In contrast to carcinomas of the breast, which rank

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1 Primary Breast Atypical Lipomatous Tumor/ Well-Differentiated Liposarcoma and Dedifferentiated Liposarcoma Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and its higher-grade counterpart, dedifferentiated liposarcoma (DDL), are extraordinarily rare tumors in the breast. The main differential diagnostic consideration of primary breast ALT/WDL is malignant phyllodes tumor with liposarcomatous differentiation, and the main differential diagnostic consideration of DDL in the breast is metaplastic breast carcinoma, particularly the spindle cell type, with heterologous sarcomatous differentiation. These differential diagnoses may be particularly challenging when evaluating limited core needle biopsy sampling. MDM2 and/or CDK4 protein overexpression and gene amplification are beneficial ancillary studies that can help establish the diagnosis of primary breast ALT/WDL and DDL, and effectively rule out the diagnoses of malignant phyllodes tumor and metaplastic breast carcinoma. (Arch Pathol Lab Med. 2018;142: ; doi: / arpa rsr2) In contrast to carcinomas of the breast, which rank amongst the most prevalent types of cancer in women worldwide, malignant breast lesions with either true mesenchymal origin or sarcomatous differentiation are relatively uncommon. Specifically, primary liposarcoma of the breast, including the most common variant, atypical lipomatous tumor/well-differentiated liposarcoma (ALT/ WDL), is extraordinarily rare, with several case reports and series in the literature accounting for just 44 cases 1 17 in our review. Additionally, many reports were published prior to testing for MDM2/CDK4 protein overexpression/gene amplification, tests that confirm the diagnosis of ATL/WDL. Only 2 publications report strong positivity for MDM2/ CDK4, supporting a diagnosis of primary breast ALT/ WDL. 2,8 Therefore, the true incidence of primary ALT/ WDL of the breast may even be overestimated in the sparse literature. Primary breast dedifferentiated liposarcoma Accepted for publication January 10, From the Department of Pathology, University of Michigan, Ann Arbor. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Julie M. Jorns, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Rm 2G332, Ann Arbor, MI ( jjorns@med.umich.edu). Laurence M. Briski, MD; Julie M. Jorns, MD (DDL), which can be seen in transformation of ALT/WDL, is even rarer, and is represented only by case reports in the literature. 18 The main differential diagnoses of primary breast ALT/ WDL and DDL are malignant phyllodes tumor (MPT) with heterologous liposarcomatous differentiation, and highgrade metaplastic breast carcinoma (MBC), respectively. On limited sampling, as with needle core biopsy, these entities may be difficult to distinguish via routine histology alone. Specifically, MPT with heterologous liposarcomatous differentiation may have areas that are morphologically indistinguishable from ALT/WDL of soft tissue. Although heterologous sarcomatous differentiation in MPT is uncommon, it is most frequently liposarcomatous, although fibrosarcomatous, osteosarcomatous, rhabdomyosarcomatous, and chondrosarcomatous differentiations have also been described. 19 Likewise, high-grade MBC may have areas that are morphologically indistinguishable from DDL. Metaplastic breast carcinoma is a poor-prognosis breast cancer subtype that constitutes less than 1% of breast carcinomas and includes a heterogeneous group of poorly differentiated carcinomas with spindle, squamous, chondroid, and/or osseous elements. The spindle subtype of MBC is morphologically most similar to DDL. 20 We review the features of primary breast liposarcoma, including ALT/WDL and DDL, and the main differential diagnostic entities, MPT with ALT/WDL-like features, and MBC, respectively, with an emphasis on ancillary studies that aid in their distinction. CLINICAL FEATURES Liposarcoma is the most common soft tissue sarcoma, accounting for approximately 20% of cases. Liposarcomas are only very rarely described as arising within the breast. Specifically, in the review by Adem et al, 1 primary breast sarcomas comprised just % (18 of ) of primary breast malignancies at The Mayo Clinic between 1940 and 1999, and, in their review of the literature, just 19 of 304 primary breast sarcomas (6.3%) were liposarcomas. Austin and Dupree 3 report the largest series, with 13 cases of primary breast liposarcoma. The Table outlines features of 44 cases of primary breast liposarcoma identified in the literature. At various soft tissue sites ALT/WDL is the most common histologic subtype of liposarcoma, accounting for approximately 40% to 45% of cases. 21 ALT/WDL usually arises 268 Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns

