presented with a lumbar mass andan enlarged lymph node.

Fig. 3: Malignant mesothelioma.: Desmoplasticreaction surrounding a papillary tumor pattern.H&E; 10X

Fig. 4: Malignant mesothelioma involving alymph node. H&E; 10X

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Fig. 5: High Power view showing the invasivetumor with desmoplastic reaction; H&E; 20x

Fig. 6: High Power view showing Papillarytumor. H&E; 40x

The patient from whom the figures above havebeen obtained, has presented to the hospital witha lumbar mass and lymphadenopathy. Uponresection and histological processing it isevident that the patient has a malignantneoplasm due to the invasive nature of thegrowth and the desmoplastic reaction that canbe seen in the figures above. The cells presentin the mass are not sufficient to diagnose thelesion or determine the primary source of theneoplasm. Immunohistochemical stains areordered to obtain a definitive diagnosis ofmalignant mesothelioma. Involvement of alymph node by malignant mesothelioma is rare,and presentation of mesothelioma as anenlarged lymph node is even rarer. On H&Esections, it is difficult to discern themalignant mesothelioma cells within the lymphnode; however, on immunohistochemical stainsthe lymph node involvement is obvious.Without prior knowledge of malignantmesothelioma in the patient, diagnosing thelymph node as involved by mesothelioma would

have been difficult.Malignant mesothelioma (MM) is a rareneoplasm usually of the visceral or parietalpleura that often spreads widely along the pleuraand may invade adjacent thoracic structures.Malignant mesothelioma may also arise fromother serous surface of the body, such as theperitoneum and pericardium, however the mostcommon location is the pleura [30]. There arethree commonly described subtypes:epithelioid, sarcomatoid, and biphasic [31].Epithelioid mesothelioma often shows densecellularity with stromal invasion and occasionalnecrosis, with cells displaying scallopedborders [32].It is often difficult to distinguish MM fromseveral other pathological entities given itsbland morphology, diffuse and invasive nature,and penchant for mimicking other morecommon neoplasms clinically & radiologically.These include lung adenocarcinoma, reactivemesothelial cell hyperplasia, and metastasis tothe pleura or peritoneum from other primary

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sites. Table 2 below helps distinguishepithelioid mesothelioma frommorphologically similar clinical entities basedon immunohistochemical profile.The most difficult, and frequently encountered,entity to distinguish from malignantmesothelioma is lung adenocarcinoma. It isespecially challenging to make a definitivediagnosis, since lung adenocarcinoma mayinvolve the periphery of the lung and spreadalong the pleura, mimicking mesothelioma

Table 2: Immunostaining in Epithelioid Mesothelioma & Common Differential Diagnoses

IHC Profile

WTI

CK5/6D2-40

PodoplaninCalretinin

MesothelinVimentin

MOC31BG8

TTF1Factor VIII

CD31

-

--

--

++

+

Mesothelioma[35, 34, 60]

PulmonaryAdenocarcinoma

[34-36]

Reactive Mesothe-lial Cell Hyperplasia

[61]

Metastasis fromOther Primary Site

+

++

++

++

--

--

-

Use tissue specificimmunomarkers for

suspected site

CD34Fli-1

SMACalponin

Desmin

OtherDiagnosticClues

--

+ (42.3%)+ (38.9%)

- (90.0%)

*Clinical andradiological findingssuggest metastasis

- (90.9%)- (95.5%)

+ (86.4%)

radiologically [33]. Immunohistochemistry isan integral tool that must be used to help makethis distinction [32]. Several studies haveattempted to define the most sensitive andspecific immunohistochemical marker panel tomake this distinction, since a unique marker formesothelioma has yet to be found. However,consensus is lacking on which panel is best,although the use of both positive and negativemesothelial markers is widely suggested [32,34]. One study has recommended that MOC-

