Borderline Phyllodes Tumors Research Articles

Increased p53 Protein Expression in Malignant Mammary Phyllodes Tumors

The authors reviewed 143 cases (87 benign, 37 borderline, and 19 malignant) of mammary phyllodes tumors (PTs) and used immunohistochemistry to detect p53 protein product semi-quantitatively as negative, weak, moderate and strong (scored 0 to 3). For all PTs, an increasing trend of tumor size and malignancy was detected with increasing age. For p53 staining, 60 cases (42%) were negative, 55 (38%) stained weakly, 28 (13%) stained moderately, and 10 (7%) stained strongly. Of the 87 benign PTs, 41 (47%) were negative, 37 (43%) stained weakly, and 9 (10%) stained moderately. For the 37 borderline PTs, 16 (43%) were negative, 14 (38%) stained weakly, 6 (16%) stained moderately, and 1 (3%) stained strongly. Of the 19 malignant PTs, 3 (16%) were negative, 4 (21%) stained weakly, 3 (16%) stained moderately, and 9 (47%) stained strongly. The mean intensity score for p53 staining increased progressively from benign to borderline to malignant PT, with established statistical significance (P < .0001). This is significantly correlated with mitotic count but not stromal cellularity, pleomorphism, margin, and stromal overgrowth. When considering strong staining alone (score, 3), 47% of malignant, 3% of borderline, and none of the benign PTs were positive. The use of strong positive staining for diagnosing malignant PT gave positive and negative predictive values, specificity, and sensitivity of 90%, 92.5%, 99%, and 47%, respectively. Thus diffuse strong p53 protein staining can be used as a soft sign in assisting the diagnosis of malignant PT. Conversely, negative or weak staining of p53 protein in PT is of little discriminatory value. The role of p53 gene mutation in the malignant transformation of PT is unclear; but this may not be the sole mechanism as many malignant PT were p53 protein negative.

Expression of c-kit protein in proliferative lesions of human breast: sexual difference and close association with phosphotyrosine status.

The c-kit gene which codes transmembrane tyrosine kinase receptor protein plays an important role in several types of normal and/or neoplastic human tissues. We examined the expression patterns of c-kit protein in proliferative lesions of human breast tissues in both sexes. The localization of c-kit protein was examined immunohistochemically in human breast, consisting of 366 normal tissue, 156 benign lesions (fibroadenoma, fibrocystic change, intraductal papilloma, benign phyllodes tumor, and gynecomastia), 13 borderline diseases (atypical ductal hyperplasia, atypical lobular hyperplasia, and borderline malignant phyllodes tumor), and 197 malignant lesions (non-invasive and/or invasive ductal carcinoma and malignant phyllodes tumor). In normal tissues and benign proliferative lesions, c-kit product was consistently detected on epithelial cell membranes and/or cytoplasms regardless of gender difference. In contrast, we failed to find c-kit product in female borderline epithelial lesions, including atypical lobular hyperplasia, or in female malignant lesions, except for two carcinomas. In situ hybridization analysis of c-kit mRNA in female tissues gave results comparable to those obtained by immunohistochemistry. On the other hand, c-kit product was consistently detected in male benign and malignant proliferative lesions. Apart from the female breast carcinomas which lacked c-kit, c-kit expression was almost always accompanied by positivity for phosphotyrosine in the breast tissues examined, suggesting possible phosphorylation of tyrosine residues of the c-kit receptor protein. Loss of c-kit product was related to malignant transformation in female breast, but not in the case of male breast. We suggest that the oncogenesis pathway of breast epithelium is different between males and females in terms of c-kit expression.

Immunoreactivity of p53, Ki-67, and c-erbB-2 in phyllodes tumors of the breast in correlation with clinical and morphologic features.

