—  INTERNATIONAL SOCIETY OF BREAST PATHOLOGY   —

Fibroepithelial Lesions of the Breast


David Hicks
The Cleveland Clinic Foundation
Cleveland, OH


Introduction:
The fibroepithelial lesions of the breast represent a spectrum of morphologic entities with a diverse biologic potential ranging from a benign clinical course and involution with age to malignant behavior with a potential for local recurrence and metastases. The majority of fibroepithelial lesions encountered in the practice of pathology are indeed benign, however an awareness of the clinical, morphologic and biologic features of lesions with the potential for a more aggressive clinical course is important in order to correctly identify lesions with a potential for local recurrence and/or distant metastases at the time of diagnosis.

Differential diagnosis of fibroepithelial lesion of the breast:
  1. Fibroadenoma and variants

  2. Phyllodes Tumors

  3. Pseudoangiomatous stromal hyperplasia

  4. Metaplastic spindle cell carcinoma

Fibroadenoma:
Fibroadenomas (FA) of the breast are common benign lesions typically occurring in younger patients between the ages of 20-35. These lesions tend to regress as the patient ages. The usual FA is a well-circumscribed firm mass on gross examination with a solid gray to white cut surface. Microscopically, these lesions consist of an admixture of glandular and stromal elements, and can vary in appearance depending on the relevant amounts and configuration of each of these components. The stroma is typically loose and myxoid, however, may be partially or totally composed of a dense fibrous type matrix, a change usually seen in older patients. Stromal spindle cells are predominantly CD34 positive fibroblasts [29], which concentrically cuff glandular structures or array themselves perpendicular to the basement membrane [12]. CD34 positive spindle cells are seen in the perilobular and to a lesser extent the interlobular stroma of the normal breasts [46], suggesting that the mesenchymal component of FA arise from a resident population of normal fibroblasts in breast parenchyma [29]. The cellularity of the stroma in FA can vary from case to case, however stromal atypia is absent and mitotic figures in stromal cells are rarely seen. For lesions with undue stromal cellularity, the alternative diagnosis of phyllodes tumor should be considered. The epithelial component of a FA is composed of cuboidal or columnar cells with uniform nuclei surrounded by a supportive myoepithelial layer. These glandular elements are typically elongated and compressed with a beaded appearance (intracanalicular pattern) or arranged as small open acinar structures (pericanalicular pattern) [12]. Fibrocystic changes within the epithelial component have been described and can include sclerosing adenosis [2, 22] and atypical hyperplasia [27], a finding with little clinical significance. Although rare, both lobular and ductal carcinoma in situ has also been described in FA, and can be found entirely within the confines of the lesion or may involve surrounding breast tissues as well [10, 15] .

Phyllodes tumors
Phyllodes tumors (PT) of the breast are uncommon fibroepithelial neoplasms accounting for less than 1% of primary mammary tumors. Originally named cystosarcoma phylloides [14], the term PT is now preferred given the broad spectrum of biologic and clinical behavior of these lesions ranging from a benign clinical course to malignant neoplasms with the potential for local recurrence and metastasis. Although PT can arise in younger individuals, they typically occur in the same age group as breast cancer, and the median age at the time of diagnosis is 45. On gross examination these tumors are typically well circumscribed (although infiltrating margins can be encountered), may be solid, vaguely lobulated, or demonstrate leaf-like fronds projecting into cystic spaces [12]. As with FA, these lesions consist of both stromal and benign glandular elements as integral components of the neoplasm. PT are characterized by a more cellular stroma compared with the conventional FA, and this stromal cellularity is frequently more pronounced in the periglandular regions of the lesion [2]. Characteristic of PT, the epithelial elements line variable sized cystic spaces into which projects the hypercellular stroma, resulting in the formation of leaf-like fronds within the lesion. The epithelial elements of a PT, although probably not neoplastic, can on occasion have a marked proliferative appearance as is sometimes seen in FA [34]. Both the amount and the appearance of the stromal component is responsible for determining whether a fibroepithelial lesion should be considered a PT, as well as for the determination of the potential for a PT to behave clinically in an aggressive fashion. A wide range of morphologic features can be seen in PT and significant heterogeneity can exist within a given lesion necessitating through sampling of these tumors. Most clinically malignant PT demonstrate at least focally an overgrowth of an overtly sarcomatous element within the stromal component which may be heterologous. Considering this tumor heterogeneity, close examination of stroma in multiple sections is important in that the truly malignant component of a PT may be present in only a portion of the tumor [5].