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31, BG8, CK5/6 and WT1 be used to diagnoseepithelioid mesothelioma [35]. However, it isnoted that WT1 and CK5/6 do not distinguishbetween benign and malignant mesothelial cellproliferations. WT1 is also expressed inovarian serous carcinomas and some renalneoplasms, while CK5 is also expressed onsquamous epithelia reducing the utility of theseas specific markers for mesothelioma [8]. D2-40, podoplanin, and caveolin-1 have beendescribed in some case series as having utilityin differentiating mesothelioma fromadenocarcinoma, however, further research isneeded [36,37].Another study has found that using calretinin,BG8, and MOC-31 provides over 96%specificity & sensitivity for distinguishingepithelioid mesotheliomas from adenocarcinomaof the lung [34]. Calretinin is expressed onmesothelial cells, while BG8 and MOC-31 areused as negative mesothelial markers.Mesothelin and WT1 are excluded from thispanel, given that they are also expressed inovarian serous carcinomas.Distinguishing epithelioid mesothelioma fromreactive mesothelial cell hyperplasia alsopresents a clinical challenge. To date no singlemarker specific to either condition has beenidentified, and again a panel of markers isrequired. A study during 2010 has found thatdesmin is expressed in 86.4% of non-neoplastic mesothelial cells (NMC), while itis only expressed in 10% of epithelioidmesothelioma (EM) tumor cells [7]. The samestudy has found that smooth muscle actin(SMA) is expressed in 42.3% of EM cells and9.1% of NMC, while muscle specific actin(MSA) is only expressed in EM; however the

positivity rate is low. A 2009 statement fromthe International Mesothelioma Interest groupconfirms the utility of desmin, and alsosuggests the use of EMA and p53, which aremore often positive in benign proliferations ofmesothelial cells [32].Finally, primary malignant mesothelioma mustbe distinguished from primary malignantneoplasms of other sites that have metastasizedto the pleura. Malignant tumors from thebreast, ovary, prostate, colon, and kidneycommonly metastasize to the pleura, and thusit is important to use tissue specificimmunohistochemical markers [5]. Forexample, TTF-1 can determine the lung originof carcinoma, while RCC Ma can identify thoseof renal origin [36].

Case 3: Lennert�s lymphoma:46 years old female has presented with a rightgroin lymph node.

Fig. 7: Lymph node showing numerous clusteredepithelioid histiocytes, imparting it a moth-eatenappearance, H&E; 10X

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Fig. 8: High power view showing epithelioidgranulomas. H&E; 40X

H&E sections show lymph node fragments withcomplete effacement of normal architecture byan infiltrate of predominantly small tomedium-sized lymphocytes with condensedchromatin, irregular contours, and scantcytoplasm. Occasional large lymphoid cells andeosinophils are admixed. Of note, numerousclustered epithelioid histiocytes are presentthroughout the lesion, imparting it a moth-eatenappearance (Figure-7). The H&E stainedsections show clusters of cells with abundanteosinophilic cytoplasm with large nuclei andprominent nucleoli. The initial diagnosis hasbeen a reactive lymph node with sinushistiocytosis. However, immunohistochemicalmarkers to rule out a monoclonal populationhave revealed a Lennert�s lymphoma. Thediagnosis would have been missed without theIHC stains. PCR studies have shown clonalrearrangement of the TCR gamma gene. IHCstudies have revealed the majority of thelymphoid infiltrate to be comprised of T-lymphocytes with diffuse expression of CD3,

CD5, and CD2. Overall, the morphologic,immunophenotypic, & molecular findings havebeen consistent with involvement by aperipheral T-cell lymphoma, not otherwisespecified. The morphology is consistent withthe entity historically described aslymphoepithelioid lymphoma by Lennert.Lennert�s lymphoma is classified by the WorldHealth Organization as �lymphoepithelioid cellvariant of the peripheral T-cell lymphomas,unspecified� due to the lack of consensusregarding from which cell this lymphoma isderived. Several conflicting studies havesuggested that this lymphoma may be CD4, CD8or even helper-T cell derived [38-40].Histologically, Lennert�s lymphoma appears asa proliferation of atypical small lymphocyteswith a large presence of admixed epithelioidhistiocytes [38, 41].It is important to differentiate Lennert�slymphomas from other, more common,lymphoma variants, as well as otherpathologies that have a prominent epithelioidhistiocyte infiltrate. Table 3 below demon-strates the immunohistochemical profiles ofLennert�s lymphoma and clinical entities forwhich it may be mistaken.As it is evident from the table, similarlypresenting diseases can be ruled out using aspecific panel of immunohistochemicalmarkers. Hodgkin lymphoma is positive forCD15 and CD30, unlike Lennert�s lymphoma,and shows characteristic Reed Sternberg cells.The neoplastic cells in SHML and LCH are bothpositive for S100 and CD68, while only thebackground epithelioid cells in Lennert�slymphoma may be positive for these markers(the neoplastic lymphocytes will be negative).

