Alveolar soft part sarcoma: The role of prognostic markers

Annals of

DIAGNOSTIC PATHOLOGY VOL 4, NO 3

ORIGIN&

JUNE 2000

ARTICLES

Alveolar Soft Part Sarcoma: The Role of Prognostic Markers Xavier Sanjuan, MD, Mark E. Sobel, MD, PhD, James Yang, MD, and Maria J. Merino, MD Alveolar soft part sarcoma (ASPS) is a rare malignant neoplasm characterized by slow growth and indolent behavior. The role of proliferative markers and tumor suppressor genes is unknown in these tumors. To investigate their potential role in diagnosis and prognosis, we studied 13 cases of primary ASPS and 14 metastases and correlated them with clinicopathologic parameters. Immunohistochemistry was performed with anti-p53 and anti-Ki-67 antibodies. Polymerase chain reaction after tumor microdissection was performed to search for possible loss of heterozygosity in chromosomes lp, 9p, 17q, 22q, and TP53 to identify possible changes that may clarify the histogenesis of these tumors. Four of five (80%) primary ASPS cases were positive for Ki-67 and all of them developed later metastases. One patient whose tumor did not stain for Ki-67 remained free of disease for 9 years. Eleven of 13 (85%) metastases were positive for Ki-67; however, there was no correlation with final outcome. All the primary ASPS cases analyzed for p53 yielded negative results, but two (15%) of 13 metastases were weakly positive. There was no correlation of these markers with prognosis or clinicopathologic parameters. No loss of heterozygosity was found except in one of nine (11%) informative metastases for DlS165 (at 1~36). Our preliminary data suggest that Ki-67-positive immunostaining may be a prognostic indicator for the development of metastases in ASPS.

Ann Diagn Path01 4: 135-142,200O. Index somal

Words: markers

Alveolar

soft

part

Copyright sarcoma,

0 2000 by W.B. Saunders Company Ki-67,

A

LVEOJAR soft part sarcoma (ASPS) is a rare malignant neoplasm found predominantly in adolescents and young females that is characterized by slow growth and potential for metastasis.‘,’ The tumors are found mainly in the deep soft tissues of thighs, buttocks,

Anna/s

of Diagnosfic

Pathology

~53,

loss

of heterozygosity,

chromo-

and the abdominal wall, but can also occur in the orbit,3 tongue,’ oral cavity,j female genital tract,6 lung,7 thoracic wall,” breast,g retroperitoneum,tO stomach,” and sacral bone.” Despite many immunohistochemical and ultrastructural studies, the origin of ASPS remains unclear. Since the first description by Christopherson et al in 1952,‘” it has been postulated that these neoplasms may represent malignant granular cell myoblastoma,‘” angioreninoma,‘j paraganglioma,‘” or a muscle-derived tumor,t7.t8 with the last hypothesis having the widest acceptance. The role of prognostic indicators in this specific type of sarcoma has been analyzed very few times. Ki-67, a nuclear antigen found in proliferative cells in Gt phase, Vol4,

No 3 (June),

2000:

pp 135-l

42

135

136

Sanjuan

et al

has proved to be a reliable marker of aggres&zncss in other soft tissue sarcomas (STSs), correlating with mitotic counts, tuiiior grade. and ~un-i\~al.“‘-~ Prc\ious studies using monoclonal antibodies against this protein have sholvn positi1.e imliillnostaining in -k-O% to 68% 01 the sarcomas.“” In one report, IQ-67 \GIS not corrclatccl with short-term suni\.al of ASPS.“” Other txvo cases 01 ASPS halve been studied for G-67 and both sho\ved a lo\\. index of Ki-67 staining.“’ Similarly, the tumor suppressor gene p53 is !ino\vn to play an important role in the pathogcncsis of sarcomas correlating sometimes \\ith prognosis.“’ p53-positi1.c immunoreaction has been obsen.ed in 17% to 55% of STS in different series. Tumors frequentI>. immunorcactive lzith anti-p53 antibodies include malignant fibrous hystioc)-toma, liposarcoma, I-haMom).os3rcoma, Icioni!osarcoma, and malignant neurogcnic tumors.J”.L)i.‘J+ Fibrosarcomas are kno\\n to lack p53 immunorcaction.“’ With regard to ASPS, only one report found p53 immunostaining (two of 9 cases) \\ithout correlation to sur\i\ral or prognostic factors.?? Several c)togenctic studies ha1.e described a numbc1 of chromosomal alterations in ASPS, \\-ith great \xiability of trisomies, deletions, translocations, and ~osscs.“~-“~ h?ost of the chromosomes ha1.e been founcl altcrcd at least once in ASPS, but the most frequent anomalies have occurred on 1p, 9p, 17q, and 22q.““:jH The purpose of the current stud), \vas to in\.estigatc the expression of possible prognostic markers (~53, Ki-67) in ASPS, to search for possible tumor supprcsso~ genes through LOH analysis, and to correlate thcsc results 12ith patient outcome ancl clinicopathologic information. Table

