Phyllodes Studies

Found this site from a facebook Phyllodes Support Group.

Found it very informative, albeit bringing sudden sense of panic in me.

But I'm okay now. Nothing that a couple of breath in breat outs couldn't cure:


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Background

The phyllodes tumor, like the fibroadenoma, arises from the intralobular stroma of the breast. Overall, they are rare and all have the potential for metastasis. Thus, these tumors are divided into low-grade and high-grade tumors. The high grade tumors are sometimes referred to as cystosarcoma phyllodes. The vast majority of the tumors, however, are of low-grade behavior. They are variable in size but may grow to be many times larger than most fibroadenomas, sometimes encompassing the entire breast. Grossly, there is lobulation of the tumor as the stroma proliferates resembling a leaf (phyllodes means leaf-like in Greek).

The low grade tumors do have a potential for local recurrence while high grade tumors behave aggressively with increased local recurrence and potential for distant metastasis.

Tumors that do metastasize often do so after a local chest wall recurrence and usually spread to the lungs. Unlike carcinomas of the breast, these tumors spread by blood vessel invasion bypassing the lymph nodes.

OUTLINE

Pathogenesis
Histopathological Features and Variants
Special Stains/
Immunohistochemistry/
Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS CHARACTERIZATION
CELL CYCLE
Progressive Deregulation of the Cell Cycle With Higher Tumor Grade in the Stroma of Breast Phyllodes Tumors


Arno Kuijper, MD, etal. Am J Clin Pathol 2005;123:690-698 Abstract quote

We studied cell cycle–regulating proteins in phyllodes tumor pathogenesis by immunohistochemical analysis for Ki-67, cyclin A, cyclin D1, retinoblastoma protein (pRb), p53, p16INK4A, bcl-2, and p21waf1 in the epithelium and stroma of 40 primary (benign, 21; borderline, 8; malignant, 11) and 7 recurrent tumors of different grades.
In most cases, the epithelium showed no altered expression of cell cycle regulators.

Stromal overexpression of p16INK4A, p53, cyclin A, pRb, and p21waf1 correlated significantly with tumor grade. The number of altered proteins in stroma increased with higher grade and was accompanied by increased proliferation. Stromal cyclin A expression was the best separating marker between tumor grades. Correlations existed between stromal overexpression of p16INK4A and p21waf1, p16INK4A and p53, and p53 and pRb. No immunostaining differences were detected between primary tumors and recurrences. Four or more altered proteins and p53 expression in the stromal component were independent negative prognosticators for disease-free survival.


The stromal component of mammary phyllodes tumors displays an increasing level of cell cycle deregulation with higher tumor grade; the epithelial compartment mostly remains inconspicuous. Several combinations of aberrantly expressed cell cycle proteins seem important in the stromal progression of phyllodes tumors. The number of stromal cell cycle aberrations and stromal p53 expression might predict clinical behavior.


Tumour angiogenesis and p53 protein expression in mammary phyllodes tumors.

Tse GM, Lui PC, Scolyer RA, Putti TC, Kung FY, Law BK, Lau TS, Lee CS.

Departments of Anatomical and Cellular Pathology, Prince of Wales Hospital, Hong Kong, China. Mod Pathol. 2003 Oct;16(10):1007-13. Abstract quote


We examined 186 phyllodes tumors (106 benign, 51 borderline, 29 malignant) for angiogenesis by assessing stromal microvessel density by the hot spot method and assessing p53 protein expression; we correlated these factors with stromal cellularity, margin status, nuclear pleomorphism, mitosis, and stromal overgrowth.

Increased degree of malignancy in phyllodes tumors is associated with increased patient age and tumor size. Microvessel density and p53 protein expression also showed a similar increase with malignancy. Using a logistic regression model, microvessel density was shown to be useful in predicting malignancy in phyllodes tumors, independent of key criteria of stromal overgrowth, nuclear pleomorphism, and mitosis. Microvessel density showed correlation with stromal cellularity and margin status, suggesting an interrelationship between these parameters. P53 protein expression showed a positive correlation with microvessel density, suggesting possible overlap in the underlying mechanism of these two factors in the pathogenesis of phyllodes tumors. The numbers of recurrences and metastases are small in our series, and no significant difference was demonstrated in microvessel density and p53 protein expression compared with the primary.