2 Previously Reported Cases of Primary Breast Liposarcoma and Pertinent Features (N ¼ 44) Histologic Type(s) (No. if.1 Case) Age, y, Median (Range if.1 Case) Gross Size, cm, Median (Range if.1 Case) Gross Tumor Borders (No. if.1 Case) MDM/ CDK4 Status Survival, mo, Median (Range, if.2 Cases) [No. if.1 Case] No. of Source, y Cases Al-Rikabi et al, WDL 22 8 Pushing Positive ANED 12 Austin and Dupree, 3 13 WDL (5) 48 (26 76) 8 (3 19) Pushing (7) Unknown ANED 48 (12 180) 1986 Infiltrating (5) [10] ML (4) Indeterminate LWD 10 PL (4) (1) DOD (5, 12) [2] Barnes and Pietruszka, ML 26 9 Infiltrating N/A ANED 240 Berg et al, NS (6) 48 (25 64) a 6 (NS) a Pushing (6) Unknown NS Callery et al, NS 66 3 NS Unknown ANED 168 Charfi et al, WDL Pushing Unknown ANED 72 Gutman et al, NS (2) N/A (45, 56) NS b NS Unknown NS c Johnstone et al, NS 29 NS NS Unknown ANED 119 Mardi and Gupta, PL Pushing N/A NS Mazaki et al, WDL Pushing Unknown ANED 20 Nandipati et al, PL Pushing N/A ANED 12 Norris and Taylor, NS (3) 49 (13 84) a 4 (1 19) a NS Unknown NS North et al, NS (2) 55 (15 75) a 6 (2 40) a NS Unknown NS Pollard et al, NS (6) 55.4 (24 79) a 5.9 (2 36) a NS Unknown DOD NS [3] d Raj et al, DDL Pushing Unknown NS Smola et al, WDL (1) N/A (53, 56) N/A (7, 15) NS Unknown ANED 14 SZ (1) DOD 12 Valero et al, WDL Pushing Positive NS Abbreviations: ANED, alive with no evidence of disease; DDL, dedifferentiated liposarcoma; DOD, died of disease; LWD, living with disease; ML, myxoid liposarcoma; N/A, not applicable; NS, not specified; PL, pleomorphic liposarcoma; SZ, spindle cell type; WDL, well-differentiated liposarcoma. a Other primary breast sarcoma subtypes included in median (range) data. b Mean size reported as cm. c Disease-free survival reported as 38% at 5 and 10 years. d Remaining data unavailable. within the deep soft tissues of the extremities or retroperitoneum, comprising 50% (46 of 92) and 25% (23 of 92) of cases, respectively, in the series by Weiss and Rao. 22 ALT/ WDL was the most common subtype among primary breast liposarcomas reported by Austin and Dupree 3 (5 of 13; 38.5%). Patients with ALT/WDL typically present in the sixth and seventh decades (range, years). Both sexes are equally represented, with the exception of male predilection for tumors of certain sites like the groin, trunk, mediastinum, and head and neck ALT/WDL usually develops as a painless, slowly enlarging mass that may be present for a long time before a patient seeks medical attention. Radiologic imaging usually shows a multilobulated mass with a mottled appearance, with areas of lower density corresponding to an adipocytic component and those of higher density corresponding to more fibrous/sclerotic regions. Depending on the proportion of the mass that is adipocytic, it may be difficult in some cases to distinguish ALT/WDL from benign lipoma radiographically. However, in general, ALT/WDL tends to be larger and has less welldelineated borders than lipoma. GROSS PATHOLOGY Most commonly, ALT/WDL often appears as a large multilobular lesion on gross examination. A total of 58 cases of ATL/WDL from various soft tissue sites had a mean size of 22.6 cm (range, 4 71 cm) in the series studied by Lucas et al. 23 ALT/WDLs may have varying proportions of adipocytic tissue and fibrous tissue. They tend to be vaguely circumscribed and light tan to yellow, with lobules of fat separated by variably thick fibrous bands. They may also display focal necrosis, gelatinous zones, and/or areas with punctate hemorrhage. Although they may appear circumscribed with pushing margins on gross examination, many are microscopically infiltrative. 