Phyllodes tumor (PT) is a biphasic tumor with unpredictable behavior. Our study aimed to evaluate clinicopathologic factors and biomarkers that may be helpful in predicting the outcome of these tumors. We evaluated immunoreactivity of p53, c-erbB-2, and Ki-67 in 23 PT treated over a 10-year period. The proliferative activity in PT and expression of p53 and c-erbB-2 were correlated with clinicopathologic features of the tumors and patients' outcome. Positive stromal p53 immunoreactivity was found in PT with atypia, infiltrative borders, high cellularity, as well as in PT that displayed higher then average proliferation index, although none of these parameters reached statistical significance. There was a good correlation between proliferative stromal cell activity expressed Ki-67-labeling index and the malignant features of the tumors. Primary tumors that recurred displayed high proliferative activity. Three of four recurrent tumors showed a progression toward higher malignant phenotype with concomitant increase in proliferative stromal cell activity. c-erbB-2-positive tumors had no particular histologic features or association with either p53 positivity or higher proliferative indices. p53 expression tends to be more frequent in PT with higher malignant potential but did not predict recurrence. Incompletely excised tumors that recurred displayed high proliferative activity in their primary tumors. Progression toward more malignant phenotype in the recurrent PT was accompanied with increase in stromal cell proliferative activity, suggesting the presence of biological continuity between benign, borderline, and malignant PT.

Increased microvessel density in malignant and borderline mammary phyllodes tumours.

Tumour vascularity is considered a prognostic indicator in breast carcinoma, but its utility in mammary phyllodes tumour has not been explored. The authors report the correlation between intratumoral microvessel density and the histological grade of phyllodes tumour. Forty cases of phyllodes tumour were reviewed for stromal cellularity, overgrowth, cytological pleomorphism, mitotic count and margin pattern. Using established criteria, these were diagnosed as benign (n=28), borderline (n=10) and malignant (n=2). Microvessel density was counted on CD31-stained slides as the number of vessels per high power field. For benign phyllodes tumour, the range was 7-26.2 (mean 13.1); for borderline phyllodes tumour the range was 17.2-32.5 (mean 22.4); for malignant phyllodes tumour the range was 25.9-33.3 (mean 29.6). The difference between the benign and borderline groups was significant (P < 0.0001) but that between the borderline and malignant groups was not, due to the small number of malignant cases. There is a significant difference in stromal microvessel density between benign and borderline phyllodes tumour. Although the small number of cases of malignant phyllodes tumour limits further interpretation, we believe that microvessel density can be used as an additional objective histological parameter in the evaluation of phyllodes tumour.

Phyllodes Tumor of the Breast

To study the cytologic features of phyllodes tumor (PT) of the breast and determine the accuracy of their subclassification in fine needle aspirates. Eighty cases of histologically diagnosed PT between 1982 and 1997 with a previous fine needle aspiration (FNA) were evaluated. The FNA smears of each case were reviewed without knowledge of the initial cytologic diagnosis and subclassified into benign, borderline or malignant PT. Benign PTs were characterized by a dimorphic mixture of stromal and epithelial cells. The stromal fragments showed mild to moderate cellularity with absent to minimal pleomorphism and no mitosis. There were occasional, if any, single stromal cells. Borderline PTs had stromal fragments with moderately cellular stroma exhibiting moderate pleomorphism. Two additional features were the presence of single stromal cells and an occasional mitosis in the stromal fragments/single cells. Aspirates from malignant PT were very cellular, with a high stromal/epithelial ratio and marked stromal cellularity. The stromal cells were highly pleomorphic, with frequent mitosis and atypical single stromal cells in the background. Fifty-seven of the 80 histologically documented cases (71.3%) were diagnosed as PT on FNA (40 benign, 10 borderline and 7 malignant). In 81% (46 of 57 PTs), good cytohistologic correlation (32 benign, 8 borderline and 6 malignant) was observed. In another eight cases, one grade differentiation between cytologic and histologic grade was observed. Six of the nine malignant PTs on histology were correctly subclassified on cytology. There were one false positive and two false negative cases. Cytologic diagnosis and grading of PT on FNA is possible. Special care should be undertaken in interpreting phyllodes fragments, cellularity of stroma, pleomorphism and mitosis. Single stromal cells are also important morphologic criteria for subclassification. Multiple-site aspiration is advisable to avoid diagnostic errors.