We conclude that microvessel density and p53 are useful as independent criteria in evaluating malignancy in phyllodes tumors.


Increased p53 Protein Expression in Malignant Mammary Phyllodes Tumors.

Tse GM, Putti TC, Kung FY, Scolyer RA, Law BK, Lau TS, Lee CS.

Departments of Anatomical and Cellular Pathology (GMKT, FYLK), Surgery (BKBL), Prince of Wales Hospital, and Statistics (T-SL), Chinese University of Hong Kong, Hong Kong.
Mod Pathol 2002 Jul;15(7):734-40 Abstract quote
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.

ESTROGEN RECEPTOR-BETA
Estrogen receptor-beta is expressed in stromal cells of fibroadenoma and phyllodes tumors of the breast.

Sapino A, Bosco M, Cassoni P, Castellano I, Arisio R, Cserni G, Tos AP, Fortunati N, Catalano MG, Bussolati G.

1Department of Biomedical Science and Human Oncology, University of Torino, Torino, Italy.

Mod Pathol. 2006 Apr;19(4):599-606. Abstract quote

An estrogen dependency has been suggested for the growth of fibroadenomas: however, thus far, none of the steroid hormone receptors acting on breast tissues has been demonstrated in the stroma of breast fibroepithelial lesions.

In this study, the expression of estrogen receptor (ER)-alpha and -beta was investigated by immunohistochemistry in 33 fibroadenomas and in 30 benign, three borderline and seven malignant phyllodes tumors, all with spindle cell growth and in one distant metastasis. In addition, the presence of ER-beta mRNA and its variants was evaluated by RT-PCR in microdissected stroma. The possible correlation between hormone receptor expression and differentiation processes of stromal cells was investigated by smooth muscle actin and calponin immunostaining. ER-beta was the only hormone receptor expressed by stroma of fibroadenomas and phyllodes tumors, both at protein and mRNA level.

The highest percentage of ER-beta was observed in fibroadenomas with cellular stroma and in phyllodes tumors. In both lesions, ER-beta-positive stromal cells showed expression of smooth muscle actin and/or calponin, as demonstrated by double immunostaining. In addition, the mean age at diagnosis was significantly lower in patients with ER-beta-positive vs ER-beta-negative fibroadenomas. In contrast, in phyllodes tumors, ER-beta expression was higher in older patients. In conclusion, (i) only ER-beta is detected in the stroma of fibroadenomas and phyllodes tumors; (ii) its expression correlates with the expression of smooth muscle markers and suggests a role of ER-beta in myofibroblastic differentiation of stromal cells.

These two results, together with the young age of patients carrying fibroadenomas with highly ER-beta-positive stroma cells, may further indicate a hormone-receptor mechanism involved in regulating the growth of fibroadenomas. Conversely, the older age of patients with ER-beta-rich phyllodes tumors suggests that mechanisms, probably independent from estrogen stimulation, act on the growth of these tumors.



HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL The histologic hallmark of all phyllodes tumors is stromal hypercellularity and overgrowth.

Low grade tumors are sometimes difficult to distinguish from fibroadenomas, especially if only a small core or limited biopsy is performed.

High grade tumors have considerable cellularity, stromal overgrowth, and atypia of the stromal cells with an increased mitotic rate. These mitotic counts should be performed within the stroma away from the epithelial component. There is no absolute number and mitotic counts alone do not make a diagnosis of malignancy.

In general, however, counts of 10 mitoses per 10 high power fields favor a diagnosis of malignancy. The margins of the tumor are infiltrating rather than pushing and there is often necrosis and hemorrhage. In some cases, the stroma may undergo metaplasia with bone, fat, cartilage, and skeletal muscle identified. If these metaplastic elements are cytologically malignant, a poorer prognosis is portended.

METASTATIC TUMOR

Phyllodes Tumor Metastatic to Thyroid HurthleCell Adenoma.

Giorgadze T, Ward RM, Baloch ZW, LiVolsi VA.

Departments of Pathology, East Tennessee State University, Johnson City (Dr Giorgadze), the Craven Regional Medical Center, New Bern, NC (Dr Ward), and the University of Pennsylvania Medical Center, Philadelphia (Drs Baloch and LiVolsi).
Arch Pathol Lab Med 2002 Oct;126(10):1233-6 Abstract quote
We present a case of a malignant phyllodes tumor metastasizing to a Hurthle cell adenoma of the thyroid. A 55-year-old woman underwent mastectomy for a malignant phyllodes tumor. Two years later, she presented with a left thyroid mass, which was a single, circumscribed, soft, deep red-brown nodular lesion with an eccentric area of firmer consistency.