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CD1aCD2

CD3CD4

CD5CD8

CD15CD20

CD23CD30

CD31CD35

CD56CD68

S100Other

DiagnosticClues

Table 3: Immunostaining in Lennert�s Lymphoma and Common Differential Diagnoses

IHC Profile

+

+

ReedSternberg

Cells

Lennert�sLymphoma[38-41,1]

HodgkinLymphoma

[41-62]

Sinus Histiocytosis withMassive Lymphadenopathy

[63,64,41]

Langerhans CellHistiocytosis[63, 64, 41]

++

+/-+

+/--

-

-

-

-

BackgroundEpithelioid

-

-

-

-

++

Emperipolesis

+

+

++

Case 4: Leiomyoma:

Fig. 9: Epithelioid cells arranged in a spindledpattern. H & E 20X

Fig. 10: High Power view showing cells with abun-dant cytoplasm. H&E; 40x

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48 year old premenopausal woman haspresented with menorrhagia, with a potentialdiagnosis of leiomyoma. Figures 9 and 10illustrate a neoplasm that is not a typicalleiomyoma. The abundant cytoplasm andcellularity may lead to a mis-diagnosis of aleiomyosarcoma. Leiomyoma is a benignneoplasm of smooth muscle origin. It mostcommonly appears as spindle cells arranged ina whorled or interlaced fascicular pattern,though cells can be pleomorphic, epithelioid,or with multinucleated giant cell features [42-43]. The epithelioid cells are often plump;spindle shaped and show deeply eosinophiliccytoplasm, and may dissuade one from thediagnosis of a benign leiomyoma. Table 4:below illustrates typical immunohistochemicalprofiles of leiomyoma and other neoplasms thatmay arise as differential diagnoses.Leiomyosarcoma is a malignant neoplasm that

is also of muscular differentiation. It issometimes positive for smooth muscle antigen(SMA), although has been found to show nostaining for both estrogen receptor (ER) andprogesterone receptor (PR) in one case series[44]. Spindle cell carcinoma can be excludedvia immunostains for cytokeratin and EMA,which are negative in leiomyoma. Perivascularepithelial cell tumor can be excluded viademonstration of negative staining formelanogenesis markers (MiTF, tyrosinase,MelanA).Ki-67 proliferative index also holds someweight in differentiating benign and malignantneoplasms. Leiomyomas typically stainnegatively or focally for Ki-67, while moremalignant lesions such as leiomyosarcoma andspindle cell carcinoma show diffuse stainingfor Ki-67 [45-46].

Table 4: Immunostaining in Leiomyoma and Common Differential Diagnoses

IHC ProfileLeiomyoma

[42- 45]Leiomyosarcoma

[44,46]Spindle CellCarcinoma

[45]

Perivascular EpithelialCell Tumor (PEComa)

[65, 10]+/-

--

+++

+/-+/-+/------ -

++

+

++++

SMAVimentinPRERDesminHMB-45CytokeratinsEMAS100MiTFTyrosinaseA-103Melan-A

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Case 5: Myxoid Liposarcoma:87 years old male has presented with a right groin mass

Fig. 11: Cellular neoplasm with microcysticareas. H&E; 20X

Fig. 12:Tumor heterogeneity with focal areasshowing a pure myxoid neoplasm. H&E;40X

Fig. 13:High power view showing microcysticareas. H&E; 20X

Fig. 14:Lipocytes are seen adjacent to cellularmyxoid areas. H&E; 40X

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The patient from whom this biopsy has beenexcised has been an 87 year old man with themass in his groin. Initially, the mass has beenthought to be a hernia. However, at surgery, thesurgeon has found it difficult to enucleatecompletely, and it has been apparent that this

has not been a hernia, but has been indeed aneoplasm. The advanced age of the patient hasraised the suspicion for malignancy. Softtissue neoplasms can present at unusuallocations, as seen in this instance. Figures 11through 14 are representative of this myxoid

