Resident Short Review. Pleomorphic Lobular Carcinoma of the Breast. A Morphologically and Clinically Distinct Variant of Lobular Carcinoma

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1 Resident Short Review Pleomorphic Lobular Carcinoma of the Breast A Morphologically and Clinically Distinct Variant of Lobular Carcinoma Pleomorphic lobular carcinoma is an uncommon variant of lobular carcinoma, characterized by significant cytologic atypia that contrasts with the low pleomorphism of classical lobular carcinoma. It accounts for approximately 1% of all epithelial breast malignancies. In addition to its pleomorphism, it is characterized by aggressive behavior and shortened patient survival. Although the morphologic features of pleomorphic lobular carcinoma are well described, it often eludes accurate pathologic characterization. Some controversy surrounds the pathogenesis of pleomorphic lobular carcinoma; however, it is now considered a well-defined variant of invasive lobular carcinoma. Pleomorphic lobular carcinoma shares molecular alterations with classical lobular carcinoma, such as alterations in the gene CDH1 on chromosome band 16q22 that results in changes in E-cadherin protein function. The aggressive biology of pleomorphic lobular carcinoma relates to the acquisition of genetic alterations typical of high-grade ductal carcinoma, such as overexpression of HER2/neu and c-myc. (Arch Pathol Lab Med. 2013;137: ; doi: /arpa RS) Pleomorphic lobular carcinoma (PLC) was first described by Dixon et al 1 (1982) and Page 2 (1987) as a variant of invasive lobular carcinoma, characterized by a diffuse spreading pattern similar to classical invasive lobular carcinoma (ILC) but without its typical cytologic features. Its more aggressive nature, when compared to classical ILC, is evidenced by its larger tumor size, higher-grade cytologic features, higher incidence of distant metastasis, presence of lymphovascular invasion, and a more advanced stage at presentation. 3 7 Pleomorphic lobular carcinoma represents 10% of all lobular carcinomas. 8 It is often seen in association with pleomorphic lobular carcinoma in situ and classical Dawn Butler, MD; Marilin Rosa, MD lobular carcinoma in situ. 9 Similar to ILC, PLC is often multicentric and bilateral. 3,7,10,11 PATHOGENESIS The origin of PLC has been a matter of controversy because it has morphologic and immunophenotypic characteristics that overlap between ILC and invasive ductal carcinoma (IDC). The histologic architecture and pattern of tissue invasion closely resemble ILC; however, the cellular pleomorphism and nuclear atypia are more consistent with IDC. In fact, some authors 12,13 have suggested that PLC is a high-grade IDC that had lost E-cadherin expression. However, molecular studies have demonstrated that PLC and ILC share several molecular features such as inactivation or down-regulation of E-cadherin, a cell-to-cell adhesion molecule, as well as recurrent genomic changes affecting 1qþ, 11q, 16pþ, and 16q and genomic amplifications in the region of 8q24, 11q13, 12q13, 17q12, and 20q13. 13,14 Additionally, it has been proposed that PLC may develop through a molecular pathway similar to that of classical ILC with the acquisition of further molecular alterations, more typical of high-grade ductal carcinomas, such as gains of HER2/neu, c-myc, p53 positivity, and amplification of 8q24, 12q13, and 20q13. 3,12 15 These alterations are not seen in classical ILC and may be the contributing factors explaining its higher grade and more aggressive biology. 5,12 Owing to the similarities in molecular alterations and morphologic features, PLC is better classified as a variant of ILC. CLINICAL FEATURES Pleomorphic lobular carcinoma predominantly affects postmenopausal women between the ages of 60 to 80 years. 