Case No. 1 2 3 4 5 6 7

a 9 10 11 12 13

1. Data

for the 13 Primary

Alveolar

Age Wr)

Sex

Location

Tumor Size (cm)

12 30 34 24 31 22 26 10 19 21 14 19 13

F F F F M F F F F M F F F

Chest wall Thigh Thigh Thigh Abdominal wall Arm Achilles tendon Thigh Thigh Abdominal wall Leg Flank Tongue

NA 13.0 9.5 6.0 6.0 NA NA 2.3 2.5 21.0 5.7 1.5 NA

Abbreviations: NA, not available; NM, no metastasis; ANED, of disease; DUR, died (unknown reason); LFU, lost to follow-up.

Soft

Part

Sarcoma

Ki-67

P53

NA NA Positive NA NA NA Positive Negative NA NA Positive Positive NA

NA NA Negative NA NA NA Negative Negative NA NA Negative Negative NA

alive with no evidence

of disease;

Cases Metastases (mo) 1 0

aa 0 NM 41 0 NM Unknown 36 3 54 Unknown AWD,

Follow-up ANED, AWD, DOD, ANED, DUR, ANED, DOD, ANED, LFU AWD, AWD. AWD, LFU

alive with disease;

16 yr 2 yr 10 yr 9 yr ? yr 11 yr 2 yr 9 yr 6 yr 4 yr 4 yr

DOD,

died

Aheolar

Soft

(IlIcaIl , “6 >em). l’hcsc \\‘crc the ages at the I” to ii yc’ars time ol‘tliagnosis ol‘thc mctastatic. implant. Scvcn ol‘thc tight patients \\‘c’r~’ I’cmalcs. .\I~~Iastascs \VCI’C present in the lun,q (fi-k%). brain (It?0), boric (I-I-%), and ileum (7%). The mean siLc ul‘th~~ nictastas~‘s \\‘;Is I .” cm (rall~e, 03 to 3.0) (l‘aldr 2). ‘l‘lic I.~stmetastasis in one ol‘thr~ cxvs appcarrcl I-l years slier rc.s~di4m ol‘llic primai>- tumor.

Pathology Gross. xribcd tissutx rirbb~n~ orrh+g:(,

‘l‘lic t tiniors

ol‘largc, solid, poorly circumrstc~ndud into adjacent soft C:ut surlhcc re\.calctl ii white to tan tissue of soli to c.onsistc.nc\.. Ocxxsionall!-, arc;1s of necrosis ancl hcm~x~ultl 1,~ li)und. One, cast had a diniise m\xoicl nussrs

that

consisted

li.rclwntl~.

;lp,“‘;Ll-;ulc’.

.\lctast,isc.s to the lungs app~xrcd as \vhitc or ~cllo\\ish to tan notlulcs of lirm consistcncv. I\Ictastascs to the brain \\TI‘c’ sc~l’t and pinkish. blending r>risily \lls \~c’r(’ surrounded 1~1.dclicatc librous tissue. and \xsc~ul;ir spxxs. I’rriotlic acid-Schilf staining rc\.caJcd pcl-icdic .l~itl-SchilI~I,ositi\.e nccdlc-likr inclusions in ill<, c.~~tqdaslll

01’50111(.

(‘.lSCS.

Ilisttrlogicnll!~. the nict;tst;iscs rcxcniblcd the primal-). Iesit ~IIS, bolt c,r*lls l?cquciitl!. slio\~~tl ;i lar,gc. iingularl~ shaped 01 h!.l”.r(‘hrcllnatic, iiuc~l~~us. binuclcatrd crlls. pnl~nuclcoli. and \‘(‘I?- pi-cmiinrnt nucl~~~Ji.

Table

2. Data for the 14 Metastatic Alveolar Sarcomas From Eight Patients

Case No.

Age (yr)

Sex

Location

Tumor Size (cm)

1 1 3 4 6 6 11 11 14 14 14 15 15 16

12 14 42 24 25 27 14 15 23 26 26 41 55 NA

F F F F F F F F F F F M M F

Lung Lung Vertebral Lung Lung Lung Lung Lung Brain Brain Ileum Lung Lung Sternum

0.5 0.3 NA NA 0.5 0.7 0.5 0.5 3.0 3.0 2.5 0.7 1.4 NA

Abbreviation:

NA, not available.

