115J UOEH 36（ 2 ）: 115－121（2014）

Introduction

　Lipoblasts are a distinct type of mesenchymal cells that more or less recapitulate the differentiation process of normal fat. They are morphologically immature-ap-pearing fat cells ranging from the earliest cells closely resembling fibroblasts to those having acquired lipid droplets throughout the cytoplasm [1].　According to Shaw, Todd and Bowman initially pro-posed in 1845 the concept that lipoblast is a specialized mesenchymal cell differing from fibroblast [2]. Wells emphasized in his review that fat cells are probably not just modified fibroblasts but are derived from units

which are segregated from undifferentiated mesoderm during embyonal life and persist throughout postnatal life as specialized ʻlipoblastsʼ [3]. Subsequently, lipo-blasts were regarded as ordinarily specialized fat-form-ing mesenchymal cells which on occasion could produce a very wide variety of different and complex tissues [4]. Despite some morphologic overlap with embryonal fat, lipoblasts are indeed poorly identified in tissues other than those in neoplasms. In contrast, non-neoplastic, im-mature forms of fat cells, designated as preadipocytes or preadipose cells, are well recognized and have been ex-tensively investigated morphologically and physiologi-cally [5-7]. Currently, ̒ lipoblastsʼ thus refer to a range of

［Review］

Lipoblast: Morphologic Features and Diagnostic Value

Masanori Hisaoka1, 2*

1 Department of Surgical Pathology, University Hospital, University of Occupational and Environmental Health, Japan. Yahatanishi-ku, Kitakyushu 807-8555, Japan

2 Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Japan. Yahatanishi-ku, Kitakyushu 807-8555, Japan

Abstract : Lipoblasts are conceptually a precursor or immature form of adipocytes and histologically defined as lip-id-containing, mono－ or multivacuolated cells possessing hyperchromatic, indented or often scalloped nuclei. They are essentially identified in neoplastic conditions and assumed to recapitulate, to some extent, the differentiation process of normal fat (adipogenesis) like their potential normal counterpart, preadipocyte or preadipose cell. Tra-ditionally, great emphasis has been placed on the identification of lipoblasts in diagnostic pathology, particularly of liposarcoma. However, it is not always an easy task for pathologists because of a variety of histological mimics such as Lochkern cells, brown fat cells and pseudolipoblasts. Currently, lipoblasts are not a prerequisite for the diagnosis of liposarcoma partly because of some benign tumors harboring lipoblasts or lipoblast-like cells such as spindle cell/pleomorphic lipoma and chondroid lipoma, although their presence is still crucial for proper diagnosis. This review summarizes the clinicopathologic features of lipoblasts, their histological mimics and representative benign tumors carrying lipoblasts to facilitate routine pathology practice and to avoid erroneous diagnosis of liposarcoma.

Keywords : adipose tissue, lipoblast, pathologic diagnosis, tumor.

（Received February 4, 2014, accepted April 24, 2014）

*Corresponding Author: Masanori Hisaoka, MD, PhD, Department of Surgical Pathology, University Hospital and Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Japan. Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel: +81-93-691-7425, Fax: 093-692-0189, Email: hisaoka@med.uoeh-u.ac.jp

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neoplastic immature fat cells [1].　Preadipocytes usually resemble fibroblasts and have the ability to proliferate and differentiate into mature adipocytes [8]. Although the capacity of lipoblasts to fully differentiate remains poorly assessed, they are as-sumed to be cellular intermediates between mesenchy-mal stem cells and mature adipocytes like preadipocytes. Therefore, the distinction between lipoblasts and preadi-pocytes is not clear, and preadipocytes may represent a normal counterpart of lipoblasts. 　Since Stout described for the first time that liposar-coma is a malignant tumor of lipoblasts, the identifica-tion of lipoblasts has been overemphasized in the diag-nosis of liposarcoma. It is obviously an essential task for pathologists to explore lipoblasts in some situations (i.e. liposarcomas) where their presence is crucial for proper diagnosis. However, there are many types of cells simulating lipoblasts in variable neoplastic or non-neoplastic conditions, which may create some diagnostic difficulties. In addition, lipoblasts are not only confined to liposarcoma but also appear in benign lipogenic tu-mors. Lipoblasts may be inappreciable or totally absent in atypical lipomatous tumor (synonymously referred to as well differentiated liposarcoma) [9]. Consequently, lipoblasts are not a prerequisite for the diagnosis of lipo-sarcoma in the currently used diagnostic system for soft tissue and bone tumors [10].　This review describes the clinicopathologic features of a variety of neoplastic or non-neoplastic conditions with lipoblasts or their morphologic mimics in order to facilitate routine pathology practice and avoid erroneous pathologic diagnoses.