Table 5: Immunostaining in Myxoid Liposarcoma and Common Differential Diagnoses

IHC Profile

+

++

MyxoidLiposarcoma

[66,49]

Lymphangioma[67]

Hemangioma[66,68]

Pleomorphicsarcoma NOS or

MFH [66,69]

++

--

--

- -

No specificIHC Markers

are known

+/-+

++ (infantile)

+ (infantile)+ (infantile)

+

+

-

+

--

Focal SMAMuscle Specific

ActinDesmin

S100Keratins

CD68Factor XIIIa

PodoplaninVEGFR-3

Flt-4CD34

CD31Fli-1

PCNAVEGF

Type IVcollagenase

vWFGLUT1

Factor VIIIOsteocalcinin

ALPOther Diagnostic

Clues

+/- (involuting)

+/- (involuting)

+ (involuting)

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liposarcoma. The microscopic findings ofmyxoid liposarcoma resemble the morphologyseen in developing fetal fat. The adipose cellsmay be present in different stages of developmentbecause the cells attempt, albeit unsuccessfully,to differentiate. The bland fusiform cells formnodules that are surrounded by myxoid matrixcontaining mostly hyaluronic acid. Theabundance of myxoid stroma may create acribiform pattern. If the cells become flattenedand do not stain well, they may be mistaken fora lymphangioma or if there is a hemorrhagewithin the interstitial space it could bemisdiagnosed as a hemangioma. The cells withinthe neoplasm can also become cartilaginous [47-48], leiomyomatous or osseous (myxoidliposarcoma subtypes). Myxoid liposarcomasmay be distinguished from myxomas due to thepresence of plexiform capillary vasculature[49]. Myxoid liposarcomas generally arise inthe lower extremity during the 6th decade of life.Myxoid liposarcoma expresses a variety ofproteins which have been listed above in Table 5.The presence of focal SMA & muscle-specific actin indicate that there is a smoothmuscle component to the neoplasm. These,however, are not a differentiating factors dueto their presence in pleomorphic sarcoma NOSor MFH. Staining for CD68, a glycoproteinfound on monocytes, macrophages, andneutrophils, would indicate that the lesioncontains histiocytes & is therefore pleomorphicsarcoma NOS or MFH. Hemangioma can beeasily excluded if stains reveal the presence ofendothelial cell markers such as factor VIII,CD34, CD31 and VEGF. The positive stainingof podoplanin in lymphangioma illustrates thatthere are lymphatic vessels within the neoplasm

which are not present in myxoid liposarcoma.Although there are no specific markers knownfor myxoid liposarcoma, a combination ofstains negative for lymphatic, endothelial andhistiocyte markers can be used to exclude thedifferential diagnosis. Furthermore, thepresence of smooth muscle proteins can be usedto confirm a myxoid liposarcoma [50].

Case 6: Desmoplastic Small Round CellTumor:21 years old with retroperitoneal adenopathyand abdominal mass.

Fig. 15: Core biopsies showing a small round blue celltumor infiltrating dense stromal tissue; H&E 10X

Fig. 16: High power view shows cells with verylittle cytoplasm. H&E ;40X

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JKIMSU, Vol. 1, No. 2, July-Dec. 2012 Megha Joshi et al

Fig. 17: High power view showing cells with clearcytoplasm in sheets. H&E; 40X

This 21 years old male has presented with apalpable abdominal mass in the emergencyroom (ER). The patient has been an exchangestudent from Brazil and with no healthinsurance. CT scan done in the ER has revealedlarge retroperitoneal lymphadenopathy andhepatosplenomegaly. The diagnosis afterimaging has been an obvious malignancy. Phonecalls made to a regional cancer center haveasked that referral be made only after aconfirmed tissue diagnosis. This has led to anultrasound guided core biopsy of the mass onan outpatient basis.At H&E, the small round blue cell tumor hasbeen thought to be extraskeletal primitiveneuroectodermal tumors (PNET),rhabdomyosarcoma, neuroblastoma,lymphoma, poorly differentiated carcinoma,small-cell carcinoma, Merkel cell carcinoma.IHC has confirmed the diagnosis asDesmoplastic small round cell tumors. Thesetumors are usually found in the abdominal and/