Soft

Part

Ki-67

P53

Negative Positive Positive Positive Positive Positive Positive Positive Positive Positive NA Negative Positive Positive

Negative Negative Negative Positive Negative Negative Negative Negative Negative Positive NA Negative Negative Negative

Part

Sarcoma

137

Methods Zmmunohistochemistty. Immunohistochemical staining was clone in li1.e prima? ASPS cases and 13 metastases. Five-micrometer, formalin-fixed, paraffin-embedded sections \cere deparaflinized and blocked \\ith methanol-30% H202. After antigen retric\.al by boiling in citrate buffer, slides were incubatccl \vith monoclonal antibodies anti-p53 (Ab6; Oncogene, Cambridge, MA) and anti-IQ-67 (MIB-1; Oncogene), both diluted I :20. The slides \+‘ere then immunostained with a\idin-biotin-pcrosidasc complex and developed with diaminobcnzicline. Harris’ hematoxylin \cas used to counterstain the slides. Sonimmune mouse immunoglobulin was used as a negative control. ~53 and Ki-67 expression were evaluated as positive or ncgati1.e. Staining was considered positive when more than 5% of the nuclei showed immunoreaction. Polymerase chain reaction analysis of microdissected tissues. Five-micrometer unstained sections from formalinftscd, parafin-embedded tissues \vere deparaflinized, rehydrated, and stained \\ith hematoxylin-eosin. Specific populations 01‘ tumor ancl normal cells \. heated at 9-l”C for 9 minutes to activate the AmpliTaqGold DYA pol\merasc. Pol>merase chain reaction analysis consisted of 30 to 35 cycles of denaturation at 91°C for I minutes. annealing at .55”C: for 1 minute (except CRTM at 33°C:. IFSA at 37”C, and TP53 at 60°C). and extension at 72°C li)r I niinutc. All pol>merase chain reactions \\‘ere finall) elongated at 72°C lix 3 to IO minutes. Pollmerase chain reaction products \vcrc mised \cith 5 PL of loading dye containing 9.5% lixmamide, 0.25% (IV/~) bromophenol blue, 0.25% (\\Yv) sylcne c~mol, and 12 mmol/L EDTA, pH 8. The mix was drnaturccl i minutes at 9CC. put into ice, loaded onto a 6% or 8% urca
Sanjuan

et

al

Figure 1. Primary (Aand B) and metastatic (C and D) ASPS cases before (A and C) and after (B and D) microdissection.

Depending on the size of the amplicon, some DNA could not be amplified for various markers. For example, two cases could not be amplified with markers CACNLBI and D22S430, which detect products of 81 to 12 1 bp and 84 to 98 bp, respectively. Conversely, the amplicons of HGH and D22S264, which are 201 to 221 bp and 190 to 2 10 bp long, respectively, could not be amplified in IO cases.

Statistical Analysis Qualitative variables were analyzed in contingency tables by &i-square test or Fisher’s exact test when needed. Quantitative variables were analyzed with Student’s /-test. Significance was considered P < .05. All calculations were performed with

the BMDP statistical package (BMDP Statistical Software Inc, Los Angeles, CA).

Results Ki-67 Analysis Fifteen (83%) of 18 lesions stained positively for MEL 1. Four of five (80%) primary tumors were positive (Table 1; cases 3,7, 1 I, and 12). One ofthe positive cases had synchronous metastasis at presentation, the other three developed metastases 3,54, and 88 months later. Two of the positive patients died of sarcoma; the other

Alveolar

Figul ‘e 1.

Soft

Part

Sarcoma

(Cont’d).

two are currently alive with multiple lung and bone metastases after chemotherapy. The negative case (Table 1; case 8) is alive with no evidence of disease 9 years later. Therefore, Ki-67 expression in the primal); tumor seemed to correlate with presence or further development of metastases, although the small size of the sample made the statistical analysis unpracticable. Eleven of 13 (85%) metastases analyzed for Ki-67 expression were positive. These cases corresponded to eight patients, ofwhom three are alive with no evidence of disease, two are alive with disease, two have died due to disease, and one is lost to follow-up. Therefore, Ki-67

expression sis.

in metastatic

lesions did not relate to progno-

p53 Analysis All five primary ASPSs analyzed by immunohistochemistr). for p53 were negative. On the other hand, two (15%) of 13 metastases were weakly positive. One was a lung metastasis (Table 2; case 4); the other was a brain metastasis that clcveloped 46 months after diagnosis (Table 2; the second metastasis in case 14). There was no correlation between the positive staining and clinicopathologic parameters. Heterozygosity analysis at TP53