Histologic features predict local recurrence after breast conserving therapy of phyllodes tumors.

Pathologists can distinguish benign phyllodes tumors, which very rarely metastasize, from malignant phyllodes tumors, which metastasize in approximately one fourth of patients. However, whether these same histologic criteria can be used to predict the likelihood that a phyllodes tumor will locally recur after breast conserving therapy remains controversial. Since few patients with malignant phyllodes tumors have been treated with breast conserving surgery in any individual series, the literature was reviewed using a Medline search. After local excision, 21% (111/540), 46% (18/39), and 65% (26/40) of patients with benign, borderline, and malignant phyllodes tumors, respectively, recurred in the breast. Following wide local excision, 8% (17/212), 29% (20/68), and 36% (16/45) of patients with benign, borderline, and malignant phyllodes tumors recurred in the breast. Malignant phyllodes tumors are much more likely than benign phyllodes tumors to recur in the breast after breast conserving surgery. This high rate of local recurrence of borderline and malignant phyllodes tumors suggests that wide local excision is less than optimal therapy, and challenges us to look for methods to improve local tumor control.

P53 expression in phyllodes tumours is associated with histological features of malignancy but does not predict outcome.

To study p53 protein expression in phyllodes tumours of the breast, with particular attention to its prevalence and to its relationship with histological features and clinical outcome. Stromal and epithelial p53 immunohistochemical expression was studied in 57 phyllodes tumours (27 benign, 17 borderline, 13 malignant) using an avidin-biotin peroxidase method. High levels of expression (> 30% of stromal nuclei) were found in eight phyllodes tumours (14%). p53 expression was associated with tumour grade (P = 0.001), prominent stromal overgrowth (P = 0.0003), prominent stromal nuclear pleomorphism (P = 0.006), high stromal mitotic count (P = 0.05), and an infiltrative tumour margin (P = 0. 05). Six patients were lost to follow-up after surgery. Mean follow-up time of the remaining 51 patients was 7.3 years (median 4. 3, range 0.5-25) or until death. Sixteen patients (31%) experienced tumour recurrence. Recurrence was more likely if there was an infiltrative tumour margin (P = 0.006) or prominent stromal overgrowth (P = 0.04) but not p53 expression (P = 0.55). A minority of recurrences expressed p53 more extensively than their primary counterparts. There were five tumour-related deaths (10% of patients). Death was associated with high grade (P = 0.0002), prominent stromal overgrowth (P = 0.0001), an infiltrative margin (P = 0.0002), prominent nuclear pleomorphism (P = 0.005), a high mitotic count (P = 0.01) and tumour size (P = 0.03). Again, p53 expression was not associated with tumour-related survival (P = 0. 13). p53 abnormalities occur in a minority of borderline and malignant phyllodes tumours. p53 expression is associated with known negative prognostic factors, but does not appear to be a useful determinant of tumour recurrence or long-term survival.

Phyllodes tumors of the breast: A clinicopathological study of 118 cases

The clinical and pathological features of phyllodes tumors of the breast were evaluated through a study of 118 cases: 110 benign tumors, four borderline tumors, and four malignant tumors. Local excision was utilized in 105 patients (88%) and radical mastectomy was performed in 10 patients (8%) as the initial treatment. Estrogen receptor (ER) status was positive in seven (50%) of 14 cases and progesterone receptor (PgR) status was positive in nine (75%) of 12 cases. Local recurrence developed in eight patients, six of those having benign tumors, and two having malignant tumors, all of whom were treated by local excision. Of the four patients with malignant tumors, one died of lung and liver metastases 47 months after her first operation. We believe that excision with sufficient free margin may be the treatment of choice for most benign or borderline phyllodes tumors, whereas an Auchincloss modified radical mastectomy or a total glandectomy with lymph node dissection is recommended for patients with malignant tumors. However, a number of problems regarding the treatment of patients with distant metastasis remain yet to be addressed.

