6
151 The Korean Journal of Pathology 2008; 42: 151-6 Background : The aim of the study is to evaluate the difference of immunophenotypes of stromal cells between the pure phyllodes tumor (PT) type and the co-existent type of phyllodes tumor and fibroadenoma, and between benign and malignant PT. Methods : Immunohisto- chemical staining for actin, CD34, CD10, c-kit, bcl-2, p53 and MIB-1 was performed using tis- sue microarray blocks that contained 25 cases of pure PT (16 benign tumors, 4, borderline malignant tumors, and 5 malignant tumors) and 6 cases of co-existent type. Results : The expression rates of CD34 and MIB-1 in the pure PT type were significantly higher and the expression rate of actin in the pure PT was significantly lower than that of the co-existent type. However, there were no significant differences in the bcl-2, CD10, and p53 expressions bet- ween the pure PT type and the co-existent type, and no c-kit expression was observed in both types. No significant differences in the CD34, actin, bcl-2, CD10, and p53 expressions between the benign and borderline/malignant PT cases were found. However, a significant difference of the MIB-1 expression rate was noted. Conclusions : The stromal cells of the pure PT type are regarded as less mature myofibroblasts, and the CD10 reactivity in some phyllodes tumors suggests a myoepithelial origin. The MIB-1 labeling index would be useful for the grading of phyllodes tumor. Key Words : Immunohistochemistry; Phyllodes tumor; Breast Joo Yeon SongHye-Kyoung Yoon 151 Immunohistochemical Phenotypes of Phyllodes Tumor of the Breast 151 151 Corresponding Author Hye-Kyoung Yoon, M.D. Department of Pathology, Pusan Paik Hospital, College of Medicine, Inje University, 633-165 Gaegeum-dong, Busanjin-gu, Busan 614-735, Korea Tel: 051-890-6628 Fax: 051-891-1834 E-mail: [email protected] *This work was supported by the 2005 Inje University research grant. Department of Pathology, Pusan Paik Hospital, College of Medicine, Inje University, Busan, Korea Received : November 1, 2007 Accepted : May 23, 2008 Fibroadenoma and benign phyllodes tumor (PT) are two common types of fibroepithelial tumors of the breast. PT shows predominantly shows a fibroadenomatous architecture with more cellular stroma and some distortion and elongation of its glan- dular elements. 1,2 Fibroadenoma and PT are usually not diffi- cult to differentiate, 2 but areas of fibroadenoma and PT have co- existed within a single nodule in some cases, and evidence of transition evidence from fibroadenoma to PT could be found. PT shows unpredictable behavior, 3 and the biologic behavior of this tumor cannot be predicted with certainty on the basis of only the morphologic criteria only. 1,4 The stroma of this tumor can undergo malignant progression to sarcoma. The frequency of malignant progression varies in different series from 5% to 30%. 5 The histological distinction between benign and malig- nant PT is often difficult and arbitrary. 6 The stromal cellularity, stromal cellular atypism, high mitotic activity, infiltrative tumor contour and heterologous stromal elements were reported to be the significant features of the malignant PT. According to Tan et al., 7 the relative incidence of benign, borderline and malig- nant PT was 74.6%, 16.1% and 9.3%, respectively, and the recurrence rate of PT was 12.8%, and recurrence was related to the grade, atypia, cellularity and permeative borders. The histogenesis of fibroepithelial tumors of the breast is still debatable. PT arises from periductal stromal cells, and the stro- ma of PT shows positive reaction for vimentin, a variable reac- tion for actin, CD34 and desmin, and a negative reaction for S- 100 protein. Ultrastructurally, the stromal cells of PT are com- posed of cells with features of both fibroblasts and myofibrob- lasts. These stromal cells resemble the normal mammary stromal cells. 8 The combined expression of CD34 and bcl-2 in fibroade- nomas, PT and pseudoangiomatous hyperplasia suggests that theses lesions may arise from long-lived bcl-2-positive mesenchy- mal cells in the breast. 9 According to Sawyer et al. 6 the overex- pression of c-kit contributes to the growth of malignant PT, and c-kit may also be a new therapeutic target for patients with PT. CD10 was recently found to be consistently positive in normal breast myoepithelial cells, 10,11 and CD10 may be a use- ful adjuvant in assessing the malignancy of the fibroepithelial lesions of the breast. 10 The proliferating activity, as determined by PCNA and Ki- 67 immunostaining, did not reveal significant differences bet- ween PT and fibroadenoma. 5 Yet the p53 protein and Ki-67 antigen expressions are correlated with the histological grade of PT, 2,12 and stromal Ki-67 and p53 positivity are more often asso- ciated with high-grade tumors. 12 The Ki-67 expression may assist in distinguishing benign from malignant PT in diagnos-

Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

  • Upload
    others

  • View
    4

  • Download
    0

Embed Size (px)

Citation preview

Page 1: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

151

The Korean Journal of Pathology2008; 42: 151-6

Background : The aim of the study is to evaluate the difference of immunophenotypes ofstromal cells between the pure phyllodes tumor (PT) type and the co-existent type of phyllodestumor and fibroadenoma, and between benign and malignant PT. Methods : Immunohisto-chemical staining for actin, CD34, CD10, c-kit, bcl-2, p53 and MIB-1 was performed using tis-sue microarray blocks that contained 25 cases of pure PT (16 benign tumors, 4, borderlinemalignant tumors, and 5 malignant tumors) and 6 cases of co-existent type. Results : Theexpression rates of CD34 and MIB-1 in the pure PT type were significantly higher and theexpression rate of actin in the pure PT was significantly lower than that of the co-existent type.However, there were no significant differences in the bcl-2, CD10, and p53 expressions bet-ween the pure PT type and the co-existent type, and no c-kit expression was observed inboth types. No significant differences in the CD34, actin, bcl-2, CD10, and p53 expressionsbetween the benign and borderline/malignant PT cases were found. However, a significantdifference of the MIB-1 expression rate was noted. Conclusions : The stromal cells of thepure PT type are regarded as less mature myofibroblasts, and the CD10 reactivity in somephyllodes tumors suggests a myoepithelial origin. The MIB-1 labeling index would be usefulfor the grading of phyllodes tumor.

Key Words : Immunohistochemistry; Phyllodes tumor; Breast

Joo Yeon Song∙∙Hye-Kyoung Yoon

151

Immunohistochemical Phenotypes of Phyllodes Tumor of the Breast

151 151

Corresponding AuthorHye-Kyoung Yoon, M.D.Department of Pathology, Pusan Paik Hospital, College of Medicine, Inje University, 633-165Gaegeum-dong, Busanjin-gu, Busan 614-735, KoreaTel: 051-890-6628Fax: 051-891-1834E-mail: [email protected]

*This work was supported by the 2005 Inje Universityresearch grant.

Department of Pathology, Pusan PaikHospital, College of Medicine, Inje University, Busan, Korea

Received : November 1, 2007Accepted : May 23, 2008

Fibroadenoma and benign phyllodes tumor (PT) are twocommon types of fibroepithelial tumors of the breast. PT showspredominantly shows a fibroadenomatous architecture with morecellular stroma and some distortion and elongation of its glan-dular elements.1,2 Fibroadenoma and PT are usually not diffi-cult to differentiate,2 but areas of fibroadenoma and PT have co-existed within a single nodule in some cases, and evidence oftransition evidence from fibroadenoma to PT could be found.

PT shows unpredictable behavior,3 and the biologic behaviorof this tumor cannot be predicted with certainty on the basis ofonly the morphologic criteria only.1,4 The stroma of this tumorcan undergo malignant progression to sarcoma. The frequencyof malignant progression varies in different series from 5% to30%.5 The histological distinction between benign and malig-nant PT is often difficult and arbitrary.6 The stromal cellularity,stromal cellular atypism, high mitotic activity, infiltrative tumorcontour and heterologous stromal elements were reported to bethe significant features of the malignant PT. According to Tanet al.,7 the relative incidence of benign, borderline and malig-nant PT was 74.6%, 16.1% and 9.3%, respectively, and therecurrence rate of PT was 12.8%, and recurrence was related tothe grade, atypia, cellularity and permeative borders.