Histologically, the thyroid tumor was composed of 2 distinct types of cellular proliferation. Atypical spindle cells were infiltrating between the Hurthle cell cords and follicles in a fibrosarcomatous pattern. A battery of immunohistochemical stains was applied to both the thyroid and breast tumors for comparison.

Based on the histologic and immunophenotypic features of the fibrosarcomatous components of both the breast and thyroid tumors, we rendered a diagnosis of cystosarcoma phyllodes metastatic to Hurthle cell adenoma. To the best of our knowledge, this unusual case is a first report of tumor-to-tumor metastasis of a sarcoma to a primary thyroid neoplasm.


PERIDUCTAL STROMAL TUMOR

Periductal stromal tumor: a rare lesion with low-grade sarcomatous behavior.

Burga AM, Tavassoli FA.
Am J Surg Pathol 2003 Mar;27(3):343-8 Abstract quote
Biphasic breast tumors with benign ductal elements and a sarcomatous stroma lacking a phyllodes architecture are a source of diagnostic problems, particularly because of the lack of an appropriate designation. At the Armed Forces Institute of Pathology, we have used the term "periductal stromal sarcoma" to distinguish these from phyllodes tumors. All cases coded as periductal stromal sarcoma or PDSH were retrieved from the files of the Armed Forces Institute of Pathology. Cases that fulfilled the following criteria were included in this study.

The histologic features of periductal stromal sarcoma were defined as 1) a predominantly spindle cell stromal proliferation of variable cellularity and atypia around open tubules and ducts devoid of a phyllodes pattern, 2) one or more often multiple nodules separated by adipose tissue, 3) stromal mitotic activity of >/=3/10 high power fields, and 4) stromal infiltration into surrounding breast tissue.

Criteria for periductal stromal hyperplasia included 1) nodular, bland stroma growing as cuffs around normal or altered ducts, 2) no to minimal atypia, and 3) at most 0-2 stromal mitotic figures per 10 high power fields. Immunohistochemistry was used to further characterize these neoplasms. Of the cases retrieved, 20 qualified as periductal stromal sarcoma and seven as periductal stromal hyperplasia. Patients with periductal stromal sarcoma ranged in age from 37 to 89 years (mean 55.3 years). The tumors measured 0.2-6.0 cm (mean 2.97 cm). Eighteen patients had excisional biopsies and two had partial mastectomies. Overall follow-up time ranged from 1 to 72 months (mean 25.3 months) with two patients (10%) showing recurrence or probable metastasis. The neoplastic cells of periductal stromal sarcoma were at least focally immunoreactive for CD34 (13 of 15), CD117 (6 of 15), less reactive for actin (HHF35, 2 of 15), and negative for estrogen and progesterone receptors. Periductal stromal sarcoma is a useful descriptive designation for generally low-grade biphasic tumors with sarcomatous stroma that do not have features of a phyllodes tumor.

The development of focal phyllodes pattern in the recurrent tumor as well as development of a specific soft tissue sarcoma in one of the above cases suggest that some and possibly all periductal stromal sarcoma may evolve into a phyllodes tumor with time. Given the presence of infiltrative margins, excision with a rim of uninvolved tissue is required.




IMMUNOPEROXIDASE AND SPECIAL STAINS CHARACTERIZATION
CD117
p53 and c-kit (CD117) protein expression as prognostic indicators in breast phyllodes tumors: a tissue microarray study.

Tan PH, Jayabaskar T, Yip G, Tan Y, Hilmy M, Selvarajan S, Bay BH.

1Department of Pathology, Singapore General Hospital, Singapore.
Mod Pathol. 2005 Dec;18(12):1527-34. Abstract quote

Breast phyllodes tumors are fibroepithelial neoplasms whose clinical behavior is difficult to predict on histology. There is relatively scant data on the role of biological markers.