or pelvic peritoneum of young males as hasbeen seen here. As the name suggests, thetumor is comprised of small round cellssurrounded by hypervascular desmoplasiacreating rounded nests of cells. The small cellshave small dark blue nuclei lacking prominentnucleoli. The cytoplasm of the tumor cells iseosinophilic and not abundant [51]. Thesecharacteristics, however, are not diagnostic ofDSRCT. Although there is a plethora ofdifferential diagnosis, DSRCT can bedistinguished using immunohistochemistry.Table 6 below lists several differentimmunohistochemical stains that may be usedto diagnose desmoplastic small round celltumor. EWS-WT1 is a reliable marker whentrying to diagnose a desmoplastic small roundcell tumor because it is the product of thechromosome 11 and chromosome 22translocation. More stains need to be conductedif EWS-WT1 results are negative todifferentiate between the differentialdiagnosis of desmoplastic small round celltumor. PNET neoplasms will contain proteinsconsistent with neuroendocrine cell origin suchas chromogranin and synaptophysin whilerhabdomyosarcoma will have muscle cellmarkers such as myogenin, myoD1, and smoothmuscle actin. Lastly Merkel cell carcinoma�sepithelial cell origin is apparent due to thepositive staining for a variety of cytokeratinswhich do not stain positively in a case ofdesmoplastic small round cell tumor.CK-20 cytokeratin 20, TTF-1 thyroidtranscription factor 1, NSE neuron-specificenolase, GrA gromogranin A, NFPneurofilament proteins, CD56 neural adhesionmolecule, MAP-2 microtubule associated

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IHCPROFILE

OtherDiagnostic

Clues

Table 6: Immunostaining in Desmoplastic small round cell tumor & Common Differential Diagnoses

TypeDSRCT[70,51]

PNET[66]

Rhabdomyosarcoma[66,71]

Merkel cell carcinoma[72-74,75]

EWS-WT1 �Fli-1 +

Vimentin +S100 +CD56 +

Chromogranin +Synaptophysin +Cytokeratin +/-

CD99 +

EWS-WT1 +Desmin +/-. If

positive will have adot-like pattern

MOC-31 +Ber-EP4 +Leu-M1 +

Cytokeratins 5/6 �Thrombomodulin �Cytokeratin 20 �

MyoD1 andmyogenin �PDGFA+

T(11;22)(q24;q12)

EWS-WT1 �Desmin +

Myogenin +MyoD1 +

Smooth muscle actin-/+

CK -/+S100 -/+

Neuroilament -/+Synaptophysin +

(if pure rhabdomyo-sarcoma)

CK8+CK18+CK19 +

CK20+ (negative in 5-25% of lesions)

TTF1 -NSE+S-100-GrA+/-SYP+/-NFP +CD5+

MAP-2+LCA-

protein 2, LCA leukocyte common antigen.Other differential diagnoses not included in thetable are: neuroblastoma, lymphoma, poorlydifferentiated carcinoma, small-cell carcinoma.

Fig. 18: Biphasic tumor with glandular andstromal elements. H&E; 20X

Fig. 19: High power view showing malignantstromal component. H&E; 40X

Case 7: Synovial Sarcoma65 years old female has presented with large ab-dominal wall mass measuring 8 x 5.5 x 3.8 cm

31



Fig. 20: High power view showing the glandularcomponent. H&E; 40X

This mass has been thought to be metastaticcolon carcinoma. At frozen section, a tumor hasbeen diagnosed as a carcinosarcoma. However,IHC stains have revealed it to be a synovialsarcoma.Unlike what their name suggests, syn-ovial sarcomas are not found within the syn-ovial space. Most often these lesions are seenaround the joints. Rarely, synovial sarcomasmay occur in the parapharyngeal region,retropharyngeal region [52], orofacial region[53], retroperitoneum [54], mediastinum [55],pleura, and heart or, as in the case presentedhere, in the abdominal wall. In fact thislocation is very rare for synovial sarcomas.Most abdominal wall sarcomas consist of casereports. Among synovial sarcomas which havebeen accessioned over a 10 years period at theArmed Forces Institute of Pathology (AFIP),only 2.6% have arisen in the abdominal wall[48].