The histogenesis of fibroepithelial tumors of the breast is still

debatable. PT arises from periductal stromal cells, and the stro-ma of PT shows positive reaction for vimentin, a variable reac-tion for actin, CD34 and desmin, and a negative reaction for S-100 protein. Ultrastructurally, the stromal cells of PT are com-posed of cells with features of both fibroblasts and myofibrob-lasts. These stromal cells resemble the normal mammary stromalcells.8 The combined expression of CD34 and bcl-2 in fibroade-nomas, PT and pseudoangiomatous hyperplasia suggests thattheses lesions may arise from long-lived bcl-2-positive mesenchy-mal cells in the breast.9 According to Sawyer et al.6 the overex-pression of c-kit contributes to the growth of malignant PT,and c-kit may also be a new therapeutic target for patients withPT. CD10 was recently found to be consistently positive innormal breast myoepithelial cells,10,11 and CD10 may be a use-ful adjuvant in assessing the malignancy of the fibroepitheliallesions of the breast.10

The proliferating activity, as determined by PCNA and Ki-67 immunostaining, did not reveal significant differences bet-ween PT and fibroadenoma.5 Yet the p53 protein and Ki-67antigen expressions are correlated with the histological grade ofPT,2,12 and stromal Ki-67 and p53 positivity are more often asso-ciated with high-grade tumors.12 The Ki-67 expression mayassist in distinguishing benign from malignant PT in diagnos-

Page 2: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

152 Joo Yeon Song∙Hye-Kyoung Yoon

tically difficult cases.3 However, neither Ki-67 nor p53 can reli-ably predict recurrences.6

The aim of the study is to evaluate the difference of the im-munophenotype of the stromal cells in the pure PT type andthe co-existent type, and to evaluate the differential featuresbetween the pure PT type, the benign to malignant categoriesof PT and the co-existent type. The utility of CD34 and bcl-2to define a histogenesis from long-lived mesenchymal cells, theutility of actin for defining a smooth muscle origin, the utilityof c-kit as a malignant PT marker, and the utility of CD10 foridentifying human breast myoepithelial cells and to assess malig-nancy of the fibroepithelial lesions were all examined. Evalua-tions for Ki-67 and p53 expressions were performed to deter-mine their usefulness for making the differential diagnosis bet-ween the pure PT type and the co-existent type, and betweenthe benign and malignant PT.

MATERIALS AND METHODS

Materials

Those fibroepithelial lesions of the breast, and especially thecellular fibroadenomas and PT that were seen during the recent10 years at Pusan Paik Hospital were reviewed, and 31 cases ofPT were selected.

Histopathological review

First, the presence of fibroadenoma component was evaluat-ed microscopically, and then the 31 cases were sub-classifiedinto the pure PT type, which consisted of only the PT compo-nent only, and the co-existent type that showed mixed featuresof PT and fibroadenoma. The next step was microscopical eval-uation of the stromal cells, that is, the cellularity (mild, moder-ate, marked), cytologic atypia (mild, moderate, marked) andmitotic count per 10 HPF. The cases of pure PT type were cat-egorized into benign, borderline, and malignant.8 The mostimportant diagnostic criterion for discriminating between benign,borderline and malignant PT was the mitotic count: less than2, between 2 and 4, and more than 5 per 10 HPF, respectively.The cytologic atypia or cellularity was also considered, and thecases that showing 2 and 4 mitoses per 10 HPF and conspicu-ous cytologic atypia or markedly increased cellularity were up-graded into malignant PT.