In this study, we determined if p53 and CD117 (c-kit) protein expression was predictive of behavior in a series of 335 phyllodes tumors diagnosed at the Singapore General Hospital, using immunohistochemistry on tissue microarrays. Representative areas from 250 (75%) benign, 54 (16%) borderline and 31 (9%) malignant phyllodes tumors were selected for construction of tissue microarrays using the 2 mm punch.

Immunohistochemistry for p53 and CD117 was carried out using the streptavidin-biotin method. Staining proportion and intensity of both epithelial and stromal elements were analyzed. p53 immunostaining was observed in the epithelium of 28 (10%) of 278 microarrays; myoepithelium of 53 (21%) of 251 microarrays; and stromal cells in 105 (36%) of 289 microarrays. CD117 immunohistochemical reactivity was noted in epithelial and stromal components of 175 (of 267, 66%) and 17 (of 273, 6%) microarrays, respectively. Stromal p53 and CD117 protein expression was associated with tumor grade (P<0.05). Of 43 (13%) women who suffered recurrences during the follow-up period, CD117 stromal staining predicted recurrent disease (P<0.05), but p53 was not correlative.

We conclude that tissue microarrays are a convenient method for evaluating immunostaining results of large numbers of phyllodes tumors. Although positive p53 stromal immunohistochemical detection may corroborate histologic malignancy, it is CD117 protein expression in phyllodes tumor stromal cells that may be of potential utility in predicting recurrent disease.
Increased c-kit (CD117) expression in malignant mammary phyllodes tumors.

Tse GM, Putti TC, Lui PC, Lo AW, Scolyer RA, Law BK, Karim R, Lee CS.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong. Mod Pathol. 2004 Jul;17(7):827-31. Abstract quote

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST).

With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (chi2=13.844, P=0.001).

In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.



DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
FIBROADENOMA
Fibroepithelial Lesions With Cellular Stroma on Breast Core Needle Biopsy
Are There Predictors of Outcome on Surgical Excision?


Timothy W. Jacobs, MD, etal. Am J Clin Pathol 2005;124:342-354 Abstract quote


Fibroepithelial lesions with cellular stroma (FELCS) in breast core needle biopsy (CNB) specimens may result in either fibroadenoma or phyllodes tumor at excision.

We evaluated histologic features, proliferation indices (by Ki-67 and topoisomerase II a immunostaining) and p53 expression in 29 cases of FELCS in CNB specimens and correlated these with excision findings in a blinded manner. On excision, 16 patients had fibroadenomas and 12 had phyllodes tumors. All CNB specimens with mildly increased stromal cellularity were fibroadenomas on excision (n = 4), and all with markedly cellular stroma were phyllodes tumors (n = 4). Among CNB specimens with moderate cellularity (12 fibroadenomas and 8 phyllodes tumors), only stromal mitoses were discriminatory histologically. Stromal proliferation indices were significantly higher in CNB that were phyllodes tumors vs fibroadenomas.

Assessment of stromal cellularity, mitoses, and proliferation indices might help determine the probability of phyllodes tumor occurring and guide management of these cases.

Aggressive giant fibroepithelial lesion with unusual vascular stroma--a case report.

Hanna W, AL-Maghrabi J, Malik A.

Department of Anatomical Pathology, Sunnybrook and Women's College Health Science Center, University of Toronto, Ontario, Canada.
Mod Pathol. 2003 Aug;16(8):823-7. Abstract quote
The stroma of fibroadenoma and phyllodes tumor usually consists of fibroblastic proliferation. Rarely the stroma contains bundles of smooth muscle. Pseudoangiomatous hyperplasia of the mammary stroma has been described in fibroadenomas. However, true benign vascular stroma has not been reported.

We report a case of a 34-year-old Chinese woman who presented with a large mass occupying the entire left breast. Left mastectomy was performed and showed a large, well-circumscribed, lobulated, rubbery-firm tumor measuring 13 x 10 x 6 cm. Microscopic examination revealed a fibroepithelial tumor formed by an organoid pattern of ductal structures with a very striking stromal appearance composed of extensive vascular proliferation and that demonstrated strong immunoreactivity for CD31, CD34, and Factor VIII. Ultrastructural examination revealed intercellular junctions, basal lamina, pinocytotic vesicles, and Weibel-Palade bodies in the cells lining the vascular spaces, confirming their endothelial nature.