A CASE OF RECURRENT MALIGNANT PHYLLODES TUMOR OF THE BREAST WITH FEATURES OF MALIGNANT FIBROUS HISTIOCYTOMA

We have encountered a rare case of recurrent malignant phyllodes tumor of the breast with features of malignant fibrous histiocytoma. A 53-year-old woman underwent a resection and transposition of the latissmus dorsi muscle for a benign phyllodes tumor in the breast. Three months later, a painful induration was observed into the wound. Fine-needle aspiration cytology was carried out three times and showed only blood. There was a suspicion of hematoma on ultrasonography and computed tomography. Soon, redness and induration at the punctured skin were observed and thus a biopsy was conducted. Moderate mitotic activity and stromal atypia were revealed and the tumor was diagnosed as borderline phyllodes tumor. Clinically, infiltration into the pectralis major muscle was suspected, and a mastectomy was added to the patient. Histopathologically, spindle shaped cells were arranged in a storiform pattern and tumor cells were pleomorphic with benign duct epithelium. Cellularity and mitotic activity were considered high. The tumor was diagnosed as malignant phyllodes tumor with features of malignant fibrous histiocytoma. Pathological fracture of the humerus occurred 3 months after the operation and metastases to the lung and liver were found. The patient did not respond to chemotherapy and died 8 months after the operation.

The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases.

The study addresses the controversial prognostic and therapeutic aspects of phyllodes tumor of the breast. Records of 170 women with phyllodes tumor of the breast were reviewed. On the basis of the criteria proposed by Azzopardi and Salvadori et al., including estimation of tumor margin, growth of the connective tissue component, mitoses, and cellular atypia, the entire series was divided into three histotypes of phyllodes tumor, i.e., benign (92 cases, 54.1%), borderline (19 cases, 11.2%), and malignant (59 cases, 34.7%). Ninety-eight patients (57.6%) were treated by wide local excision (79 benign, 15 borderline, and 4 malignant), 43 (25.3%) by simple mastectomy (13 benign, 4 borderline, and 26 malignant), and 29 (17.1%) by radical mastectomy (all malignant). Of the 170 treated patients, 141 (82.9%) survived 5 years without evidence of disease. In the Cox multivariate analysis the histotype of the tumor was the only independent prognostic factor: 5-year NED survival was observed in 95.7% of the patients with benign phyllodes tumor, 73.7% with borderline phyllodes tumor, and 66.1% with malignant phyllodes tumor. After a wide local excision 98.7% of the patients with benign tumor, and 80% with borderline tumor, were cured. Local recurrence was found in 14 patients (8.2%) (4 benign, 3 borderline, and 7 malignant); 10 of these underwent reoperation (7 wide local excision, 3 radical mastectomy) and survived 5 years NED. The histotype of phyllodes tumor (benign, borderline, and malignant), assessed on the basis of the criteria proposed by Azzopardi and Salvadori et al., was the only prognostic factor in our group of patients. Based on the data from literature and our own observations, we observed that a wide local excision, with an adequate margin of normal breast tissue, is the preferred initial therapy for phyllodes tumor of the breast.

A Malignant Phyllodes Tumor of the Breast in a 6-Year Old Girl.