Morphologic criteria of lipoblasts

　The morphologic criteria of lipoblasts described in the literature may vary. However, in a narrow sense, lipo-blasts are the cells having hyperchromatic indented or sharply scalloped nuclei and lipid-rich mono- or mul-tivacuolated cytoplasm [1, 11]. The intracytoplasmic vacuoles should be sharply marginated, which is distinct from ill-defined vacuoles of pseudolipoblasts that con-tain mucin [12]. The nucleus of lipoblast may be pushed aside by a single large lipid vacuole, resulting in a sig-net ring configuration, or remain centrally located with small indentations by multiple small vacuoles, simulat-

ing sebaceous cells or adrenal spongiocytes [13]. In ad-dition to the above typical lipoblasts, atypical or giant forms having large bizarre or multiple nuclei are appre-ciated. Such pleomorphic lipoblasts are an integral com-ponent of pleomorphic liposarcoma [14]. It should also be noted that some investigators prefer the designation of ʻatypical adipocytesʼ to univacuolated lipoblasts [15].

Histological mimics of lipoblasts

　Lipoblast-like cells are occasionally encountered in a variety of neoplastic and non-neoplastic conditions [1]. One well-known example is the adipocyte having intra-nuclear vacuoles (so-called Lochkern that means ̒ hole in the nucleusʼ in German) [16], which are visible in a his-tological slice grazing the nucleus of adipocyte viewed en face (Fig. 1A). Lochkern cells can be observed in benign lipogenic tumors as well as normal fat, particu-larly in thick sections. However, such nuclei are never hyperchromatic or pleomorphic as seen in liposarcoma. 　Starvation, malnutrition or local trauma often re-sults in atrophy of fatty tissue with lipoblast-like cells, which show reduction of intracellular lipid content and pronounced nuclei. In contrast to neoplastic lipoblasts, such atrophic fat cells are almost uniform in shape, and arranged in pre-existing lobular structures [1]. Foreign body granulomatous reactions against silicone, paraffin or other injected agents may create multivacuolated his-tiocytes that also simulate lipoblasts (Fig. 1B) [17, 18]. However, immunohistochemical expression of some his-tiocytic markers, such as Cluster of differentiation (CD) 68 and CD163, and clinical settings of patients would be helpful for leading to their correct diagnoses. It should be noted that histiocytes are also commonly positive for Mouse Double Minute 2 (MDM2) [9], which is a use-ful immunohistochemical marker of atypical lipomatous tumor (synonymously referred to as well differentiated liposarcoma) and dedifferentiated liposarcoma.　Multivacuolated cells resembling lipoblasts may also be recognized in brown fat or its neoplastic counterpart, hibernoma, but their nuclei are usually centrally locat-ed or slightly eccentric with often prominent nucleoli, features distinguishable from lipoblasts (Fig. 1C) [19]. Although brown fat cells or hibernoma cells express their marker protein, Uncoupling Protein 1 (UCP-1), immunohistochemically [20], lipoblasts in atypical lipo-

117Lipoblasts in Soft Tissue Pathology

matous tumor/well differentiated liposarcoma may also be positive for this marker (Fig. 1D, unpublished obser-vation). Conversely, atypical lipomatous tumor may dis-play differentiation toward brown fat.　Pseudolipoblasts containing mucin may be present in a variety of myxoid tumors such as myxofibrosarcoma and myxoinflammatory fibroblastic sarcoma (Fig. 1E). Their distinguishing features from lipoblasts are men-tioned above.