23 Austin and Dupree 3 and others 2,4 8,10,18 report similar gross findings in the breast, with most appearing grossly circumscribed but with microscopically infiltrative margins. Specifically, in the series by Austin and Dupree, 3 8 of 11 cases of primary breast liposarcoma (72.7%) had microscopically infiltrative margins (Table). HISTOPATHOLOGY ALT/WDL has a spectrum of histologic appearances. The fourth edition (2013) of the World Health Organization (WHO) classification of soft tissue and bone tumors accordingly divides ALT/WDL into 3 histologic subtypes: adipocytic (lipoma-like), sclerosing, and inflammatory types. 24 Previous editions included spindle cell liposarcoma as a fourth subtype. However, because of a lack of characteristic molecular findings of ALT/WDL in this group of tumors, it has been suggested that these lesions may actually represent a different entity. The histologic classification of ALT/WDL is not generally predictive of behavior and prognosis, and therefore it is not necessary to subclassify these lesions in daily practice. Regardless of subtype, the key microscopic finding in ALT/ WDL is the presence of scattered atypical stromal cells with enlarged, hyperchromatic nuclei (Figure 1, A). Diagnosis of Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns 269

3 Figure 1. Example case of a primary breast well-differentiated liposarcoma with atypical stromal cells, adipocytes, and occasional lipoblasts (A), with corresponding positive MDM2 immunohistochemical stain (B). The tumor was also positive for MDM2 (12q15) gene amplification by fluorescence in situ hybridization (not pictured; D12Z3:MDM2 ratio, 8.35; average MDM2 signals per cell, 17.3) (hematoxylin-eosin, original magnifications 32 [A] and 340 [A, inset]; original magnification 310 [B]). Figure 2. Example case of malignant phyllodes tumor with liposarcomatous differentiation with atypical stromal cells, adipocytes, and lipoblasts (A), and corresponding negative MDM2 immunohistochemical stain (B) (hematoxylin-eosin, original magnifications 32 [A] and 340 [A, inset]; original magnification 310 [B]). Figure 3. Example case of metaplastic breast carcinoma, spindle cell type, with interspersed adipocytes (A) and corresponding positive cytokeratin 903 immunohistochemical stain (B) (hematoxylin-eosin, original magnifications 310 [A] and 340 [A, inset]; original magnification 310 [B]). 270 Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns

4 ALT/WDL does not require histologic evidence of lipoblasts, although they are often present. Lipoblasts are neoplastic cells with a generally round shape and large lipid-rich cytoplasmic vacuoles that indent or scallop a hyperchromatic and eccentrically located nucleus. 21,24 However, there are numerous lipoblast mimics, including atrophic fat cells, signet ring cells, hibernoma cells, necrotic fat cells, and reactive fat cells associated with silicone reaction and artifact. The adipocytic variant of ALT/WDL is predominantly composed of mature fat cells of varying size and shape with enlarged, hyperchromatic nuclei and variable numbers of hyperchromatic and multinucleated stromal cells, with involvement of fibrous septae and large vessel walls by atypical cells. Lipoblasts are usually less frequent in this subtype. In addition, there may be areas of prominent myxoid/chondroid stromal change. The sclerosing variant of ALT/WDL is most frequently observed in the groin and retroperitoneum, and typically has denser fibrotic zones, which alternate with mature adipocytes. Fibrotic areas are usually composed of collagen bundles and fibrils of varying thickness admixed with scattered atypical stromal cells. Finally, the inflammatory variant of ALT/WDL is primarily limited to the retroperitoneum and may look similar to adipocytic or sclerosing variants but additionally has a superimposed lymphocytic or plasmacytic infiltrate Dedifferentiated sarcoma was first described by Dahlin et al 25 in 1977 to describe histologic progression of low- to higher-grade sarcoma. Although Dahlin et al originally introduced this concept in the context of well-differentiated chondrosarcoma, it has since been shown to occur in other low-grade mesenchymal neoplasms, including ALT/WDL. Dedifferentiated liposarcoma has molecular and cytogenetic findings similar to those of ALT/WDL. Dedifferentiation occurs in approximately 10% of cases of ALT/WDL, and it is most frequent in retroperitoneal tumors. 