On histological examination two cell types areapparent: spindle cells and epithelial cells. Theratio of these two cell types had led to subtypesof synovial sarcomas. These subtypes includethe biphasic type, monophasic fibrous types,monophasic epithelial type and poorlydifferentiated (round cell) type. The epithelialcells mimic the epithelial cells within anormal synovium, range from cuboidal tocolumnar and may arrange themselves in toglands and secrete granular or pink secretions.These epithelial cells may cover papillarystructures whose fibrovascular core has beenreplaced by spindle cells. Due to the epithelialcell content, squamous metaplasia, keratinpearls and keratohyalin granules may be presentwhich leads to the misdiagnosis of squamouscell carcinoma [56]. The spindle cells withinsynovial sarcoma have scant cytoplasm and darkblue oval nuclei. These cells occur in highdensities that can be confused withfibrosarcoma. The characteristics that allow thepathologist to discern that they are in factlooking at a synovial sarcoma are the lack of aherringbone pattern, a more irregulararchitecture and fewer cells undergoingmitosis [56]. Between the spindle cells andepithelial cells there may be areas of thickenedbasement membrane, hyaline, myxomatousmaterial or calcifications. The amount ofcalcification and whether or not thiscalcification has ossified becomes importantwhen rendering a diagnosis. Othercharacteristics of biphasic synovial sarcomainclude a varying degree of vasculature and thepresence of mast cells.The two ends of the spindle cell and epithelialcell ratio are designated as monophasic fibrous

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synovial sarcoma and monophasic epithelialsynovial sarcoma. Both contain thecharacteristics discussed for biphasic synovialsarcomas however the monophasic epithelialsubtype of synovial sarcoma is much rarer. Itsrarity has led to a discussion about whether thissubtype truly exists or whether its lowprevalence may be due to the difficulties inexcluding other differential diagnoses. Thesedifferential diagnoses include metastaticcarcinoma, melanoma, adnexal tumors,epithelioid sarcoma, and epithelioid malignant

peripheral nerve sheath tumor (MPNST).The last subtype of synovial sarcoma is thepoorly differentiated subtype. All synovialsarcomas independent of the ratio of spindle toepithelial cells may become poorlydifferentiated. The lack of differentiation posesa problem in diagnosis for the pathologist andworsens the prognosis for the patient. Animportant differential diagnosis to rule out in acase of poorly differentiated synovial sarcomais that of malignant hemangiopericytoma dueto the abundance of thin walled vasculature.

IHCPROFILE

OtherDiagnostic

Clues

Table 7: Immunostaining in Synovial Sarcoma and Common Differential Diagnoses

TypeSynovial Sarcoma

[66]Fibrosarcoma

[76,77]Hemangiopericytoma

[78, 79]Adnexal

carcinoma [80]MPNST

[60]

S100+FactorVIII-

CD31-CD34-

Fibronectin+collagen type I,

III, V +(III>I)

collagen typeIV-

Vimentin +Desmin -

Vimentin +EMA +

AE1/AE3 + (epithelialcells)

CK7 + (epithelial cells)CK8 + (epithelial cells)CK18 (epithelial cells)CK19 (epithelial cells)

BerEp4 +E-cadherin +Calretinin +/-

S100 +/-CD34 +/-SMA �/+

Desmin -/+Bcl-2 + (spindle cells)

CD99 +

T(x;18) or SYT-SSXfusion transcript

CD34+vimentin+

Actin +/- (focal)SMA +/-(focal) CD 31-

cytokeratin-S100 �p75+/-

CK7+CK20-ER+/-PR+/-

GCDFP-15+/-CK5/6 +

Podoplanin +

33



Poorly differentiated synovial sarcoma mayalso resemble extraskeletal Ewing�s sarcoma/primitive neuroectodermal tumor (PNET);however, IHC can be utilized in this case.The abundance of differential diagnoses forsynovial sarcoma makes cytogenetic andmolecular genetic investigations of suspectedcases of synovial sarcoma essential.Other differential diagnoses not included in thetable include carcinosarcoma & mesenchymalchondrosarcoma.The synovial sarcoma diagnosis is mostconfidently made using FISH to determine ifthere is a translocation between the Xchromosome and chromosome 18.Immunohistochemical staining can also helpdetermine whether FISH should be ordered.