Histologic features predicting local recurrence and potential for metastasis
Given the considerable variability in the histologic appearance of phyllodes tumors, pathologists have attempted to correlate various histologic features with the biologic behavior and the likelihood of recurrence and metastatic spread. Based on the morphologic features of these tumors including; infiltration of adjacent breast parenchyma, stromal cellularity, stromal overgrowth, tumor necrosis, and mitotic activity, attempts have been made to classify PT into "benign", " borderline", and malignant categories [18, 35] . The widely accepted criterion for classification of PT as proposed by Azzopardi [2], and Salvadori [37] is shown in Table 1. As can be seen from Table 1, morphologically malignant PT tend to demonstrate infiltrating borders, a markedly hypercellular stroma, nuclear pleomorphism, a high mitotic index, and loss of the relationship between glandular and stromal elements with stromal overgrowth. Stromal overgrowth as defined by Ward and Evans [45] is present when the stroma occupies at least one low power field to the exclusion of epithelial elements.

Table 1: Phyllodes Tumors: Histologic Classification

Criteria Benign Borderline Malignant
Margins pushing +/- infiltrative
Cellularity low moderate high
Mitosis (/10HPF) <5 5-9 >10
Pleomorphism mild moderate high

Other authors include stromal overgrowth, necrosis,
and heterologous elements as criterion for malignancy [2, 37]

In three large series using the above outlined criterion, 2% (3/138), 9% (5/57), and 23% (24/105) of patients with benign, borderline and malignant PT respectively, developed metastases [3]. It should be pointed out that while histologic features appear to be useful in identifying a subgroup of PT with an increased likelihood for metastasis, tumors with a benign (low-grade) appearance are capable of local recurrence and in rare instances metastatic spread [28, 36] . While most distant metastases develop from borderline or malignant tumors, size of the primary lesion also appears to be an important factor in predicting for metastatic spread [6, 8, 16] . The most important predictor for local recurrence appears to be incomplete surgical excision, regardless of the apparent histologic classification of the tumor [8, 28] ; therefore, breast-conserving surgery with appropriate margins should be considered when technically possible, the preferred primary therapy [6].

Biologic features predicting local recurrence and potential for metastasis
A number of investigators have begun to examine markers of tumor biology in an effort to better predict the biologic and clinical behavior of PT. The majority of these reports have demonstrated a positive correlation between histologic grade and certain markers, however, add little if any additional prognostic significance in terms of predicting clinical outcome. Studies of p53 mutations [21] and altered expression in stroma [13] have shown that increased p53 immunoreactivity correlates with standard histologic features of malignancy but were not predictive for malignant behavior. Similarly, studies of DNA content and cell proliferation have demonstrated a positive correlation with the histologic grade of PT [19, 20, 24] . Some of these studies have suggested a correlation between markers of cellular proliferation and outcome [11, 31] ; however, most have failed to predict for recurrence or metastasis [19, 20, 24, 30] . Other investigators have studied epidermal growth factor receptor families [39], c-kit [7, 38] , vascular endothelial growth factor [43], hormone receptor expression [42] and numerous other markers, however none of these factors has been able to reliably predict unfavorable outcome beyond histologic parameters. While these studies have added greatly to our understanding of the biology of PT, they have not as yet brought us closer to predicting the clinical course of disease for individual patients. Therefore, for the time being, careful histologic evaluation along with adequate tumor sampling appears to still provide the most clinically relevant and useful information [5].