21,24 Transition between well-differentiated and dedifferentiated zones is commonly abrupt and well delineated; however, it may be more gradual and/or admixed in some tumors. Dedifferentiated liposarcoma is usually cellular and predominantly composed of spindled cells arranged in a storiform or herringbone pattern, mimicking nonlipogenic sarcomas. In the vast majority of cases, DDLs have high-grade histologic features (eg, pleomorphic nuclei and increased mitoses), which many authors have described as resembling either high-grade fibrosarcoma or undifferentiated pleomorphic sarcoma. However, it has recently been acknowledged that some DDLs may exhibit low-grade morphology with areas of intermediate cellularity composed of relatively bland spindle cells arranged in fascicles. Additionally, a small percentage of DDLs (5% 10%) may exhibit heterologous rhabdomyosarcomatous, leiomyosarcomatous, osteosarcomatous, chondrosarcomatous, or angiosarcomatous differentiation. 21 ANCILLARY STUDIES Immunohistochemistry (IHC), cytogenetics, and molecular studies may not be necessary in the diagnosis of ALT/ WDL at typical soft tissue sites because the diagnosis is often based on histologic findings and many ancillary studies, although fairly sensitive, have lower specificity. However, ancillary studies may prove useful in establishing diagnosis at an unusual site, such as the breast, or in cases from conventional sites that lack classic histologic features. These studies may be very beneficial in distinguishing ALT/ WDL from MPT with liposarcomatous differentiation and DDL from MBC, especially when there is limited sampling, as with core biopsies. Immunohistochemistry The most commonly used IHC markers in the diagnosis of ALT/WDL are MDM2 and CDK4. Binh et al 26 studied 559 soft tissue tumors, including 44 ALT/WDL, 61 DDL, 48 benign adipose tumors, and 403 other sarcomas. They found that for ALT/WDL and DDL, 100% (44 of 44) and 95.1% (58 of 61), respectively, were MDM2 positive (Figure 1, B), and 90.9% (40 of 44) and 91.8% (56 of 61), respectively, were CDK4 positive. Another potentially useful marker reported in the literature is p16 (CDKN2A), a tumor suppressor protein that binds to and prevents CDK4/6 from promoting cellular proliferation as described above. Overexpression of p16 can be seen in a variety of neoplastic and preneoplastic processes, including ALT/WDL and DDL. Thway et al 27 examined IHC staining with p16, MDM2, and CDK4 in 216 adipocytic neoplasms, which included 31 ALT/WDL and 57 DDL. They found rates of sensitivity and specificity comparable to those of Binh et al 26 with respect to MDM2 and CDK4 in the diagnosis of ALT/WDL and DDL. With respect to p16 IHC in ALT/WDL and DDL, Thway et al 27 found 93% sensitivity and 92% specificity. 26 In addition, when p16, MDM2, and CDK4 were used in conjunction, they found a sensitivity of 71%; however, specificity was 98%. These results support MDM2 and CDK4 as sensitive markers and show p16 to be similarly sensitive, but they also demonstrate improved specificity when used in conjunction. 27,28 Molecular and Cytogenetic Studies The defining karyotypic finding in ALT/WDL is the presence of supernumerary ring and giant rod chromosomes that contain amplified sequences of the 12q13-15 region. 24 This region within the long arm of chromosome 12 encodes many genes, including MDM2, CDK4, HMGA2, SAS/TSPAN31, YEATS4, CPM, and FRS2. MDM2 is important in the ubiquination and degradation of tumor suppressor protein p53, and overexpression of MDM2 thereby helps to limit cellular apoptosis. CDK4 plays an important role in the phosphorylation of RB1, which prevents RB1 s interaction with E2F transcription factor, allowing the cell cycle to bypass the checkpoint between the G 1 and S phases and thereby stimulating cellular proliferation. 24,29 Fluorescence in situ hybridization (FISH) analysis for MDM2 and CDK4 gene amplification has been shown in several studies to be both more sensitive and more specific in the diagnosis of ALT/WDL than IHC. 24,29 As a result, there is debate among soft tissue pathologists over the role of IHC. Some prefer to start with IHC and use FISH for confirmation of positive cases because of the greater specificity of FISH. Like its well-differentiated counterpart, DDL also characteristically demonstrates amplification of 12q13-15, withafrequencysimilartothatofalt/wdl.however, cytogenetic abnormalities documented in DDL tend to be more complex than those in ALT/WDL. 24 Binh et al 26 observed that 53 of 55 DDLs (96%) demonstrated amplification of MDM2 and/or CDK4 by either comparative genomic hybridization or quantitative real-time polymerase chain reaction. Although highly sensitive, Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns 271