5,16,17 However, in cases associated with BRCA2 mutation, it can present at a much younger age. 13,18 This may explain the published data suggesting that the age range of PLC is wide, varying from 35 to 80 years of age. 5 Accepted for publication December 17, There are no specific clinical features that distinguish From the Department of Pathology and Laboratory Medicine, University of Florida, Jacksonville. (Dr Butler), and the Moffitt these tumors at presentation. Patients may present with an Cancer Center, Department of Anatomic Pathology, Tampa, Florida insidious growing, ill-defined, palpable breast mass. Patients usually have poor prognosis owing to advanced stage (Dr Rosa). The authors have no relevant financial interest in the products or at presentation, large tumor size, lymphovascular invasion, companies described in this article. Reprints: Marilin Rosa, MD, Moffitt Cancer Center, Department of and lymph nodes metastasis. 3,19 In addition, patients with Anatomic Pathology, Magnolia Drive, Tampa, FL PLC are more likely to develop distant metastasis and marilin.rosa@moffitt.org. recurrence than those with the classical form of ILC Arch Pathol Lab Med Vol 137, November 2013 Pleomorphic Lobular Carcinoma of the Breast Butler & Rosa

2 Figure 1. A, Classical invasive lobular carcinoma and lobular carcinoma in situ of the breast are characterized by loosely cohesive cells displaying low cytologic atypia, absence of significant pleomorphism, and scant cytoplasm. B and C, In contrast, pleomorphic lobular carcinoma cells display significant nuclear pleomorphism, abundant eosinophilic cytoplasm, nuclear hyperchromasia, nuclear membrane irregularities, and prominent nucleoli. Occasional intracytoplasmic mucin vacuoles are present. D, Lymphovascular invasion is commonly found in pleomorphic lobular carcinoma (hematoxylin-eosin, original magnifications 3400 [A through C]) and 3200 [D]). RADIOLOGIC FEATURES There are no significant differences between classical ILC and PLC on radiologic studies. 20 Radiologically, the tumor is most commonly detected as a spiculated mass on mammography or ultrasonography. Alternatively, it can present as an architectural distortion, a vague asymmetric density, or calcifications. 11,20 Despite improved imaging modalities, the single-cell infiltrative pattern of these tumors makes detection difficult, and cases of radiographically occult tumors that present with distant metastasis continue to be reported. 9 PATHOLOGIC FINDINGS Grossly, PLC is commonly seen as an irregular fibrotic area. Therefore, tumor size is often determined upon careful histologic examination. Tumor size ranges from 3 to 12.5 cm in the literature. 3,4,9,10,12,16,17 Microscopically, similar to classical ILC, PLC is characterized by dissociated cells arranged singly or in a loosely cohesive pattern. Additionally, PLC also displays a linear invasive pattern, targetoid growth pattern, and occasional intracytoplasmic mucin vacuoles (targetoid mucin). In contrast to ILC cells, PLC cells display a greater degree of cellular pleomorphism, have abundant eosinophilic cytoplasm, greater mitotic activity, and nuclear abnormalities such as hyperchromasia, nuclear membrane irregularities, and prominent nucleoli (Figure 1, A through D Figure 2, A). 3,5,6,8,12,13,16 The presence of abundant eosinophilic cytoplasm suggests apocrine differentiation, which is further confirmed by positivity with gross cystic disease fluid protein 15 (GCDFP-15), a marker of apocrine differentiation. 4,21 Cytologically, the smears are cellular and the cells are arranged predominantly in a dyshesive pattern, occasionally forming a few, small aggregates. Tumor cells display significant nuclear pleomorphism, prominent nucleoli, and abnormal chromatin distribution. Cytoplasm is abundant, pale to eosinophilic, and can be granular or vacuolated. Multinucleated malignant cells can be seen and mitoses are frequent (Figure 2, B and C). 7,22 Owing to the degree of pleomorphism and occasional tendency of the cells to aggregate in small groups, the distinction from high-grade ductal carcinoma in cytology may be challenging. Arch Pathol Lab Med Vol 137, November 2013 Pleomorphic Lobular Carcinoma of the Breast Butler & Rosa 1689