These findings rule out the diagnosis of pseudoangiomatous hyperplasia. The patient developed local recurrence a year later, and the resection showed malignant phyllodes tumor with ductal carcinoma in situ.The extensive vascular stroma noted in the primary tumor may have played a role in the malignant transformation of the epithelial and stromal components in this tumor.

Distinction of phyllodes tumor from fibroadenoma: a reappraisal of an old problem.

Krishnamurthy S, Ashfaq R, Shin HJ, Sneige N.

Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston 77030, USA.
Cancer 2000 Dec 25;90(6):342-9 Abstract quote

BACKGROUND: Using fine-needle aspiration (FNA) smears, it is difficult to distinguish low grade phyllodes tumor (PT) from fibroadenoma (FA) due to overlapping cytologic features between the two lesions. The authors retrospectively studied 45 histologically proven fibroepithelial breast tumors of which 33 were FA and 12 were PT (1 malignant, 8 borderline, and 3 benign) to define cytologic features that can help in the accurate categorization of these lesions by using FNA samples.

METHODS: The cytologic features analyzed included: 1) epithelial component for number (<5 or >5), architecture, apocrine metaplasia, squamous metaplasia, nuclear pleomorphism, and mitosis; 2) stromal fragments for number (<5 or >5), cellularity (on a scale of 1+ to 3+), borders, cell characteristics, nuclear pleomorphism, and mitosis; 3) individual dispersed stromal cells in the background for cellularity (on a scale of 1+ to 3+), and cellular shape (short/round/oval or long spindle) based on whether they were smaller or larger than 2 times the size of a small round lymphocyte.

RESULTS: The mean age of patients with FA was 34 years and of those with PT 44 years. The average size of FA was 2.0 cm, and the average size of PT was 4.0 cm. The characteristics of the epithelial fragments of PT and FA were not significantly different. Stromal fragments were noted in 60% of FA and 83% of PT samples examined. Fifty-six percent of PT and 30% of FA exhibited hypercellular stromal fragments (3+ cellularity), and the difference was not statistically significant. Large club-shaped hypercellular stromal fragments were present only in FA (in 21% of the samples). There was no difference in the overall cellularity of the background stromal nuclei in the two types of lesions. Long spindle nuclei averaging greater than 30% of the dispersed stromal cell population in the background were found only in cases of PT (in 57% of the samples; P < 0.001). Short/round/oval nuclei characterized most FAs. Long spindle nuclei constituting 10-30% of the dispersed stromal cells, however, occurred in both PT and FA to the extent of 43% and 21%, respectively.

CONCLUSIONS: Hypercellular stromal fragments occur not only in PT, but also in FA, and hence they cannot be used as the sole criterion for making a diagnosis of PT on FNA. The proportion of individual long spindle nuclei (>30%) amid the dispersed stromal cells in the background is the most reliable discriminator between the two lesions. Lesions in which long spindle nuclei constitute between 10% and 30% may represent either PT or FA, and therefore such lesions should be categorized as indeterminate on FNA.




PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
Phyllodes Tumors of the Breast
The Role of Pathologic Parameters


Puay-Hoon Tan, MD, etal. Am J Clin Pathol 2005;123:529-540 Abstract quote


We aimed to establish whether morphologic parameters were prognostically important in a large series of breast phyllodes tumors in Asian women. Of 335 phyllodes tumors diagnosed at the Department of Pathology, Singapore General Hospital, Singapore, between January 1992 and December 2002, 250 (74.6%) were benign, 54 (16.1%) borderline, and 31 (9.3%) malignant, based on histologic review of archival slides.

Of the women, 43 (12.8%) experienced recurrences during the follow-up period. Recurrent disease was correlated with grade or classification (P = .028), stromal atypia (P = .016), stromal hypercellularity (P = .046), and permeative microscopic borders (P = .021). Multivariate analysis revealed that independent predictors of recurrence were pseudoangiomatous stromal hyperplasia (PASH) and margin status, whereby the presence of PASH and complete or negative margins reduced recurrence hazards by 51.3% and 51.7%, respectively.

The 7 women who died of disease during follow-up had malignant phyllodes tumor at the outset and experienced recurrences, and death was preceded by distant metastases.
Pathologic, Immunohistochemical, and Molecular Features of Benign and Malignant Phyllodes Tumors of the Breast

Celina G. Kleer, etal.
Mod Pathol 2001;14:185-190 Abstract quote

The histologic distinction between benign and malignant Phyllodes tumors (PT) is often difficult and arbitrary.