We recently encountered a 6-year-old girl with a malignant phyllodes tumor of the breast. The patient's mother noticed a tumor on the right breast of her first doughter at 8 months after from her birth. The baby was brought to the Second Depertment of Surgery, University of Tokushima, at age 20 months. We recommended removal of the 3.5 x 2.9 cm tumor in the right breast, but it was not done. Next, she visited our department at 6 years of age because the tumor had gradually enlarged, reaching a size of 4.3 &timus; 4.0 cm. She underwent excisional resection of the tumor, and the tumor was diagnosed as a malignant phyllodes tumor of the breast coexisting with a borderline phyllodes tumor. To our knowledge, this is the youngest reported case of a malignant phyllodes tumor of the breast. Moreover, the malignant lesion was positive for estrogen receptor (ER) and showed strong proliferating cell nuclear antigen (PCNA) staining. On the other hand, the borderline part was negative for ER and showed weak PCNA staining. Thus, in the present case, the expression of ER, the exposure to estrogen (for example, the mother's estrogen during gestation) and increase in the proliferation rate may have played important roles in the mechanism of the transformation of the phyllodes tumor.

Karyotypic changes in phyllodes tumors of the breast

Cytogenetic analysis of short-term cultures of five phyllodes tumors of the breast-classified as benign (one tumor), borderline malignant (two tumors removed from the same breast in 1991 and 1993), and malignant (two tumors) - revealed clonal changes with simple structural abnormalities in the benign tumor, the borderline malignant tumors, and one malignant tumor in which benign areas and areas of borderline malignancy were also present. In contrast, the malignant tumor without admixed borderline malignant or benign areas had a complex karyotype. The karyotype of the benign phyllodes tumor was 46,XX,del(12)(p11p12)/46,XX,t(8;18)(p11;p11)/46,XX. The first borderline malignant phyllodes tumor had t(3;20)(p21;q13) as the sole abnormality. When the tumor recurred, this was no longer the only clone detected and the tumor karyotype was now 46,XX,t(3;20)(p21;q13)/46,XX,t(9;10)(p22;q22)/46,XX,t(1;8)(p34;q24)/46,XX,del(11)(q22–23)/46,XX. The malignant/borderline malignant/benign tumor had t(1;6)(p34;p22) as the sole clonal abnormality. Finally, the karyotype of the malignant phyllodes tumor which contained no benign or borderline malignant areas was 42,XX,der(1)t(1;4)(q21;q21),der(3)t(3;17)(q29;q21), −4,i(8)(q10), −10, −13,i(13)(q10),der(14)t(1;14)(q21;p11),der(14)t(4;14)(p12;p11), −17/80–90,idemx2, +del(1)(q12), +i(1)(p10), +dic(5;5)(p14;p14), +i(6)(p10), +del(7)(p11), +dup(7)(q11q36), +i(15)(q10),inc/46,XX. The findings indicate some cytogenetic similarities between benign/borderline malignant phyllodes tumors and fibroadenomas of the breast, presumably reflecting similar pathogenetic mechanisms in the two types of mixed-lineage tumors.

A CASE OF MALIGNANT PHYLLODES TUMOR

Phyllodes tumors are fibroepithelial tumors which peculiar to the breast. Among of them, mamlignant phyllodes tumors are rare. This paper presents a case of malignant phyllodes tumor with a 30-year ailing period, together with a review of the literature. A 44-year-old female was admitted to the hospital because of a progressively enlarging which existed for 30 years on the left breast. It was diagnosed as benign-malignant borderline phyllodes tumor by aspiration biopsy cytology. Simple mastectomy with axillary lymph node dissection was performed. Postoperative chemotherapy was done, because pathological diagnosis revealed malignant phyllodes tumor. As phyllodes tumors have a variety of morphology, histology, or biology, prudent studies are needed for making the diagnosis and performing therapies.