3 Figure 2. A, Metastatic pleomorphic lobular carcinoma in an axillary lymph node. B, On fine-needle aspiration biopsy, smears of pleomorphic lobular carcinoma tend to be cellular with predominantly dyshesive malignant cells, occasionally forming small aggregates. Tumor cells are pleomorphic with prominent nucleoli and abundant cytoplasm. C, Multinucleated malignant cells are seen in the cell-block preparation. D, Immunostain for E-cadherin shows absence of membranous staining (hematoxylin-eosin, original magnification 3200 [A]; ThinPrep, Papanicolaou, original magnification 3400 [B]; Cell-block, hematoxylin-eosin, original magnification 3400 [C]; original magnification 3200 [D]). IMMUNOHISTOCHEMISTRY Absence of E-cadherin membranous staining is characteristic of lobular carcinomas, including PLC (Figure 2, D). 13 The E-cadherin complex, essential for the formation of intercellular tight junctions, is composed of the transmembrane E-cadherin protein and a, b, c, and p120 catenins, which anchor the E-cadherin protein to the cytoplasmic actin filaments. The a and b catenins are complexed with the carboxy-terminal cytoplasmic tail of E-cadherin, whereas the p120 catenin is anchored to the E-cadherin in a juxtamembranous site. p120 is actively involved in cell motility, E-cadherin trafficking and turnover, promotion of cell junction formation, and regulation of the actin cytoskeleton. b-catenin is a cofactor implicated in the Wntsignaling pathway, a powerful regulator of cell proliferation. In lobular neoplasms, p120 yields a diffuse cytoplasmic immunostaining pattern. Conversely, ductal neoplasms retain the dominant membrane immunostaining pattern of p120 catenin. 23 The presence of weak membranous positivity for p120 may be observed in a small subset of ductal carcinoma cases, which could lead to misinterpretation as a lobular phenotype. 24 Complete lack of b-catenin membranous expression is associated with lobular histologic type, while expression of b-catenin is observed in virtually all cases of ductal carcinoma, both in situ and invasive. 25 There are conflicting data in the literature regarding the estrogen and progesterone hormone receptor status of PLC, since some case series describe a decreased expression of these hormone receptor markers. 5,8,15 17 However, most PLCs exhibit a luminal phenotype, being positive for estrogen and progesterone hormone receptors, therefore constituting a rare, high-grade, estrogen receptor positive spectrum of tumors. 8,14 Owing to the evolving definition of HER2/neu positivity, conflicting results are found in the literature regarding its overexpression in PLC. 16 Additionally, some of the published studies have classified both immunohistochemistry IHC 2þ and IHC 3þ as positive, with positive rates ranging between 40% to 80% of cases. 11,15,18 When only IHC 3þ cases are considered, the positivity rate is much lower, being 13% in one study. 8 A higher frequency of positivity for p53 has been demonstrated in PLC when compared with classical 1690 Arch Pathol Lab Med Vol 137, November 2013 Pleomorphic Lobular Carcinoma of the Breast Butler & Rosa

4 ILC. 8,12,15 18 p53 is a tumor suppressor protein that is encoded by the TP53 gene, which has the role of conserving genome stability, thus preventing malignant transformation. Tumor expression of p53 is associated with aggressive clinical course. In congruence with this observation, p53 is rarely expressed in classical ILC; however, 20% to 60% of cases of IDC are positive. 12 Additionally, supporting the clinical observation of its aggressive nature, PLC has a significantly higher proliferative index (as measured with Ki- 67) when compared to classical ILC. 5,8,15,17 As mentioned before, PLC shows diffuse staining with GCDFP-15 in most cases ,22 DIFFERENTIAL DIAGNOSIS Although histologic features alone are often enough to trigger the suspicion of PLC, owing to its mixed morphologic features that overlap with classical ILC and IDC, these tumors are often considered in the differential diagnosis. Immunohistochemistry using E-cadherin, p120, and b- catenin as described above is useful in separating PLC from the ductal group. However, because PLC and classical ILC share the same E-cadherin, p120, and b-catenin expression, these stains are not helpful in this context and cytologic features of the malignant cells are the most important diagnostic clue. 5,13 The pathologist should be aware that E- cadherin immunostain can show cytoplasmic granular staining, which can be a source of misinterpretation and a potential diagnostic pitfall. Therefore, some authors 25 encourage the combined use of E-cadherin and p120 in ambiguous cases. Pleomorphic lobular carcinoma should be also distinguished from apocrine carcinoma owing to their similar cytologic features and expression of GCDFP-15 and androgen receptors. 