We analyzed a group of benign and malignant PT to determine whether specific histologic features and expression of Ki-67 and p53 could be useful in distinguishing benign PT from malignant tumors. We also determined whether deletions in Chromosome 3p at the FHIT and hMLH1 loci are common abnormalities in PT. Twenty PT were histologically classified as benign (7) or malignant (13). Seven of the malignant PT were low grade, and six were high grade. Ki-67 and p53 immunohistochemistry was performed on all tumors and analyzed for the stromal and for the epithelial component. PCR-based loss of heterozygosity analyses were performed with the following markers on Chromosome 3p: D3S1478 (3p21.2–21.3), D3S1289 (3p21.1–21.2), and D3S1295 (3p14.3–21.1). The distribution of immunoreactivity for Ki-67 was analyzed by quantifying the percentage of positive nuclei and expressed as the labeling index (LI).

Patients’ ages ranged from 13 to 71 years (median: 51 y). After a mean follow-up period of 8 years, none of the PT metastasized, whereas three recurred locally. Although malignant PT were larger than benign PT (means, 7.1 versus 4.3 cm), this difference was not statistically significant. Five tumors had infiltrating margins, and 14 were circumscribed.

The Ki-67 LI in low-grade malignant PT (16 ± 25.5) was significantly higher than that in benign PT (3.6 ± 4.8), whereas the LI in the high-grade malignant PT group (50 ± 21.9) was significantly higher than that in low-grade malignant tumors (P = .012). The Ki-67 LI in the three tumors that recurred was less than 10%. Two of seven (29%) benign PT were focally positive for p53, whereas four of seven (57%) low-grade malignant and three of six (50%) high-grade malignant PT were diffusely positive for p53. The three tumors that recurred initially were histologically benign, as were two of the recurrences. One recurrent tumor evolved to a high-grade malignant PT. Margins were greater than 1 cm in all tumors except four, three of which recurred locally. No allelic loss of 3p was found.

In summary, Ki-67 expression may assist in distinguishing benign from malignant PT in diagnostically difficult cases. 3p deletions do not play a significant role in the development of these tumors. Neither Ki-67 nor p53 can reliably predict recurrence. Histologically high-grade malignant PT have a favorable prognosis if widely excised. We emphasize the importance of adequate margins in the treatment of benign and malignant PT.


Hormonal receptors expression in epithelial cells of mammary phyllodes tumors correlates with pathologic grade of the tumor: a multicenter study of 143 cases.

Tse GM, Lee CS, Kung FY, Scolyer RA, Law BK, Lau TS, Putti TC.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, NT, Hong Kong, People's Republic of China.


Am J Clin Pathol 2002 Oct;118(4):522-6 Abstract quote
We used immunohistochemical analysis to detect the presence of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) protein expression in the epithelial and stromal cells of 143 phyllodes tumors (PTs).

Expression of epithelial ER and PR proteins was common, occurring in 43% to 84% of PTs. Expression of epithelial AR protein and stromal ER, PR, and AR proteins was low (5% or less) in all tumors. An inverse relationship of epithelial ER and PR protein expression with degree of malignancy in PT was found (P < .05), and ER expression also correlated with mitotic count (P < .05).

When considering PT with the expression of ER or PR proteins and the coexpression of both, the inverse relationship with tumor grade also was significant (P < .05). As the hormonal receptor protein expression shows a consistent decrease with increasing malignancy, we infer that the epithelium has a crucial role in the pathogenesis or progression of PT.

MIB-1

p53 and Ki-67 expression as prognostic factors in cystosarcoma phyllodes.

Erhan Y, Zekioglu O, Ersoy O, Tugan D, Aydede H, Sakarya A, Kapkac M, Ozdemir N, Ozbal O, Erhan Y.

General Surgery Department, Celal Bayar University, School of Medicine, Guzelyali-Izmir, Turkey.
Breast J 2002 Jan-Feb;8(1):38-44 Abstract quote
We have reviewed the histopathological, clinical outcome and immunohistochemical status in 21 women with cystosarcoma phyllodes (CSP) tumors of the breast.