Immunohistochemical study

Four tissue microarray blocks were made, and seven or moresections from each block were obtained. The slides were dewax-ed and rehydrated in a graded series of alcohol solutions. Anti-gen retrieval was performed using microwave treatment in 10mMol/L citrate buffer for 10 min. Immunohistochemical stain-ing was performed using an automated system (Techmate 1000,DAKO, Glostrup, Denmark) and a LSAB (labelled streptavidinbiotin) kit (DAKO). The primary antibodies and their dilutiontiters were as follows; smooth muscle actin (DAKO), CD34(Neomark, Fremount, USA, 1: 300), CD10 (Novocastra, New-castle, UK, 1:100), c-kit (Santa Cruz, Santa cruz, USA, 1:200),p53 (DAKO, 1:50), bcl-2 (DAKO, 1:50) and MIB-1 (Zymed,South San Francisco, CA, USA, 1:100). The chromogen was AEC,and the slides were counterstained with Mayer’s hematoxylin.

The immunostains for smooth muscle actin, CD34, CD10,c-kit and bcl-2 were interpreted as positive if more than 10%of the stromal cells showed a cytoplasmic expression. The p53and MIB-1 immunostains were interpreted as positive if morethan 5% of the nuclei of the stromal cells were reactive.

Statisitical analysis

The differences of the expression rates of smooth muscle actin,CD34, CD10, c-kit, bcl-2, p53 and MIB-1 between the purePT type and the co-existent type and between the benign andborderline/malignant PT were analyzed using 2 tests. p-values<0.05 were considered statistically significant. All of the statis-tical tests were performed with MedCalc� Version 8.2.0.3.

RESULTS

Histologic findings

Among the 31 cases, 25 cases were the pure PT type and 6cases were the co-existent type. The pure PT type was catego-rized to 16 benign cases, 4 borderline malignancy cases and 5malignant cases.

Immunohistochemical findings

Comparison between the pure phyllodes tumor type and

the co-existent type

In the pure PT type, diffuse positive reaction for CD34 was

Page 3: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

Immunohistochemical Phenotypes of Phyllodes Tumor 153

noted in 15 (62.5%) of 25 cases, but none of the co-existent typeshowed a positive reaction for CD34. In the 25 cases of the purePT type, 14 (56.0%) cases showed a diffuse positive reactionfor actin, in contrast, all the cases of the co-existent type revealeda positive reaction for actin. The expression rates of CD34 andactin of the pure PT type and the co-existent type showed sta-tistically significant differences (p=0.0260, p=0.0267) (Fig. 1).

A positive reaction for CD10 was found in 15 (60.0%) of the25 pure PT types, and in 4 (66.7%) of the 6 co-existent type.Two (8.0%) cases of the pure PT type showed a positive reac-tion for bcl-2, but all the co-existent cases revealed a negativereaction for bcl-2. No significant differences of the CD10 andbcl-2 expressions between the pure PT type and the co-existenttype were found (p=0.3109, p=0.6912). All of the 25 pure PTtype and 6 of the co-existent type showed a negative reactionfor c-kit (Fig. 2).

A positive reaction for p53 was noted in one (4.8%) of the21 pure PT types and in one (20.0%) of the 5 co-existent types.No significant difference of the p53 expression between purethe PT type and the co-existent type was found (p=0.5448). AMIB-1 reaction was negative in 21 cases and positive in 4 (16.0%) cases of the 25 pure PT types, respectively. All of the six co-existent types showed a negative reaction for MIB-1, and a sig-nificant difference of the MIB-1 expressions between the pure

PT type and the co-existent type was noted (p=0.0041) (Table1, Fig. 3).

Comparison of immunophenotype between the benign and

borderline/malignant phyllodes tumor

A positive reaction for CD34 was noted in 11 (63.8%) of the16 cases of the benign category in contrast, a positive reactionfor CD34 was noted in 4 (50.0%) of the 8 cases of the border-line and malignant categories. A positive reaction for actin wasnoted in 11 (63.8%) of the 16 cases of the benign category andin 3 (33.3%) of the 9 cases of the borderline and malignant cat-egories, respectively A positive reaction for CD10 was noted in8 (50.0%) of the 16 cases of the benign category in contrast, apositive reaction for CD10 was noted in 7 (77.8%) of the 9 casesof the borderline and malignant categories. A positive reactionfor bcl-2 was noted in 1 (5.3%) of the 16 cases of the benigncategory, and in 1 (11.1%) of the 9 cases of the borderline andmalignant categories, respectively. No significant differences ofthe CD34, actin, bcl-2 and CD10 expressions between the benignand borderline/malignant PT categories were found (p=0.2694,p=0.1961, p=0.3495, p=0.7354).