26 However, apocrine carcinoma demonstrates the same architectural growth pattern of ductal carcinoma of no special type and is positive for E-cadherin immunohistochemistry. 21 PROGNOSIS Owing to its higher grade, the prognosis of PLC is poor and considered worse than for classical ILC, with higher risk of recurrence, nodal and distant metastasis, and shorter recurrence period. When compared with invasive ductal carcinomas, the prognosis of PLC is similar to that of highgrade tumors. 3,4,6 8,16 The most common metastatic sites in one series were bone, liver, lung, and peritoneum. 16 TREATMENT The surgical treatment of ILC has been a matter of debate. Since ILC tends to be more commonly multifocal and bilateral when compared to IDC, mastectomy has been frequently the treatment of choice. However, well-localized and small tumors without clinical and radiologic evidence of multifocality or multicentricity can be treated with conservation therapy. 3,4,27 Magnetic resonance imaging has shown to accurately depict multifocality, and its use is likely to change the surgical management in patients with ILC. 18 Unfortunately, there are not enough clinical data to support one management approach over the other for cases of PLC. Patients with PLC are managed similarly to patients with other types of high-grade breast carcinomas according to tumor staging, axillary lymph nodes status, and prognostic and predictive markers. 18 As with any type of breast carcinoma, these patients should be examined carefully in the context of a multidisciplinary team to decide the best surgical management. Owing to its distinct clinical and prognostic characteristics, some authors 3 have postulated that patients with PLC should be clinically managed more aggressively than those with classical variants of ILC. It has been suggested that the great risk of distant metastasis of PLC may justify the use of adjuvant chemotherapy. 3 Positivity for hormone receptors and amplification and overexpression of HER2/neu in PLC suggest that endocrine-related targeted therapy and trastuzumab may be valuable treatment regimens for these patients. 14 Preliminary reports by Mahtani and Vogel 28 on the use of trastuzumab, with good response in 4 patients with PLC, were promising. However, these findings have not been corroborated by others. 16 Since most series consist of a small number of cases with short-term follow-up, larger studies are necessary to draw definitive conclusions on drug efficacy for the treatment of PLC. CONCLUSIONS Pleomorphic lobular carcinoma is an uncommon variant of invasive lobular carcinoma, characterized by its poor prognosis and tendency to metastasize early. Morphologically, PLC shares features with classical ILC and IDC, which led to speculation about its true pathogenesis. However, molecular studies have established that PLC shares the same molecular genetic pathway as classical ILC; therefore, it is better classified as a variant of lobular carcinoma. 12 Currently, surgical management is the most common treatment modality. However, since most studies include a small number of cases, additional clinical treatment data are needed. References 1. Dixon JM, Anderson TJ, Page DL, et al. Infiltrating lobular carcinoma of the breast. Histopathology.1982;6: Page, DL, Anderson, TJ. Rare patterns of invasive carcinoma. In: Diagnostic Histopathology of the Breast. 1st ed. Edinburgh, United Kingdom: Churchill Livingstone; 1987: , Buchanan CL, Flynn LW, Murray MP, et al. Is pleomorphic lobular carcinoma really a distinct clinical entity? J Surg Oncol. 