Benign lipogenic tumors with lipoblasts

　Lipoblasts have been considered to be a histologic hallmark of malignant lipogenic tumors (i.e. liposarco-mas). However, they can also be indentified in benign tumors such as lipoblastoma, chondroid lipoma and spindle cell/pleomorphic lipoma. Therefore, the pres-ence of lipoblasts alone does not warrant the diagnosis of liposarcoma.　Lipoblastoma: Lipoblastoma is a benign neoplasm that resembles fetal adipose tissue with a certain risk of local recurrence. Jaffe originally coined the term ʻlipo-blastomaʼ to describe a tumor of immature fat cells [21]. The case recorded later as lipoblastomatosis by Vellios et al. was an 8-month-old female infant with multiple subcutaneous lesions of similar morphology [22]. The tumor basically affects infants or young children who are less than 10 years old (more than 90% of cases) [23], and older or adult patients are extremely rare. Accord-ing to Chung and Enzinger, tumors infiltrating into the adjacent tissue in a diffuse manner and being well cir-cumscribed are labeled as diffuse lipoblastomatosis and lipoblastoma, respectively [24]. Microscopically, the tumor is characterized by a distinctive lobular architec-ture of sheets of fat cells at varying maturation stages, including primitive stellate or spindled mesenchymal cells, mono－ or multivacuolated lipoblasts and mature-looking adipocytes (Fig. 1F). In contrast to liposarco-mas, atypical or pleomorphic lipoblasts or stromal cells are absent. Myxoid areas and a plexiform vascular pat-tern are common. Immunohistochemically, the fat cells in lipoblastoma are positive for S-100 protein and CD34 [23], and desmin-positive primitive mesenchymal cells, probably of myofibroblastic phenotype, have been re-cently described [25]. Lipoblastoma harbors character-istic genetic alterations involving the Pleomorphic Ad-

enoma Gene 1 (PLAG1) gene that result in fusion genes such as the Hyaluronan Synthase 2 (HAS2)-PLAG1 and Collagen type I alpha 2 (COL1A2)-PLAG1 and in over-expression of PLAG1 [26-28].　Chondroid lipoma: First described in 1993 by Meis and Enzinger, chrondroid lipoma is a benign and ex-tremely rare fatty tumor that is often mistaken for other neoplasms such as myxoid liposarcoma and extraskeletal myxoid chondrosarcoma [29]. The tumor mostly arises in the proximal extremities or limb girdles of middle-aged women as a slowly growing soft tissue mass. The lesion is well demarcated or encapsulated and composed of strands or nests of round tumor cells (Fig. 1G). They are often identical to mono－ or multivacuolated lipo-blasts and embedded in a myxochondroid or hyalinized background, displaying a lobular growth pattern. Eosin-ophilic finely vacuolated cells that resemble brown fat cells and mature adipocytes may be admixed in variable proportions. Cellular pleomorphism and mitotic activity are virtually lacking [29]. Immunohistochemically, the tumor cells express S-100 protein and sometimes CD68 [29, 30]. A recurrent chromosomal translocation, t (11; 16)(q13; p13), resulting in the chromosome 11 open reading frame 95-myocardin-like 2 (C11orf95-MKL2) fusion gene, has been recently described in chondroid lipoma [31].　Spindle cell/pleomorphic lipoma: Although spindle cell lipoma and pleomorphic lipoma were originally de-scribed separately [32, 33], they are currently regarded as histologic ends of the spectrum of a single entity be-cause of their significantly overlapping clinicopathologic and cytogenetic features [34]. They usually develop as subcutaneous tumors, particularly in the posterior neck, back or shoulder of middle-aged or elderly men. Spindle cell/pleomorphic lipoma shares morphologic features with ordinary lipoma; most are between 3 and 5 cm in size and well circumscribed. Histologically, spindle cell lipoma is characterized by an admixture of mature adi-pocytes, small primitive or undifferentiated spindle cells and bundles of brightly eosinophilic or ropey collagen. In pleomorphic lipoma, pleomorphic giant cells having hyperchromatic or smudgy, multiple nuclei, often show-ing a floret-like appearance, are present together with the histology almost identical to that of spindle cell lipoma. The spindle cells and pleomorphic cells are essentially positive for CD34, immunohistochemically. Notably,