A positive reaction for p53 was not noted in the 14 availablebenign PT cases, but one (14.3%) of the 7 borderline and malig-nant PT cases showed a positive reaction for p53. None of the

Fig. 2. Immunohistochemical stains for CD10, bcl-2, and c-kit. Inthe pure phyllodes tumor type, the stromal cells reveal positivereaction for CD10 (A) but negative reaction for CD10 in the co-existent type (B). Positive reaction for bcl-2 (C) and negative reac-tion for c-kit (D) are seen in the pure phyllodes tumor type.

Fig. 1. Immunohistochemical stains for CD34 and actin. In the purephyllodes tumor type, the stromal cells reveal positive reaction forCD34 (A), but negative reaction for CD34 in the co-existent type(B). Negative reaction for actin (C) in the pure phyllodes tumortype and positive reaction for actin (D) in the co-existent type areobserved.

A B

C D

A B

C D

Page 4: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

benign PT showed a positive reaction for MIB-1 (more than5%), but four (44.4%) of the 9 cases of borderline and malig-nant PT revealed a positive reaction for MIB-1. No significantdifference of the p53 expression between the benign and bor-derline/malignant PT was noted (p=0.2956), however therewas a significant difference of the MIB-1 expression betweenthe benign and borderline/malignant PT (p=0.0192) (Table 2).

DISCUSSION

The stromal cells of fibroadenomas, PT and pseudoangioma-tous hyperplasia showed CD34 and bcl-2 expressions, whichsuggests that theses lesions may arise from long-lived bcl-2 pos-itive mesenchymal cells in the breast. The CD34 immunoreac-tivity of PT could be useful in some situations for the distin-guishing of malignant PT from spindle cell carcinomas.9 Thebcl-2 positivity of PT may be helpful, to a lesser extent, for dif-ferentiating the PT and fibromatosis from metaplastic sarco-matoid carcinomas to a lesser extent.13 It was reported that a c-kit overexpression contributes to the growth of malignant PT,and c-kit may also be a new therapeutic target in PT.6 Accord-ing to Chen et al.14 a CD34 expression was associated with benignPT, while c-kit and actin were preferentially expressed in malig-nant PT, so CD34 and CD117 might be used for the histopatho-

154 Joo Yeon Song∙Hye-Kyoung Yoon

Fig. 3. Immunohistochemical stains for P53 and MIB-1 in the malig-nant phyllodes tumor. In the pure phyllodes tumor type, the stro-mal cells reveal positive reaction for p53 (A) and more than 5% ofMIB-1 labelling index (B).

No. of cases (%)

Benign PTBorderline &malignant PT

p-value

CD34Negative 5 (36.2) 4 (50.0)Positive 11 (63.8) 4 (50.0) 0.2694

ActinNegative 5 (31.2) 6 (66.7)Positive 11 (68.8) 3 (33.3) 0.1961

CD10Negative 8 (50.0) 2 (22.2)Positive 8 (50.0) 7 (77.8) 0.3495

bcl-2Negative 15 (93.8) 8 (88.9)Positive 1 (6.2) 1 (11.1) 0.7354

p53Negative 14 (100.0) 6 (85.7)Positive 0 (0.0) 1 (14.3) 0.2966

MIB-1Negative 16 (100.0) 5 (55.6)Positive 0 (0.0) 4 (44.4) 0.0192

PT, phyllodes tumor.