140

Sanjuan

et al

. in these two cases showed heterozygosity (LOH).

no evidence

of loss of

B

A

Loss of Hetenqgosity Loss of heterozygosity studies were performed on 13 primary ASPS cases and 13 metastases (case 16 was not analyzed due to limitations on tissue availability). No LOH was found in any of the informative primaly tumors, and only one (11%) of nine informative metastases showed LOH for DlS165 (at 1~36) (Table 3; Fig 2). It corresponded to a pulmonary metastases (Table 2; first metastases in case 6). This LOH did not appear to implicate worse prognosis (the patient was alive with no evidence of disease 11 years later).

N

M

N

M

Discussion Alveolar soft part sarcoma is an uncommon soft tissue neoplasm originally described by Christopherson et alI3 in 1952. In their original report, these investigators noted that the tumor predominantly affected young females and adolescents, which is also a finding in our study. The most common location for these neoplasms was the extremities, where it was frequently found in association with skeletal muscle. For this reason, Christopherson et alI3 considered these tumors a variant of myosarcomas. The tumor masses are of slow growth and are frequently asymptomatic. Metastases, however, can be present at the time of initial diagnosis. Resection of metastases (especially pulmonary metastases) frequently results in long-term survival. Three patients in the present study developed multiple pulmonary metastases, underwent surgical resection, and are alive with no evidence of disease 16,9, and 11 years after surgery. We found no statistically significant correlation in our study between age, sex, or location and metastases. There were no histologic differences between metastatic and nonmetastatic ASPS; however, metastatic

Table

Marker DlS162 DlS165 CRTM IFNA CACNLBl HGH D22S264 D22S430 TP53

3. Results of Loss of Heterozygosity With the Different Markers Mapping 1 p32 1 p36 1 p35 9p22 17q21 -q22 17q22-q24 22q11.2 22q12 17p13.1

Informative 76% 64% 61% 65% 58% 100% 81% 75% 75%

(16/21) (14/22) (11/18) (13/20) (14/24) (16/l 6) (13/16) (18/24) (12/16)

Studies

LOH 0

Dl S165 Figure 2. The results of two LOH studies for Dl S165 in lung metastases of ASPS cases. Column A shows a case with no LOH in the metastasis. Column B shows an LOH for the upper allele. Note that the alleles in this case are overlapped, with the third band of the upper allele corresponding to the first band of the lower allele. N, normal; M, metastasis.

sarcomas tended to be larger (median, 9.45 cm) than nonmetastatic tumors (median, 4.15 cm) (P = .34). The role of prognostic markers in these tumors is still unclear. The IQ-67 nuclear antigen is a nuclear matrix protein associated with proliferation, known to be expressed in all phases of the cell cycle except G0.‘29 This marker has been suggested as a potential marker of aggressiveness in other types of STS.‘O Drobnjak et a1’O found Ki-67 reactivity in 27% of liposarcomas and in 78% of synovial sarcomas. In our series of ASPS, the frequency of Ki-67 immunoreactivity is 83%, one of the highest among STS. The four patients whose primary tumors stained positive with Ki-67 developed metastases; two of them died of the disease and the other hvo are alive with multiple lung and bone metastases after receiving chemotherapy. This finding suggests that positive staining with MB-1 monoclonal antibody ma) indicate a potential for the development of metastases. This finding does not seem to agree with that ofJong et alz2 in which Ki-67 expression by the same marker did not correlate with short-term survival. These investigators did not find prognostic factors explaining a poor outcome in a short time; however, most of their cases (with Ki-67 positivity) had metastases, as did ours, and