118 M Hisaoka

lipoblasts can be seen in some cases of spindle cell/pleo-morphic lipoma, which may make the differentiation from atypical lipomatous tumor (or well differentiated liposarcoma) difficult (Fig. 1H) [34, 35]. However, in addition to their distinct clinical settings, an immuno-

histochemical or genetical assessment of recently iden-tified markers (e.g. MDM2, cyclin-dependent kinase 4 (CDK4), p16, retinoblastoma 1 (RB1)) for each of these tumors would be helpful for the distinction between them [36, 37].

Fig. 1. Microscopic findings of a variety of lipoblasts and their histologic mimics. Lochkern cells (arrows) A, multivacuolated histiocytes (arrows) in silicone granuloma B, and multivacuolated cells in the brown fatty tissue in the adult heart C. Cytoplasmic expression of Uncoupling Protein 1 (UCP-1), a marker of brown fat, is seen in mono－ or multivacuolated lipoblasts in well differentiated liposarcoma arising in the mediastinum D. Bizarre pseudolipo-blasts are present in myxoinflammatory fibroblastic sarcoma E. mono－ or multivacuolated lipoblasts are identified in lipoblastoma F or chondroid lipoma G. Pleomorphic lipoma may also contain lipoblasts (arrow) H.

AA BB

CC DD

EE FF

GG HH

119Lipoblasts in Soft Tissue Pathology

Conclusions

　Lipoblasts are abnormal or neoplastic immature-ap-pearing fat cells with still uncertain biologic properties. In routine pathology practice, they should be differenti-ated from their histological mimics, including Lochkern cells, atrophic fat cells, brown fat cells, multivacuolated histiocytes and pseudolipoblasts. In addition, lipoblasts may be present in some benign lipogenic tumors or even hardly identified in atypical lipomatous tumors/well differentiated liposarcoma. Although the current diag-nostic value of lipoblasts is less significant than consid-ered previously, diagnostic lipoblasts should always be assessed based on their strict criteria with appropriate clinicopathologic backgrounds that lead to a correct di-agnosis of liposarcoma.

References

1 . Goldblum JR, Folpe AL & Weiss SW (2013): Liposar-coma. In: Enzinger & Weissʼs Soft Tissue Tumors, 6th. (Goldblum JR, Folpe AL & Weiss SW ed ). Elsevier, Philadelphia pp 484-523

2 . Shaw HB (1902): A contribution to the study of the morphology of adipose tissue. J Anat Physiol 36: 1-13

3 . Wells HG (1940): Adipose tissue, a neglected subject. JAMA 114: 2177-2183

4 . Stout AP (1944): Liposarcoma. The malignant tumor of lipoblasts. Ann Surg 119: 86-107

5 . Green H & Kehinde O (1975): An established preadi-pose cell line and its differentiation in culture. II. Fac-tors affecting the adipose conversion. Cell 5: 19-27

6 . Dardick I, Poznanski WJ, Waheed I & Setterfield G (1976): Ultrastructural observations on differentiating human preadipocytes cultured in vitro. Tissue Cell 8: 561-571

7 . Rosen ED & MacDougald OA (2006): Adipocyte dif-ferentiation from the inside out. Nat Rev Mol Cell Biol 7: 885-896

8 . Moreno-Navarrete JM & Fernández-Real (2012): Adi-pocytic differentiation. In: Adipose Tissue Biology (Symonds ME ed ). Springer New York pp 17-38