5 these techniques were not entirely specific because they also observed variable rates of positive MDM2/CDK4 amplification in other high-grade sarcomas, including myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and undifferentiated pleomorphic sarcoma. 26 DIFFERENTIAL DIAGNOSIS Although benign breast lesions may be considered in the differential diagnosis of ALT/WDL, the main differential diagnostic consideration of primary breast ALT/WDL is MPT with liposarcomatous differentiation. Likewise, the main differential diagnostic consideration of DDL in the breast is MBC with heterologous sarcomatous differentiation. Location in the breast alone favors MPT over ALT/ WDL and MBC over DDL (or other primary or metastatic sarcomas), unless there is a history of sarcoma at another site, because these are exceedingly rare diagnoses. However, their histomorphologies may be indistinguishable, necessitating ancillary studies for definitive diagnosis. Benign Lipomatous Breast Lesions Benign tumors and tumorlike conditions of the breast that may display an adipocytic component include mammary hamartoma, lipomatous adenosis, myofibroblastoma, and lipoma variants. 30 Primary ALT/WDL can generally be distinguished from these lesions histologically; all should lack the characteristic atypical hyperchromatic and pleomorphic stromal cells of ALT/WDL. MPT With Liposarcomatous Differentiation Phyllodes tumor is a biphasic stromal-epithelial neoplasm with variably cellular stroma and broad leaflike structures lined by epithelial cells. Phyllodes tumor may be further classified as benign, borderline, or malignant based on histologic criteria established by the WHO. These criteria include stromal cellularity and atypia, stromal overgrowth, mitotic rate, and tumor borders. 31 Occasionally MPT may display heterologous sarcomatous differentiation, which may mimic liposarcoma, fibrosarcoma, osteosarcoma, rhabdomyosarcoma, or chondrosarcoma. 19 Histologically, liposarcomatous differentiation within MPT may resemble ALT/WDL, DDL, or pleomorphic liposarcoma. 32 Key histologic features that aid in the differential diagnosis are the characteristic leaflike fronds with stromal expansion and benign epithelial lining of phyllodes tumor (Figure 2, A). However, sarcomatous overgrowth and limited core needle biopsy sampling may make identification of this architecture difficult. 19 In difficult cases, IHC and/or FISH studies may aid in distinction because MPT with ALT/WDL-like features has been shown to lack MDM2/CDK4 protein expression by IHC (Figure 2, B) and gene amplification by FISH, which are commonly present in de novo liposarcoma. 30,32,33 One exception was 1 case of MPT (out of 22) described by Bacchi et al 30 that reportedly showed focal MDM2 positivity by IHC (described by the authors as scattered nuclear staining). MBC With Heterologous Sarcomatous Differentiation Metaplastic breast carcinoma typically lacks true liposarcomatous differentiation but may display heterologous mesenchymal differentiation and thus can be morphologically indistinguishable from DDL or other high-grade sarcomas (Figure 3, A). Helpful histologic features that support the diagnosis of MBC are an associated epithelial component or ductal carcinoma in situ. However, these may not be present on biopsy. 31 There is limited literature on MDM2 and CDK4 in MBC. However, Ross et al 34 showed only 1 of 20 cases of highgrade MBC had CDK4 amplification, and Mizuno et al 35 reported a lack of MDM2 overexpression in a microarray of 251 breast carcinomas (of unspecified subtype). Despite limited data on MDM2 and CDK4, other IHC stains often can aid in diagnosis of challenging cases. Metaplastic breast carcinomas have variable cytokeratin and myoepithelial expression. Thus, an IHC panel of low molecular weight and high molecular weight cytokeratins (including, but not limited to, 5/6, 7, CAM 5.2, K903, AE1/ AE3, and MNF116) and, if negative, a second tier of myoepithelial markers, will often show positivity with at least 1 marker (Figure 3, B). 