Depending on the subtype of synovial sarcomathere will be varying degrees of epithelialmarkers and spindle cell markers may bepresent. As seen in table 7, neoplasms with alarge number of epithelial cells will stainpositively for AE1/AE3, CK7, CK8, CK18, andCK19. Therefore monophasic epithelialsynovial sarcoma will stain exclusively forthese epithelial cell markers. The use ofBerEp4 can reliably distinguish epithelial cellsfrom mesothelial cells if the epithelial cellswithin the synovial sarcoma resemblemesothelial cells [50]. The presence of CD99within a synovial sarcoma may indicateleukocytic infiltrate or increasedvascularization [57].The figure 22 below shows excised mass from

Case 8: Extraosseous Osteosarcoma ofthe Chondroblastic Type:54 years old male has presented with a chin mass.

Fig. 21: Sections through the chin mass show over-lying skin and a cartilaginous tumor. H&E 10X

Fig. 22: High power view showing the malignantcartilaginous areas. H&E; 40X

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Fig. 23: Cellular areas alternate with myxoidones. H&E;40X

the chin of a 54 year old male. Whenexamining the biopsy of the tumor stained withH&E, osteoid and bone are visible as well asosteoblasts and fibroblasts. In addition to thistypical presentation of an osteosarcoma, thechondroblast type will have atypicalchondrocytes with disorganized cellular

density, areas of calcification, and myxomatousmaterial. Osteosarcoma of the chondroblastictype is associated with the use of therapeuticradiation. This has become evident due to thepresence of chronic radiodermatitis overlyingmost extraskeletal osteosarcomas. Thedifferential diagnosis for extraskeletalosteosarcoma include myositis ossificans,synovial sarcoma, epithelioid sarcoma,malignant fibrous histiocytoma, liposarcoma,parosteal osteogenic sarcoma, high-gradesurface osteosarcoma and malignantmelanoma. Luckily, many of these differentialdiagnosis can be ruled out using H&E becausethe neoplastic elements of osteoid and bone inthese tumors is focally located, thearchitecture tends to be more organized, andthe cells tend to be more differentiated, thanthat seen in osteosarcoma [58]. One of the moredifficult differential diagnoses to exclude ismalignant fibrous histiocytoma withmetaplastic bone. Studies have suggested;however, that malignant fibrous histiocytoma

VimentinOsteocalcinOsteonectin

DesminSMAS100

A-SMAMSA

Table 8: Immunostaining in Extraosseous Osteosarcoma of the Chondroblastic Type and Common Differential Diagnoses

IHC Profile Extraosseous Osteosar-coma of the Chondroblas-

tic Type (68,81-84)

Myositis Ossificans(85)

Parosteal OsteogenicSarcoma (86)

+

--

+ (focal)

+++

+ (if differentiated)+

+/-+/-

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with metaplastic bone will have osseous andchondroid elements in the fibrous septa andpseudocapsule [59].As it can be seen in Table 8, the most reliablemarker, when suspecting a diagnosis ofextraosseous osteosarcoma of thechondroblastic type is osteocalcin. This stain,however, may be problematic when trying todifferentiate extraosseous osteosarcoma of thechondroblastic type from parosteal osteogenicsarcoma because if the parosteal osteogenicsarcoma is well differentiated it will also stainpositively for osteocalcin. In this case furtherstains should be ordered such as A-SMA andMSA to illustrate the presence of muscle cells.A positive result received from a vimentin staincould further negate the likelihood of aparosteal osteogenic sarcoma. Staining forS100 will be focally positive in the case ofmyositis ossificans so if this pattern ofstaining is not seen that further indicates thediagnosis of extraosseous osteosarcoma of thechondroblastic type.

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*Author for Correspondence: Megha Joshi, Chief, Department of Pathology,Lawrence General Hospital, Lawrence, MA 01842, USA

E-mail: [email protected]

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Immunohistochemistry of Epithelioid Soft Tissue Sarcomas ... · Immunohistochemistry of Epithelioid Soft Tissue Sarcomas, Literature Review Based on Case Studies Megha Joshi 1*, Philip