9 . Dei Tos AP (2014): Liposarcoma: diagnostic pitfalls and new insights. Histopathology 64: 38-52

10 . Dei Tos AP & Pedeutour F (2013): Atypical lipomatous tumour. In: WHO Classification of Tumours of Soft

Tissue and Bone (Fletcher CDM, Bridge JA, Hogen-doorn PGH & Mertens F ed). IARC Press, Lyon pp 33-36

11 . Laurino L, Furlanetto A, Orvieto E & Dei Tos AP (2001): Well-differentiated liposarcoma (atypical lipo-matous tumors). Semin Diagn Pathol 18: 258-262

12 . Goldblum JR, Folpe AL & Weiss SW (2013): Border-line and malignant fibroblastic/myofibroblastic tu-mors. In: Enzinger & Weissʼs Soft Tissue Tumors, 6th. (Goldblum JR, Folpe AL & Weiss SW ed ). Elsevier, Philadelphia pp 288-340

13 . Rosai J (2011): Soft tissues. In: Rosai and Ackermanʼs Surgical Pathology, 10th. (Rosai J ed ). Elsevier, Edin-burgh pp 2105-2232

14 . Enzinger FM & Winslow DJ (1962): Liposarcoma: A study of 103 cases. Virchows Arch Path Anat 335: 367-388

15 . Miettinen M (2010): Atypical lipomatous tumor and liposarcomas. In: Modern Soft Tissue Pathology. Tu-mors and Non-Neoplastic Conditions. (Miettinen M ed). Cambridge Univ. Press, Cambridge pp 432-459

16 . Plaut A (1957): The notched nucleus of the normal fat cell (Unnaʼs lochkern). J Mt Sinai Hosp NY 24: 1112-1120

17 . Shvartsbeyn M & Rapkiewicz A (2011): Silicon-asso-ciated subcutaneous lesion presenting a mass: a con-founding histologic correlation. Hum Pathol 42: 1364-1367

18 . Wong KT, Lee PS, Chan YL & Chow LT (2003): Paraf-finoma in anterior abdominal wall mimicking liposar-coma. Br J Radiol 76: 264-267

19 . Furlong MA, Fanburg-Smith JC & Miettinen M (2001): The morphologic spectrum of hibernoma. A clinico-pathologic study of 170 cases. Am J Surg Pathol 25: 809-814

20 . Manieri M, Murano I, Fianchini A, Brunelli A & Cinti S (2010): Morphological and immunohistochemical fea-tures of brown adipocytes and preadipocytes in a case of human hibernoma. Nutr Metab Cardiovasc Dis 20: 567-574

21 . Jaffe RH (1926): Recurrent lipomatous tumors of the groin: Liposarcoma and lipoma pseudomyxomatodes. Arch Pathol 1: 381-387

22 . Vellios F, Baez J & Shumacker HB (1958): Lipoblasto-matosis. A tumor of fetal fat different from hibernoma. Report of a case, with observations on the embryogen-

120 M Hisaoka

esis of human adipose tissue. Am J Pathol 34: 1149-1159

23 . Coffin CM, Lowichik A & Putnam A (2009): Lipoblas-toma (LPB). A clinicopathologic and immunohisto-chemical analysis of 59 cases. Am J Surg Pathol 33: 1705-1712

24 . Chung EB & Enzinger FM (1973): Benign lipoblasto-matosis. An analysis of 35 cases. Cancer 32: 482-492

25 . Kubota F, Matsuyama A, Shibuya R, Nakamoto M & Hisaoka M (2013): Desmin-positivity in spindle cells: under-recognized immunophenotype of lipoblastoma. Pathol Int 63: 353-357

26 . Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S & Fletcher JA (2000): PLAG1 fusion onco-genes in lipoblastoma. Cancer Res 60: 4869-4872

27 . Morerio C, Rapella A, Rosanda C, Tassano E, Gambini C, Romagnoli G & Panarello C (2005): PLAG1-HSA2 fu-sion in lipoblastoma with masked 8q intrachromosomal rearrangement. Cancer Genet Cytogenet 156: 183-184

