Fibroepithelial Lesions; the WHO Spectrum
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Seminars in Diagnostic Pathology 34 (2017) 438–452 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/serndb Fibroepithelial lesions; The WHO spectrum Gregor Krings n, Gregory R. Bean, Yunn-Yi Chen Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA article info abstract Fibroepithelial lesions of the breast comprise a morphologically and biologically heterogeneous group of Keywords: biphasic tumors with epithelial and stromal components that demonstrate widely variable clinical be- Phyllodes havior. Fibroadenomas are common benign tumors with a number of histologic variants, most of which Fibroepithelial pose no diagnostic challenge. Cellular and juvenile fibroadenomas can have overlapping features with Fibroadenoma phyllodes tumors and should be recognized. Phyllodes tumors constitute a spectrum of lesions with Sarcoma varying clinical behavior and are graded as benign, borderline or malignant based on a set of histologic Breast features according to recommendations by the World Health Organization (WHO). Recent developments have significantly expanded our understanding of the pathogenesis of fibroepithelial lesions, highlighting fibroadenomas as true neoplasms and underscoring a commonality with phyllodes tumors in the form of recurrent MED12 exon 2 mutations. In addition, sequencing studies have elucidated pathways associated with phyllodes tumor progression. Accurate diagnosis and grading of phyllodes tumors are important for patient management and prognosis, as grade broadly correlates with increasing local recurrence risk, and essentially only malignant tumors metastasize. However, classification of fibroepithelial lesions in many cases remains challenging on both core biopsy and excision specimens. A commonly encountered pro- blem at the benign end of the spectrum is the distinction of benign phyllodes tumor from cellular fi- broadenoma, which is largely due to the subjective nature of histologic features used in diagnosis and histologic overlap between lesions. Grading is further complicated by the requirement to integrate multiple subjective and ill-defined parameters. On the opposite end of the histologic spectrum, malig- nant phyllodes tumors must be distinguished from more common metaplastic carcinomas and from primary or metastatic sarcomas, which can be especially difficult in core biopsies. Im- munohistochemistry can be useful in the differential diagnosis but should be interpreted with attention to caveats. This review provides an overview and update on the spectrum of fibroepithelial lesions, with special emphasis on common problems and practical issues in diagnosis. & 2017 Elsevier Inc. All rights reserved. Introduction fibroadenomas and a commonality with phyllodes tumors in the form of recurrent MED12 mutations, and also highlight the hetero- Fibroepithelial lesions of the breast constitute a heterogeneous geneity and molecular progression of phyllodes tumors. group of biphasic tumors with stromal and epithelial components Whereas the diagnosis of usual type fibroadenomas is typically that demonstrate wide ranging biologic behavior and differences in straightforward, accurate diagnosis of phyllodes tumors can be clinical management. These include common benign fibroadenomas challenging in many cases. Commonly encountered problems in- and fibroadenoma variants, as well as the spectrum of rare phyllodes clude phyllodes tumor grading and distinction of cellular fi- tumors, ranging from benign tumors with variable recurrence po- broadenomas from the lower end of the histologic spectrum of tential to frankly malignant tumors with risk of metastasis and phyllodes tumors. The diagnostic difficulty arises in large part due death.1 Periductal stromal tumors likely represent phyllodes tumor to overlapping histologic features and the subjective nature of the variants with periductal growth and are also included in this review. assessed histologic parameters. In addition, phyllodes tumor Although the pathogenesis of fibroepithelial lesions remains poorly grading is further complicated by the need to evaluate and in- understood overall, recent genomic studies have begun to uncover tegrate multiple parameters whose relative weighted importance the molecular underpinnings of fibroadenomas and phyllodes can be observer dependent in the absence of clearly defined cri- tumors.2–7 These studies provide support for a clonal origin of teria. Nonetheless, accurate diagnosis is important to help predict n Correspondence to: Department of Pathology, University of California San Francisco, 1825 4th Street, Room M-2355, San Francisco, CA 94143, USA. E-mail address: [email protected] (G. Krings). http://dx.doi.org/10.1053/j.semdp.2017.05.006 