Table 2. Comparison of immunophenotypes of stromal cellsbetween the benign and borderline and malignant phyllodestumor of the breast

No. of cases (%)

Co-existent type

Pure PT type

p-value

CD34Negative 6 (100.0) 9 (37.5)Positive 0 (0.0) 15 (62.5) 0.0260

ActinNegative 0 (0.0) 11 (44.0)Positive 6 (100) 14 (56.0) 0.0267

CD10Negative 2 (33.3) 10 (40.0)Positive 4 (66.7) 15 (60.0) 0.3109

bcl-2Negative 6 (100) 23 (92.0)Positive 0 (0) 2 (8.0) 0.6912

p53Negative 4 (80.0) 20 (95.2)Positive 1 (20.0) 1 (4.8) 0.5448

MIB-1Negative 6 (100.0) 21 (84.0)Positive 0 (0.0) 4 (16.0) 0.0041

Co-existent type, showing features of both fibroadenoma and phyllodestumor; PT, phyllodes tumor.

Table 1. Comparison of immunophenotypes of stromal cellsbetween the co-existent type and the pure type of phyllodestumors of the breast

A B

Page 5: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

logical grading of PT. In this study, all of the cases of the co-existent type revealed a

positive reaction for actin, but there was a negative reaction forCD34 in the stromal cells in contrast, 14 (56.0%) and 15 (62.5%) of the 25 PT cases showed positive reaction for actin andCD34, respectively. The positive reaction for actin was decreasedin the borderline and malignant PT (33.3%) compared withthe benign PT (63.8%). And none of the 25 pure PT type casesand 6 cases of the co-existent type showed a positive reactionfor c-kit in this study. Our CD34 immunostaining findingswere consistent compared with the results of Chen et al.,14 butthe immunostainings for c-kit and actin were different. Ourresults indicate that the stromal cells of the pure PT type andthe co-existent type are different for their histogenesis, and theorigin of the pure PT type might be the more primitive mes-enchymal cells, as compared with the co-existent type. Howev-er, immunostain for CD34 cannot be used as a reliable factorfor determining the malignancy of PT, based on the lack of sig-nificant differences of the CD34 expression between the benignPT (63.8%) and the borderline and malignant PT (50.0%).

For the bcl-2 immunostaining, all of the co-existent typerevealed negative reactions and two (8.0%) of the pure PT typeshowed a positive reaction. The low expression rate for bcl-2 inthe pure PT type suggests the uncertain role of apoptosis in thetumorigenesis of PT. There was no significant difference of thebcl-2 expression between the benign PT (5.3%) and the bor-derline and malignant PT (11.1%), which indicates that thebcl-2 expression might not be a determining factor for the malig-nancy of PT.

CD10 is also called common acute lymphoblastic leukemiaantigen (CALLA), and this was recently found to be consistent-ly positive in normal breast myoepithelial cells.10,11 Tse et al.10

reported that the stromal CD10 expression was increased in theborderline or obviously malignant PT, compared with those offibroadenoma or benign PT, and they suggested that the stro-mal CD10 expression had a high specificity for differentiatingbetween benign lesions (fibroadenoma and benign PT) and bor-derline or malignant PT. However, there were no significantdifferences of CD10 immunoreactivity between the co-existenttype and the pure PT type in this study. More than a 60% ofCD10 expression rate in both the co-existent type and the purePT type suggests a myoepithelial origin of both the co-existenttype and the pure PT type. In addition, the lack of significantdifferences of CD10 immunoreactivity between the benign andborderline types and the malignant PT in this study indicatethat CD10 immunostaining is not a reliable tool for determin-

ing the malignancy of PT. There was no correlation between the diameter of tumors and

the proliferating activity for PT and fibroadenoma. The prolif-erating activity, as determined by immunohistochemistry withPCNA and Ki-67 antibodies, did not reveal significant differ-ences between PT and fibroadenoma.5 In this study, six cases ofthe co-existent type showed a negative reaction for MIB-1 incontrast, 4 (16.0%) of the 25 cases of the pure PT type were pos-itive for MIB-1. Immunostaining for p53 showed a positivereaction in one (20.0%) of 5 cases of the co-existent type and inone (4.0%) case of the 25 pure PT type. These results suggestthat the MIB-1 expression might be helpful to differentiate thepure PT type from the co-existent type, but p53 immunostainwas not useful for the discrimination of both types.