36,37 Koker and Kleer 37 found that p63 was most the most sensitive and specific marker, detecting strong p63 expression in 13 of 15 MBCs (86.7%), including all 12 with spindle and/or squamous differentiation. They also assessed 10 phyllodes tumors and 5 primary breast sarcomas, which were all negative for p63. Metaplastic breast carcinomas are less consistently positive for other myoepithelial markers, such as CD10, myosin, and smooth muscle actin. 36,38 PROGNOSIS AND TREATMENT Attempting to predict the behavior and evaluate the optimal management of primary breast liposarcoma is particularly challenging because of the rarity of this entity and the paucity of clinical data available. The largest series by Austin and Dupree 3 included 13 primary breast liposarcomas and 7 MPTs with liposarcomatous differentiation. The authors found that no single feature was entirely prognostic; however, infiltrative margins and pleomorphic subtype were most frequently associated with recurrence. Additionally, metastases occurred in 3 of 13 patients (23.1%) with primary breast liposarcoma and were not seen in any patients with MPT. However, these 3 patients also were of the pleomorphic subtype rather than the relatively more common ALT/WDL subtype. 3 Because of the paucity of data available, prognosis and treatment of primary ALT/WDL of the breast are generally considered with other types of primary breast sarcomas. Overall, the consensus is that margin status and tumor size are the most reliable prognostic factors in determining mortality for patients with primary breast sarcomas. The presence of positive margins is most predictive of residual disease, and is therefore a major risk factor for local recurrence and potential metastasis. Published case series also have shown that tumor size less than 5 cm was associated with a better overall survival. 39 Other prognostic indicators reported in the literature include histopathologic grade, infiltrative versus noninfiltrative pattern of growth, extent of surgical resection, and patient age. 1,39 Like soft tissue ALT/WDLs, the mainstay of treatment for primary ALT/WDL of the breast is surgical resection. Historically, mastectomy was regarded as the gold standard procedure for patients with breast sarcomas. However, there may not be a significant advantage for complete mastectomy over wide local excision. If the patient and surgeon(s) elect wide local excision in lieu of mastectomy, the general recommendation is to achieve complete excision with a minimum 272 Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns

6 of 1-cm margins of adjacent normal tissue. The importance of complete resection is highlighted by increased likelihood of local recurrence, metastasis, and/or dedifferentiation with incomplete resection. However, wide excision may be difficult because there are often microscopic foci of infiltrative growth that may not be readily apparent at the time of surgery. Complete resection with at least 1-cm margins also may not always be possible because of the proximity of adjacent structures, like vital neurovascular bundles, muscles, and/or bone. A consideration in choosing the most appropriate primary surgical procedure for a patient with breast sarcoma includes breast reconstruction. Wide local excision of some lesions may have worse aesthetic outcomes than mastectomy and reconstruction, and vice versa. Therefore, operative management decisions should be made on an individual basis. ALT/WDL lacks metastatic potential, but even in cases that undergo dedifferentiation into DDL, lymph node metastasis would be extraordinarily rare; the primary mode of metastasis in DDL is via hematogenous spread as for most sarcomas. Therefore, neither lymph node dissection nor sentinel lymph node biopsy is indicated for primary breast sarcomas, including ALT/ WDL or DDL. 21,39 The use of adjuvant and neoadjuvant therapies in primary breast sarcomas has been widely debated. Many authors have found that primary breast sarcomas are not typically radiosensitive, and have thus concluded that the risks of radiation therapy (including secondary treatment related malignancies) probably outweigh any potential benefits for the use of adjuvant radiation therapy in these patients. However, other authors have found significant benefits with adjuvant radiation patients, with longer disease-free survival, particularly in those with larger tumor size and higher histologic grade. 39 Some have additionally advocated for the use of adjuvant radiation therapy for those cases with close or positive margins in order to achieve improved local control. 