Aheolar

Soft

their casts tvithout mctastases had a short follo\~-up period (<4 >,ears). In adclilion, the prcscncc of lung mctastascs dots no1 ncccssnriI>. implicate short-term suni\d in ASPS cnscs because of the systematic surgical rcscction of thcsc mctastascs. Stuclics \\ith larger numhers of cnscs ~-ill bc ncccssar?~ to further elucidntc the role of Ki-67 ancl other prognostic factors in the clinical course of ASPS. It is note\vorth). in this regard that correlation bctfveen IQ-67 positility and aggrcssi1.e bcha\ior has been dor~~n~cntcd in STS in gcncral, \vhcrc it has been correlatecl I\-ilh mitotic count, tumor grade, and sLlni\Yll.“‘-” 1153 is a nuclear l’hosl.‘hol)“oteili kno\vn to ha1.c a rcgulatoly role in the ccl1 cycle, arresting cells in G, phase and acting as a tumor suppressor gcnc. T\VO t!pcs of 1~53 proteins ha1.c been dctcctccl: \\ild-t)lx 1~53, \vhich has a short half-life and is usuall~~ not dctcctcd immunohistochcmicall~; and mutant p53, Ivhich has lost its function as a tumor suppressor gcnc ancl is more stable ancl accumulates in the ~LIC~CLIS,thus being immunohistochcmicall~. dctcctablc. “’ Alterations in ~53 ha1.e been dcmonstratccl in a large \.aricty of carcinomas and sarcomas. The incidcncc of p53 nuclear rcactility in STS ranges from 17% to 55%, clepending on the t)-pe of sarcoma.“” The greatest inciclcncc of positi1.e staining is obscnxzcl in rhabdomyosnrcomas, malignant fibrous hystioc!tonias, liposarcomas, Iciom)usarconias, ancl malignant ncurogenic tumors.‘)0.‘I~.L4 In addition, there are tumors \\ithout ~53 csprcssion, such as fibI-osarcomas.“’ It is not clear lvhat prognostic significance p53 has in STS. Some in\,estigators ha1.c nssociatcd it \\ith reduced suni\&” \\hile others ha1.c not.“’ What seems clear is that the frcqurnc!. of 1153 in\~olx.enicnt dcpcncls on the subtype and the grade of sarcoma. We did not find an! c\idcncc of mutant 1~33 in casts of primal>. ASPS, \\hich probably inclicatcs that this protein has no role in the de\,clopmcnt of this tumor. The prcscncc of 1~53 in mctnstascs does not cart?. prognostic implications, but it ma!. rcprcscnt a lntc c\xznt in the progression of some ASP%. The unicluc prc\ious report analyzing 1153 in ASPS did not lint1 a correlation bet\vccn suni\zl ancl aggrcssivcncss of tumors.?” A \xricty of chromosomal alterations ha\.c been rcportccl to occur in sarcomas ancl in ASPS cases, in\,ol\ing almost all the chromosomes. The alterations consist prcclominantl~~ ofclrlctions, tmnslocations, trisomics, ancl losses. Dclctions and losses arc LISW~I mechanisms of tumor suppressor gene inactixxtion. Therefore, scarching for LOH ma!. be a good method for dctccting possible tumor suppressor gcncs in clclctcd arcas. We scarchcd for loci kno\vn to bc clclcted or lost in the

Part

Sarcoma

141

pre\ious c)togcnetic studies of this tumor, such as lp, gp, 17q, ancj 22q?i272X as well as for 17~. No LOH \vas found in the primary tumors with any of the markers. Loss of heteroqgosity was detected in just one of nine metastases at 1~36. Cytogenetic alterations in I p have been pre\iously described in ASPS, which has been interpreted by some investigators as confirmatory c\idcncc of their neural”” or myogenicz7 origin. Deletions in Ip have been found in a variety of tumors, including those of neural origin (neuroblastomas, gliomas, neurofibromas, pheochromocytomas, medullary carcinoma of the th)-roid), muscular origin (leiomyosarcomas), and solid tumors (breast and colon carcinomas).“-” It has been reported that deletions of the distal portion of the short arm of chromosome 1 (distal to lp3l) is a remarkable feature in the genesis of ncuroblastomas’~ and that LOH at lp36 has been found in approximately 40% of breast cancers.“’ However, it also is kno\~li that chromosome I alterations are a late event in the general process of cancer progression.“5 In our study, the involvement of 1~36 region occurred in the metastasis, but there were not enough cases available to determine the possible implications of this finding. The deletions in 9p, l7q, and 22q that have been reported c)-togenetically by some investigators”7;z8 could not be demonstrated by LOH analysis with the selected primers. It is possible that c)-togenetically detected deletions represent genomic material translocated to another chromosome but still present in the genome and, therefore, not relelrant to LOH analysis. Our results indicate that occasional LOH at 1~36, as \vcll as p53 mutations, may occur in advanced sarcoma, although \ve do not kno\v if they are tumor-specific alterations. However, they have no prognostic significance. The molecular results of this study do not clarify the histogenesis of ASPS, which remains uncertain and fill riced further evaluation. More promising in elucidation of the molecular events that are involved in ASPS is our preliminan.obsenration that Ki-67 expression might be an indicator of the development of metastases, as has been found in other types of sarcoma, although this issue ncccls to be further confirmed in a larger study.

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142

Sanjuan

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