We assessed 12 tumors as histopathologically benign and 9 tumors as malignant. The median patient ages in benign and malignant CSP tumors were 39.6 and 45.4 years of age, respectively. The stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour, and heterologous stromal elements were significant features of the malignant CSP tumors. Benign CSP tumors were predominantly of fibroadenomatous architecture with cellular stroma (mild or moderate) and some distortion and elongation of glandular elements. Five malignant CSP tumors were stained positively with p53, and 6 malignant CSP tumors were stained immunohistochemically with Ki-67. All benign CSP tumors were negatively stained for p53 and Ki-67. The patients with benign CSP tumors were treated with local excision ( n=11) and with subcutaneous mastectomy ( n=1). Malignant CSP tumors were treated with wide local excision ( n=1), partial mastectomy ( n=1), simple mastectomy ( n=2), and modified radical mastectomy ( n=5). Two patients with a high mitotic rate and high values of p53 and Ki-67 received additional radiotherapy and chemotherapy. One case had liver metastasis. This tumor had high mitotic figures, stromal overgrowth, severe stromal cellularity, and 20% Ki-67 and mild p53 positivity.

We suggest that p53 and Ki-67 can play an important role in predicting prognosis and yielding additional therapy besides conventional prognostic factors in the treatment of the CSP patients.


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

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

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania
Breast J 2002 Nov-Dec;8(6):376-81 Abstract quote
Cystosarcoma phyllodes (CP) of the breast is a rare biphasic tumor composed of benign epithelium and a spindle cell stroma. Biologic behavior of CP cannot be predicted with certainty on the basis of morphologic criteria only.

We studied immunohistochemical expression of basic fibroblastic growth factor (bFGF), urokinase, Ki67, p53 protein, and microvessel density in stromal and epithelial components of 14 low-grade CP (LCP) and 9 high-grade CP (HCP). bFGF was more often positive in LCP than in HCP. The stroma was positive for bFGF in 86% of LCP and 67% of HCP, and the epithelium was positive in 64% of LCP and 14% of HCP. Urokinase was positive in stromal cells of 86% of LCP and 93% of HCP. The epithelial positivity for urokinase in both groups resembled closely that of the stroma. p53 protein was more often positive in stromal cells of HCP (67%) than in LCP (50%). Ki67 was positive in the stroma of 43% of LCP and 89% of HCP and in the epithelium of 14% of LCP and 33% of HCP. There was no significant difference in microvessel density (MVD) in low- and high-grade lesions.

Our study demonstrates that stromal Ki67 and p53 immunohistochemical positivity are more often associated with high-grade tumors. The positive immunostaining for bFGF, urokinase, Ki67, and p53 in stroma and epithelium of the majority of CP supports the existence of epithelial-stromal interactions and recognizes epithelium as an integral part of this tumor.

VASCULAR ENDOTHELIAL GROWTH FACTOR

Stromal expression of vascular endothelial growth factor correlates with tumor grade and microvessel density in mammary phyllodes tumors: a multicenter study of 185 cases.

Tse GM, Lui PC, Lee CS, Kung FY, Scolyer RA, Law BK, Lau TS, Karim R, Putti TC.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, Hong Kong.

Hum Pathol. 2004 Sep;35(9):1053-7. Abstract quote

A retrospective review of 185 mammary phyllodes tumors (105 benign, 51 borderline, 29 malignant) from 4 centers was performed by immunohistochemistry to investigate the expression of vascular endothelial growth factor in the epithelial and stromal cells of mammary phyllodes tumors.

The correlation of vascular endothelial growth factor with tumor grade, stromal cell nuclear pleomorphism, cellularity, mitotic rate, margin histomorphology, and the stromal microvessel density was evaluated.

Vascular endothelial growth factor expression was found in the epithelium in 29% and in the stromal cells in 31% of cases. There was significant increase of vascular endothelial growth factor expression in the stromal cells with increasing degree of malignancy, but not the epithelium. Microvessel density in the stroma also showed significant correlation with tumor malignancy, and a correlation was shown with the stromal vascular endothelial growth factor expression. Statistical overlap of stromal vascular endothelial growth factor and microvessel density in predicting malignancy suggests that angiogenesis may be an effector mechanism for vascular endothelial growth factor.

Assessment of stromal VEGF may be useful as an adjunctive diagnostic criterion in the histologic assessment of malignancy in phyllodes tumors.

TREATMENT Excision