For PT, the p53 protein and Ki-67 antigen expressions arecorrelated with the histology grading,15 and stromal Ki-67 andp53 positivity are more often associated with high-grade tumors.1

Positive reactions for Ki-67 and p53 in the stroma and epithe-lium of the majority of PT cases support the existence of epithe-lial-stromal interactions and the epithelium has been determin-ed to be an integral part of this tumor.1 The Ki-67 and PCNAexpressions in the PT have been suggested to be a markers ofstromal element proliferation.1 The Ki-67 expression may assistin distinguishing benign from malignant PT in the diagnosti-cally difficult cases.3 The malignant PT was stained positivelywith p53 and Ki-67, but all the cases of benign PT were nega-tively stained for p53 and Ki-67, which suggest that p53 andKi-67 can play an important roles in predicting the prognosisand for possibly employing additional therapy, besides the roleof the conventional prognostic factors, in the treatment of thePT patients.2 For patients with tumors with benign morpholo-gy, but more than a 10% of Ki-67 labelling index, it is neces-sary to properly treat and follow up these patients to avoid recur-rence and malignant transformation.16 The histological type ofPT forms the basis for predicting the prognosis of the clinicaloutcome, and the Ki-67 index is a valuable prognostic factorfor patients with the malignant variant of PT of the breast.4 Theincompletely excised tumors that recurred displayed high pro-liferative activity in their primary tumors. Progression towardthe more malignant phenotype in the recurrent PT was accom-panied with increased in the proliferative activity, suggestingthe presence of biological continuity between the benign, bor-derline, and malignant PT.17 In this study, the MIB-1 reactionwas negative in 16 benign PTs, but 4 (44.4%) of the 9 border-line/malignant PTs were positive for MIB-1. These results arevery similar to those of a previous report,2 and they suggest that

Immunohistochemical Phenotypes of Phyllodes Tumor 155

Page 6: Immunohistochemical Phenotypes of Phyllodes Tumor of the … · 2015-01-27 · Immunohistochemical Phenotypes of Phyllodes Tumor 153 noted in 15 (62.5%) of 25 cases, but none of the

the MIB-1 expression could be a useful tool to distinguish thedifferentiation of diagnostically difficult PT cases.

The p53 expression tends to be more frequent in the PT witha higher malignant potential, but this can not predict recurrence.Tse et al.11 reported that microvessel density and p53 are usefulas independent criteria for evaluating the malignancy of PT.The expression of the p53 protein in tumor cells could also bealso useful when the percentage of cells and the intensity of thep53 expression are considered.4 According to Kleer et al.,3 nei-ther Ki-67 nor p53 can reliably predict recurrences of PT. Inthis study, all of the 14 available benign PTs showed a negativereaction for p53, and 1 (14.3%) of 7 borderline and malignantPTs revealed a positive reaction. The p53 expression is not regard-ed as a reliable parameter for determining the malignancy of PT.

In summary, the origin of stromal cells in the co-existent typeseems to be the actin-positive, more mature mesenchymal cellsin contrast, the origin of the pure PT might be the less mature,primitive myofibroblastic cells. These findings suggest that thestromal cells of the pure PT type and the co-existent type aredifferent in their differentiation. However, more than 60% ofCD10 expression in both co-existent and pure PT types sug-gests a myoepithelial origin of stromal cells both types. In addi-tions, c-kit might not be involved in the tumorigenesis of PT,and the roles of p53 and bcl-2, as related to apoptosis, could notbe clarified. The MIB-1 expression is a useful tool for determin-ing the grading of PT, but immunostains for CD34, actin, bcl-2,CD10 and p53 are not reliable factors for determining the malig-nant progression of PT.