2008;98(5): Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol. 1992;23(6): Jacobs M, Fan F, Tawfik O. Clinicopathologic and biomarker analysis of invasive pleomorphic lobular carcinoma as compared with invasive classic lobular carcinoma: an experience in our institution and review of the literature. Ann Diagn Pathol. 2012;16(3): Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol. 1992;23(10): Gangane N, Anshu, Shivkumar VB, Sharma S. Pleomorphic lobular carcinoma of the breast: a case report. Acta Cytol. 2002;46(5): Frolik D, Caduff R, Varga Z. Pleomorphic lobular carcinoma of the breast: its cell kinetics, expression of oncogenes and tumour suppressor genes compared with invasive ductal carcinomas and classical infiltrating lobular carcinomas. Histopathology. 2001;39(5): Carder PJ, Shaaban A, Alizadeh Y, Kumarasuwamy V, Liston JC, Sharma N. Screen-detected pleomorphic lobular carcinoma in situ (PLCIS): risk of concurrent invasive malignancy following a core biopsy diagnosis. Histopathology. 2010;57(3): Dizdar O, Arslan C, Altundag K. Synchronous ovarian cancer in a patient with pleomorphic lobular breast cancer: a therapeutic dilemma. Clin Oncol (R Coll Radiol). 2010;22(2): Manucha V, Khilko N, Reilly K, Zhang X. Invasive pleomorphic lobular carcinoma, negative for ER, PR and Her/2neu a case report. Int J Clin Exp Pathol. 2011;4(2): Reis-Filho JS, Simpson PT, Jones C, et al. Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol. 2005;207(1): Simpson PT, Reis-Filho JS, Lambros MB, et al. Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. J Pathol. 2008;215(3): Vargas AC, Lakhani SR, Simpson PT. Pleomorphic lobular carcinoma of the breast: molecular pathology and clinical impact. Future Oncol. 2009;5(2): Arch Pathol Lab Med Vol 137, November 2013 Pleomorphic Lobular Carcinoma of the Breast Butler & Rosa 1691

5 15. Palacios J, Sarrio D, Garcia-Macias MC, Bryant B, Sobel ME, Merino MJ. Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast. Mod Pathol. 2003;16(7): Monhollen L, Morrison C, Ademuyiwa FO, Chandrasekhar R, Khoury T. Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type. Histopathology. 2012;61(3): Radhi JM. Immunohistochemical analysis of pleomorphic lobular carcinoma: higher expression of p53 and chromogranin and lower expression of ER and PgR. Histopathology. 2000;36(2): Moe RE, Anderson BO. Distinctive biology of pleomorphic lobular carcinoma of the breast. J Surg Oncol. 2005;90(2): Bentz JS, Yassa N, Clayton F. Pleomorphic lobular carcinoma of the breast: clinicopathologic features of 12 cases. Mod Pathol. 1998;11(9): Jung HN, Shin JH, Han BK, Ko EY, Cho EY. Are the imaging features of the pleomorphic variant of invasive lobular carcinoma different from classic ILC of the breast? [published online ahead of print August 14, 2012]. Breast. 21. Rosen PP. Classical and pleomorphic lobular carcinoma cells. In: Rosen s Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, a Wolters Kluwer Business; 2009: Monaco SE, Dabbs DJ, Kanbour-Shakir A. Pleomorphic lobular carcinoma in pleural fluid: diagnostic pitfall for atypical mesothelial cells. Diagn Cytopathol. 2008;36(9): Dabbs DJ, Bhargava R, Chivukula M. Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin. Am J Surg Pathol. 2007;31: Brandt S, Chen YB, Chadwick P, et al. Is p120 as effective as E-cadherin (ecad) in distinguishing lobular from ductal carcinomas of the breast? Mod Pathol. 2008;21(suppl 1):24A 25A. 25. de Deus Moura R, Wludarski SC, Carvalho FM, Bacchi CE. Immunohistochemistry applied to the differential diagnosis between ductal and lobular carcinoma of the breast [published online ahead of print May 16, 2012]. Appl Immunohistochem Mol Morphol. doi: /pai.0b013e318255bafa. 26. Masood S, Rosa M. The challenge of apocrine proliferations of the breast: a morphologic approach. Pathol Res Pract. 2009;205(3): Dabbs D, ed. Breast Pathology. 1st ed. Philadelphia, PA: Elselvier Saunders; Mahtani RL, Vogel CL. Pleomorphic lobular carcinoma of the breast: four long-term responders to trastuzumab coincidence or hint? J Clin Oncol. 2008; 26(35): Arch Pathol Lab Med Vol 137, November 2013 Pleomorphic Lobular Carcinoma of the Breast Butler & Rosa