1 It should be further noted that for ALT/WDL of soft tissue, adjuvant radiation therapy is often considered following surgical resection in cases with histologic evidence of dedifferentiation, cases with a size larger than 5 cm, and if there are microscopically close or positive margins. Because dedifferentiation is an indicator of more aggressive clinical behavior, the same consideration may be given to primary tumors in the breast. However, the evidence in favor of adjuvant radiotherapy in primary breast sarcomas remains rather limited, and no significant improvement in overall survival has been definitively shown. 21 Similarly, most authors have not found adjuvant chemotherapy to add any clinically significant benefits for primary breast sarcomas, and therefore have not made any conclusive recommendations for its use. 39 Furthermore, adjuvant chemotherapy has not been shown to provide any clinically significant benefits for ALT/WDL or DDL of soft tissue, and therefore is not routinely recommended. 21 Molecular therapeutics targeting MDM2, CDK4, and other mediators involved in the pathophysiology of ALT/WDL may play an important role in the future; however, clinical research is still ongoing in this area. References 1. Adem C, Reynolds C, Ingle JN, et al. Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review of the literature. 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Dedifferentiated liposarcoma with meningothelial-like whorls, metaplastic bone formation, and CDK4, MDM2, and p16 expression: a morphologic and immunohistochemical study. Am J Surg Pathol. 2011;35(3): He M, Aisner S, Benevenia J, et al. p16 immunohistochemistry as an alternative marker to distinguish atypical lipomatous tumor from deep-seated lipoma. Appl Immunohistochem Mol Morphol. 2009;17(1): Crago AM, Singer S. Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma. Curr Opin Oncol. 2011;23(4): Bacchi CE, Wludarski SC, Lamovec J, et al. Lipophyllodes of the breast: a reappraisal of fat-rich tumors of the breast based on 22 cases integrated by immunohistochemical study, molecular pathology insights, and clinical followup. Ann Diagn Pathol. 2016;21: Lakhani S, Ellis I, Schnitt S, et al., eds. WHO Classification of Tumours of the Breast. 4th ed. Lyon, France: IARC Press; Lyle PL, Bridge JA, Simpson JF, et al. Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification. Histopathology. 2016;68(7): Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns 273

7 33. Inyang A, Thomas DG, Jorns J. Heterologous liposarcomatous differentiation in malignant phyllodes tumor is histologically similar but immunohistochemically and molecularly distinct from well-differentiated liposarcoma of soft tissue. Breast J. 2016;22(3): Ross JS, Badve S, Wang K, et al. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. Arch Pathol Lab Med. 2015;139(5): Mizuno H, Spike BT, Wahl GM, et al. Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures. Proc Natl Acad Sci U S A. 2010;107(52): Dunne B, Lee AH, Pinder SE, et al. An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Hum Pathol. 2003;34(10): Koker MM, Kleer CG. p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol. 2004;28(11): Popnikolov NK, Ayala AG, Graves K, et al. Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrixproducing and spindle cell carcinomas. Am J Clin Pathol. 2003;120(2): Al-Benna S, Poggemann K, Steinau HU, et al. Diagnosis and management of primary breast sarcoma. Breast Cancer Res Treat. 2010;122(3): Submissions Now Accepted for the CAP18 Abstract Program Abstract and case study submissions to the College of American Pathologists (CAP) 2018 Abstract Program are now being accepted. Pathologists, laboratory professionals, and researchers in related fields are encouraged to submit original studies for possible poster presentation at the CAP18 meeting. Submissions will be accepted until 5 p.m. Central Friday, March 9, Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2018 issue. The CAP18 meeting will be held from October 20 to 24 in Chicago, Ill. Visit the CAP18 Web site ( and the Archives Web site (www. archivesofpathology.org) for additional abstract program information as it becomes available. 274 Arch Pathol Lab Med Vol 142, February 2018 Primary Breast ALT/WDL and DDL Briski & Jorns