Sarcomatoid tumours of the breast in Denmark from 1977 to 1987. A clinicopathological and immunohistochemical study of 100 cases

One hundred sarcomatoid breast tumours, which had been diagnosed and registered in Denmark from January 1977 to January 1987, were subclassified using a combination of conventional morphological evaluation and immunohistochemistry, and the diagnosis was in each case related to clinical follow-up of 5–14 years or until death of the patient. Conventional histological examination resulted in 36 benign, 19 borderline and 18 malignant phyllodes tumours, 1 angiosarcoma and 26 non-specified sarcomatous tumours, 6 with small carcinoma-like foci. Immunohistochemical staining revealed that 23 of the non-phylloid sarcomatous tumours showed a tumour cell reaction for epithelial markers, predominantly cytokeratin and, therefore, the tumours were interpreted as metaplastic carcinomas. Clinical follow-up showed for phyllodes tumours and for the three cytokeratin-negative sarcomatous tumours local recurrence rates of 21 and 33%, respectively, whereas metastases only occurred from the angiosarcoma and from one borderline phyllodes tumour with five recurrences (5%). In contrast, metaplastic carcinomas gave rise to distant metastases in 50% of cases but no local recurrences. Axillary lymph nodes had been examined in 28 cases, 13 from metaplastic carcinomas. Only two of these showed metastatic spread, both with a pattern similar to the primary tumour. The differences in survival between patients with metaplastic carcinoma and patients with a borderline/malignant phyllodes tumour or a cytokeratin-negative sarcomatous tumour has in this study proven to be highly significant ( P < 0.0001), and we find it of importance to use immunohistochemistry in the subclassification of sarcomatous breast tumours for appropriate surgery, reliable prognostic outlook and optimal postoperative therapy.

CYSTOSARCOMA PHYLLODES—ASIAN VARIATIONS

Cystosarcoma phyllodes afflicting 106 female patients in a multiracial Asian society is reviewed and some interesting variations are noted when compared with Western patients. The incidence of phyllodes tumour is 3.83% of surgically removed breast tumours compared with 0.5-2.5% in Western series. This lends weight to the belief that non-Caucasians are more prone to this enigmatic breast disease than the Caucasian population. The profile of the Asian phyllodes patient is that of a young female, aged 25-30 years, whereas her Western counterpart is in her 40s. As a result, she is liable to be mistaken clinically as having fibro-adenoma. The disease is notably rare among the females below 20 years of age but in the Asian context, as much as one-quarter-one-third may be in the adolescent group. There were only three malignant and six borderline phyllodes tumours out of 106 cases, and this incidence is far below that of many other studies in which the malignant cases are believed to constitute 23-27%. However, this may not be a racial variation but explicable by the fact that the present study is an unselected cohort from a general surgical unit. The presence of associated benign breast disease in 25.5% cases helps to reinforce the widely held belief that fibro-adenoma and phyllodes tumour are related to some degree.

Phyllodes tumor (cystosarcoma phyllodes) of the breast. A clinicopathologic study of 45 cases.

The correlation between the histology and biologic behavior of phyllodes tumor was studied in order to establish the histologic criteria of this tumor, particularly its malignant counterpart. A preliminary analysis of five tumors with metastases revealed that a single essential indicator of malignant potential was the presence of a disproportionate overgrowth of the stromal elements at the expense of the ductal element. The presence or absence of such stromal overgrowth in the tumor showed a positive correlation with the degree of stromal atypism and the rate of mitoses. Seventeen out of 45 tumors were determined to be malignant, on the basis of our criteria. The arrangement of the stromal component in malignant phyllodes tumors was usually one of the particular sarcomatous types, with or without the focal areas of one of the specified types of sarcoma. On the other hand, 24 tumors recurred locally but never metastasized, and were preferentially interpreted to be benign phyllodes tumor. Histologically, these tumors had a general architecture resembling that of fibroadenoma but were characterized by high cellularity expressed by the distinct formation of bundles or fascicles of stromal tumor cells. The remaining four tumors seemed to form a borderline phyllodes tumor subset. A follow-up study revealed that, irrespective of the mode of therapy, the outcome of patients with phyllodes tumor was well correlated with the histologic criteria we proposed.