The relationship between phyllodes tumor and fibroadenoma
Both FA and PT present as well demarcated tumors of the breast. There can also be considerable morphologic similarities between these two lesions in that they are both composed of epithelial and stromal elements. Given this clinical and histologic overlap, it has been suggested that there is an etiologic relationship between FA and PT [35]. In addition, patients have been reported who develop both lesions either synchronously or metachronously and morphologic features of both FA and PT have been identified is some tumors [41]. Whether PT develops from FA or arise de novo remains unclear, however some molecular data has been reported that supports a relationship between these two lesions. Noguchi has shown that most FA have polyclonal stromal elements and should be regarded as a form of stromal hyperplasia and not neoplastic lesions [32], while PT contain monoclonal stromal cells and therefore are true neoplasms [22, 33] . However, it has been suggested that in a subset of FA, a somatic mutation can result in a monoclonal stromal proliferation, morphologically similar to the polyclonal elements, conferring in these lesions a propensity for local recurrence and progression to PT [23]. Clonal analysis using restriction fragment length polymorphisms of the X-chromosome performed on specimen from patients who sequentially developed FA and PT at the same site demonstrated that both lesions were monoclonal and expressed the same inactivated X-chromosome, appearing to support this hypothesis [33]. Lending additional support is a report by Kuijper where three cases of FA with apparent stromal expansion were monoclonal suggesting stromal progression [23]. In addition, similar to FA, the stromal elements of PT express CD34, suggesting that both of these lesions arise from a common precursor cell, which is part of the normal mesenchymal connective tissue of breast parenchyma [29].

Pseudoangiomatous stromal hyperplasia (PASH)
PASH is characterized by a spindle cell proliferation of stromal elements containing artifactual "cleft-like" spaces resembling vascular channels [44]. The glandular elements in PASH are normal mammary ducts and terminal duct-lobular units, surrounded by these stromal cells and not an intimate component of the lesions as is seen is FA and PT. Interestingly, similar to FA and PT, the stromal proliferation seen in PASH is composed of CD34 positive fibroblastic cells suggesting a relationship among these disorders [29]. Additionally these stromal cells demonstrate strong reactivity for progesterone receptor suggesting that PASH represents a localized stromal overgrowth with an underlying hormonal etiology [1].

Malignant PT's and other malignant spindle cell neoplasms of the breast
PT with extensive stromal overgrowth may be difficult to distinguish from spindle cell carcinoma or primary sarcoma of the breast, particularly on a limited biopsy sample such as a needle core. Thorough sampling of the excised lesion to search for the characteristic biphasic areas is critically important in order to correctly identify a predominantly sarcomatous PT [12]. Similarly, a careful search of multiple sections may be necessary to identify scattered foci of invasive carcinoma [4], "epithelioid clumps" [40], or areas of in situ carcinoma to help distinguish a spindle cell carcinoma from a malignant PT with extensive stromal overgrowth or a primary sarcoma. Immuno-histochemical evaluation may be helpful in sorting out some of the more problematic and difficult cases however should not be relied upon to unequivocally differentiate between these diagnostic possibilities. In cases of monophasic spindle cell carcinoma, IHC for epithelial markers is important to help support the diagnosis however staining may be focal. In addition, the spindle cell component of these lesions frequently demonstrates staining for calponin, p63, smooth-muscle actin, and focal S-100, suggesting myoepithelial differentiation for these tumors [4]. PT typically show patchy staining for CD34 while spindle cell carcinomas are negative; these findings in combination with IHC for cytokeratins may also be useful in separating spindle cell carcinoma from the sarcomatous components of a PT [29]. Most type of sarcoma can arise within the breast however; primary mammary sarcomas are rare. Therefore, before rendering a diagnosis of primary mammary sarcoma, one must exclude the more likely diagnoses of spindle cell carcinoma, malignant PT, or an extra-mammary malignancy [4].

Utility and limitations of the interpretation of fibroepithelial lesions in core biopsy specimens
The use of percutaneous core needle biopsies with stereotactic mammography, ultrasound or MRI guidance has become a well-established, reasonable and popular alternative to open biopsy for the initial evaluation of a clinically occult breast lesion [26]. Although the subsequent management of many patients with malignant and most benign lesion diagnosed on core biopsy is straightforward, for certain non-malignant lesions there may be diagnostic uncertainty given concerns over whether the core specimen is representative of the lesion [17]. Although a diagnosis of FA can usually be made on core biopsy, provided the clinical and radiographic findings are concordant with the diagnosis, problematic fibroepithelial lesion can occasionally be encountered. The distinction between FA and PT on core biopsy of fibroepithelial lesions with increased stromal cellularity may not be possible given the limited sampling of such specimens. The literature reports on the surgical outcome of such problematic lesions on core biopsy are limited and have yielded diagnoses of both PT (5 of 16 lesions, 31%) and FA (11 of 16 lesions, 69%) after definitive excision [9, 25] . Therefore, for any fibroepithelial lesion on core biopsy with atypical features such as increased stromal cellularity, atypia, or mitotic activity, the differential diagnosis should include PT and the lesion must be excised for further evaluation [12, 17] .