0740-2570/& 2017 Elsevier Inc. All rights reserved. G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452 439 recurrence potential and guide clinical management. On the ma- features.28,30 On the other hand, a diagnosis of phyllodes tumor lignant end of the spectrum, distinction of malignant phyllodes should be carefully considered in mitotically active cellular fi- tumors from metaplastic carcinoma or sarcoma can be challenging broepithelial lesions presenting in women significantly past ado- on core biopsy and excision, in which generous sampling and lescence. Pediatric fibroadenomas may also demonstrate ill-de- immunohistochemistry can be useful to reach the correct diag- fined borders and often have small leaf-like fronds, although the nosis. Here, we provide a review on fibroepithelial lesions, in- latter should not be diffuse or well-developed for this diagnosis. cluding recent advances in molecular pathogenesis, and with an While mitotic activity 42/10 HPF correlated with recurrence in emphasis on problems and practical issues in diagnosis. one recent study on pediatric fibroepithelial lesions, stromal cel- lularity, border irregularity and frond-like growth in the absence of other features of phyllodes tumor did not.30 Fibroadenomas Practical problems and challenges in diagnosis Fibroadenomas are the most common fibroepithelial lesions and most common benign tumors of the breast. The incidence is The most challenging differential diagnosis is between cellular highest in women less than 30 years old, but these tumors are not fibroadenoma and phyllodes tumor, which is due to overlapping uncommon in older age groups.1,8,9 Fibroadenomas are often small and subjective histologic features and ill-defined criteria, as well (o3 cm) but may be large and even rapidly growing, especially as tumor heterogeneity and sampling issues in core biopsies; this juvenile fibroadenomas, which can raise clinical concern for is discussed in more detail below. In contrast, the diagnosis of a phyllodes tumor.1,10–12 An increased prevalence in younger wo- usual type fibroadenoma is often facile if typical features are men, tendency to regress or hyalinize with age, increased risk of present. Indeed, a diagnosis of fibroadenoma can be confidently development with estrogen replacement therapy, and an associa- made on core biopsy if the lesion lacks stromal fronds, stromal tion with gynecomastia or hormonal imbalance in men all suggest hypercellularity, atypia or mitotic activity. In this context, the al- a role for hormonal influence in fibroadenoma development and ternate diagnosis of phyllodes tumor on excision is o1% despite growth.10,13–17 Cyclosporine use in organ transplant patients has the heterogeneity of many phyllodes tumors.34,35 Some fi- been associated with multiple and/or bilateral fibroadenomas.18–20 broadenomas may show focal leaf-like architecture; if focal and Genetic risk factors remain unknown, but multiple and/or bilateral lacking hypercellular stroma, this should not be misinterpreted as fibroadenomas have been associated with a family history, and evidence for phyllodes tumor. Benign lipomatous metaplasia may Carney complex patients may develop multiple or bilateral myxoid raise concern for infiltrative growth, especially on biopsy; low fibroadenomas.21,22 stromal cellularity and lesional circumscription is often the clue to Fibroadenomas are well-circumscribed epithelial and stromal the correct diagnosis in this context (see Fig. 6F). Fibroadenomas proliferations derived from the terminal duct lobular unit (Fig. 1A). with lipomatous metaplasia may also mimic hamartomas, but this Growth may be intracanalicular or pericanalicular, and both pat- distinction is not clinically relevant. In limited and hypocellular terns often coexist (Fig. 1B-C). In usual type fibroadenomas, stro- biopsy material, myxoid fibroadenomas may resemble mucinous mal cellularity is similar to that of normal perilobular stroma, and carcinomas (Fig. 3A–B), which are also radiologically similar.36 there is no stromal atypia and no or only very widely scattered Mucin of mucinous carcinomas is often more fibrillary and blue- mitotic activity. The stroma may be fibrous, myxoid (Fig. 1D), tinged than the homogenous white-tan stroma of myxoid fi- hyalinized (Fig. 1E), or mixed. Benign heterologous stroma is rare broadenomas. Level sections or immunohistochemistry for but most often lipomatous, with myoid, cartilaginous or osseous myoepithelial cells may be helpful in challenging cases. Un- metaplasia being exceedingly rare. Fibroadenomas with sclerosing commonly, the stroma of higher grade phyllodes tumors can also adenosis, papillary apocrine metaplasia, cysts or epithelial calcifi- be paradoxically hypocellular and myxoid-appearing. Rarely,