REFERENCES

1. Dacic S, Kounelis S, Kouri E, Jones MW. Immunohistochemical

profile of cystosarcoma phyllodes of the breast: a study of 23 cases.

Breast J 2002; 8: 376-81.

2. Erhan Y, Zekioglu O, Ersoy O, et al. p53 and Ki-67 expression as prog-

nostic factors in cystosarcoma phyllodes. Breast J 2002; 8: 38-44.

3. Kleer CG, Giordano TJ, Braun T, Oberman HA. Pathologic, immuno-

histochemical, and molecular features of benign and malignant

phyllodes tumors of the breast. Mod Pathol 2001; 14: 185-90.

4. Niezabitowski A, Lackowska B, Rys J, et al. Prognostic evaluation

of proliferative activity and DNA content in the phyllodes tumor

of the breast: immunohistochemical and flow cytometric study of

118 cases. Breast Cancer Res Treat 2001; 65: 77-85.

5. Kaya R, Pestereli HE, Erdogan G, Gulkesen KH, Karaveli S. Prolif-

erating activity in differential diagnosis of benign phyllodes tumor

and cellular fibroadenomas: is it helpful? Pathol Oncol Res 2001; 7:

213-6.

6. Sawyer EJ, Poulsom R, Hunt FT, et al. Malignant phyllodes tumours

show stromal overexpression of c-myc and c-kit. J Pathol 2003; 200:

59-64.

7. Tan PH, Jayabaskar T, Yip G, et al. p53 and c-kit (CD117) protein

expression as prognostic indicators in breast phyllodes tumors: a

tissue microarray study. Mod Pathol 2005; 18: 1527-34.

8. Rosen PP. Rosen’s breast pathology. 2nd ed. Philadelphia: Lippin-

cott Williams & Wilkins, 2001; 176-94.

9. Moore T, Lee AH. Expression of CD34 and bcl-2 in phyllodes tu-

mours, fibroadenomas and spindle cell lesions of the breast. Histo-

pathology 2001; 38: 62-7.

10. Tse GM, Tsang AK, Putti TC, et al. Stromal CD10 expression in

mammary fibroadenomas and phyllodes tumours. J Clin Pathol

2005; 58: 185-9.

11. Moritani S, Kushima R, Sugihara H, Bamba M, Kobayashi TK, Hat-

tori T. Availability of CD10 immunohistochemistry as a marker of

breast myoepithelial cells on paraffin sections. Mod Pathol 2002;

15: 397-405.

12. Tse GM, Lui PC, Scolyer RA, et al. Tumour angiogenesis and p53

protein expression in mammary phyllodes tumors. Mod Pathol

2003; 16: 1007-13.

13. Dunne B, Lee AH, Pinder SE, Bell JA, Ellis IO. An immunohistochemi-

cal study of metaplastic spindle cell carcinoma, phyllodes tumor

and fibromatosis of the breast. Hum Pathol 2003; 34: 1009-15.

14. Chen CM, Chen CJ, Chang CL, Shyu JS, Hsieh HF, Harn HJ. CD34,

CD117, and actin expression in phyllodes tumor of the breast. J Surg

Res 2000; 94: 84-91.

15. Barwijuk-Machala M, Musiatowicz B, Cylwik J, Reszec J, Augusty-

nowicz A. AgNOR, Ki-67 and PCNA expression in fibroepithelial

tumours of the breast in correlation with morphological features.

Folia Morphol 2004; 63: 133-5.

16. Chan YJ, Chen BF, Chang CL, Yang TL, Fan CC. Expression of p53

protein and Ki-67 antigen in phyllodes tumor of the breast. J Chin

Med Assoc 2004; 67: 3-8.

17. Shpitz B, Bomstein Y, Sternberg A, et al. Immunoreactivity of p53,

Ki-67, and c-erbB-2 in phyllodes tumors of the breast in correlation

with clinical and morphologic features. J Surg Oncol 2002; 79: 86-92.

156 Joo Yeon Song∙Hye-Kyoung Yoon