References

  1. Anderson C. Am J Surg Pathol. 15:145-149;1991.

  2. Azzopardi JG. Major problems in pathology, vol. 11. W.B. Saunders, 1979.

  3. Barth RJ. Breast Cancer Res Treat. 57:291-295;1999.

  4. Brogi E. Seminars in Diagnostic Pathology. 21:57-64;2004.

  5. Carter BA, et al. Hum Pathol. 35:1051-1052;2004.

  6. Chaney AW, et al. Cancer. 89:1502-1511;2000.

  7. Chen CM, et al. J Surg Res. 94:84-91;2000.

  8. De Roos WK, et al. Br J Surg. 86:396-399;1999.

  9. Dershaw DD, et al. Radiology. 198:323-325;1996.

  10. Diaz NM, et al. Am J Clin Pathol. 95:614-622;1991.

  11. El-Naggar A, et al. Am J Clin Pathol. 93:480-485;1990.

  12. Fan-Lerwill. Seminars in Diagnostic Pathology. 21:48-56;2004.

  13. Feakins RM, et al. Histopathology. 35:162-169;1999.

  14. Fiks A. Virchows Arch. 392:1-6;1981.

  15. Fondo EY, et al. Cancer. 43:563-567;1979.

  16. Hawkins RE, et al. Cancer. 69:141-147;1992.

  17. Jacobs TW, et al. Am J Surg Pathol. 26:1095-1110;2002.

  18. Kario K, et al. J Surg Oncol. 45:46-51;1990.

  19. Keelan PA, et al. Hum Pathol. 23:1049-1054;1992.

  20. Kleer CG, et al. Mod Pathol. 14:185-190;2001

  21. Kuenen-Boumeester V, et al. J Pathol. 189:169-175;1999.

  22. Kuijper A, et al. J Pathol. 197:575-581;2001.

  23. Kuijper A, et al. Am J Clin Pathol. 115:736-742;2001.

  24. Layfield JLJ, et al. Cancer. 64:1486-1489;1989.

  25. Meyer JE, et al. Radiology. 206:717-720;1998.

  26. Meyer JE, et al. JAMA. 281:1638-1641;1999.

  27. Mies C, et al. Am J Surg Pathol. 11:184-190;1987.5

  28. Moffat CJ, et al. Histopathology. 27:205-218;1995

  29. Moore T, et al. Histopathology. 38:62-67;2001.

  30. Murad TM, et al. Arch Pathol Lab Med. 112:752-756;1998.

  31. Niezabitowski A, et al. Breast Cancer Res Treat. 65:77-85;2001.

  32. Noguchi S, et al. Cancer Res. 53:4071-4074;1993.

  33. Noguchi S, et al. Cancer. 76:1779-1785;1995.

  34. Norris HJ, et al. Cancer. 20:2090-2099;1967

  35. Parker SJ, et al. Postgrad Med J. 77:428-435;2001.

  36. Reinfuss M, et al. Cancer. 77:910-916;1996.

  37. Salvadori B, et al. Cancer. 63:2532-2536;1989.

  38. Sawyer EJ, et al. J Pathol. 200:59-64;2003.

  39. Shpitz B, et al. J Surg Oncol. 79:86-92;2002.

  40. Sneige N, et al. Am J Surg Pathol. 25:1009-1016;2001.

  41. Treves N, et al. Cancer. 4:1286-1332;1951.

  42. Tse GMK, et al. Am J Clin Pathol. 118:522-526;2002.

  43. Tse GMK, et al. Hum Pathol. 35:1053-1057;2004.

  44. Vuitch MF, et al. Hum Pathol. 17:185-191;1986

  45. Ward RM, et al. Cancer. 58:2282-2289;1986.

  46. Yamazaki K, et al. J Submicrosc Cytol Pathol. 27:309-323;1995