28 . Matsuyama A, Hisaoka M & Hashimoto H (2012): PLAG1 expression in msenchymal tumors: An immu-nohistochemical study with special emphasis on the pathogenetical distinction between soft tissue myo-epithelioma and pleomorphic adenoma of the salivary gland. Pathol Int 62: 1-7

29 . Meis JM & Enzinger FM (1993): Chondroid lipoma: A unique tumor simulating liposarcoma and myxoid chondrosarcoma. Am J Surg Pathol 17: 1103-1112

30 . Guillou L & Coindre J-M (2001): Newly described adi-pocytic lesions. Semin Diagn Pathol 18: 238-249

31 . Flucke U, Tops BB, de Saint Aubain Somerhausen N, Bras J, Creytens DH, Küsters B, Groenen PJ, Verdijk MA, Suurmeijer AJ & Mentzel T (2013): Presence of C11orf95-MKL2 fusion is a consistent finding in chon-droid lipomas: A study of eight cases. Histopathology 62: 925-930

32 . Enzinger FM & Harvey DA (1975): Spindle cell lipo-ma. Cancer 36: 1852-1859

33 . Shmookler BM & Enzinger FM (1981): Pleomorphic lipoma: a benign tumor simulating liposarcoma. A clinicopathologic analysis of 48 cases. Cancer 47: 126-133

34 . Miettinen MM & Mandahl N (2013): Spindle cell/pleomorphic lipoma. In: WHO Classification of Tu-mours of Soft Tissue and Bone (Fletcher CDM, Bridge JA, Hogendoorn PGH & Mertens F ed ). IARC Press, Lyon pp 29-30

35 . Yang TT, Reed ACC & Athanasou NA (2001): A P2 protein expression as a diagnostic marker in soft tissue tumours. Sarcoma 5: 139-142

36 . Thway K, Flora R, Shah C, Olmos D & Fisher C (2012): Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 36: 462-469

37 . Chen BJ, Mariño-Enríquez A, Fletcher CDM & Horn-ick JL (2012): Loss of retinoblastoma protein expres-sion in spindle cell/pleomorphic lipomas and cytoge-netically related tumors: An immunohistochemical study with diagnostic implications. Am J Surg Pathol 36: 1119-1128

　

121Lipoblasts in Soft Tissue Pathology

脂肪芽細胞：形態学的特徴と診断学的価値

久岡　正典1, 2

1 産業医科大学病院　病理診断科2 産業医科大学　医学部　第1病理学

要　　　旨：脂肪芽細胞は概念的に脂肪細胞の前駆的細胞ないし未成熟な細胞であり，組織学的には脂質を含んだ単ないし多空胞状の細胞質と陥凹し，しばしば帆立貝様の濃染性核を持つことを特徴とする．主として腫瘍性疾患において見られるが，前脂肪細胞のように正常脂肪組織の分化過程をある程度再現する細胞とみなされている．伝統的にその存在は特に脂肪肉腫の診断において強調されてきたが，Lochkern細胞や褐色脂肪，偽脂肪芽細胞などの組織学的に脂肪芽細胞と類似した細胞も存在することから，病理医にとっては脂肪芽細胞の同定は必ずしも容易でない．また，脂肪芽細胞は脂肪肉腫の適切な診断のために依然として重要ではあるが，脂肪芽腫や軟骨様脂肪腫，紡錘細胞・多形脂肪腫といった良性脂肪性腫瘍にも認められることがあるなどの理由で，今日の脂肪肉腫の診断における必須の条件とはなっていない．本総説では，日常の病理診断を容易にすると共に誤診の回避にも役立つように，脂肪芽細胞や脂肪芽細胞の見られる良性腫瘍および脂肪芽細胞類似細胞の臨床病理学的特徴を要約する．

キーワード：脂肪組織，脂肪芽細胞，病理診断，腫瘍．

J UOEH（産業医大誌） 36（2）：115－121（2014）