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Giant cell tumor of soft tissue of the breast: Case report with H3F3A mutation analysis and review of the literature
Journal Pre-proof Giant cell tumor of soft tissue of the breast: case report with H3F3A mutation analysis and review of the literature Thitsamay Luangxay, Tomo Osako, Rika Yonekura, Yoshiya Sugiura, Mari Kikuchi, Naoya Gomi, Takayuki Ueno, Shinji Ohno, Rikuo Machinami, Kengo Takeuchi, Futoshi Akiyama
PII:
S0344-0338(19)32069-2
DOI:
https://doi.org/10.1016/j.prp.2019.152750
Reference:
PRP 152750
To appear in:
Pathology - Research and Practice
Received Date:
23 September 2019
Revised Date:
14 November 2019
Accepted Date:
17 November 2019
Please cite this article as: Luangxay T, Osako T, Yonekura R, Sugiura Y, Kikuchi M, Gomi N, Ueno T, Ohno S, Machinami R, Takeuchi K, Akiyama F, Giant cell tumor of soft tissue of the breast: case report with H3F3A mutation analysis and review of the literature, Pathology Research and Practice (2019), doi: https://doi.org/10.1016/j.prp.2019.152750
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Case report
Giant cell tumor of soft tissue of the breast: case report with H3F3A mutation analysis and review of the literature Thitsamay Luangxay, MD, PhD 1,2,3, Tomo Osako, MD, PhD
1,4
, Rika Yonekura, MD,
PhD 5, Yoshiya Sugiura, MD 4, Mari Kikuchi, MD, PhD 6, Naoya Gomi, MD, PhD 6, Takayuki Ueno, MD, PhD 5, Shinji Ohno, MD, PhD 5, Rikuo Machinami, MD, PhD
1,7
,
1
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Kengo Takeuchi, MD, PhD 1,4,8, Futoshi Akiyama, MD, PhD 1
Division of Pathology, Cancer Institute of Japanese Foundation for Cancer Research,
Tokyo, Japan
Department of Comprehensive Pathology, Graduate School of Medical and Dental
-p
2
Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Department of Pathology, Cancer Center, Mittaphab Hospital, Vientiane, Lao PDR
4
Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer
re
3
5
Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer
Research, Tokyo, Japan
Diagnostic Imaging Center, Cancer Institute Hospital of Japanese Foundation for Cancer
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6
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Research, Tokyo, Japan
Research, Tokyo, Japan
Department of Pathology, Kawakita General Hospital, Tokyo, Japan
8
Pathology Project for Molecular Targets, Cancer Institute of Japanese Foundation for
ur
7
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Cancer Research, Tokyo, Japan
Correspondence: Tomo Osako, MD, PhD Division of Pathology, Cancer Institute of Japanese Foundation for Cancer Research, 38-31, Ariake, Koto-ku, Tokyo 135-8550, Japan E-mail: [email protected], Tel: +81-3-3570-0559, Fax: +81-3-3570-0558
1
Abstract Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. We report a unique case of breast GCT-ST coincident with ductal carcinoma in situ (DCIS), diagnosed with histological, immunohistochemical, and H3F3A (Histone H3.3) mutation analyses. A 59-year-old woman preoperatively diagnosed with DCIS underwent total mastectomy for a cystic mass. Histology revealed a tumor composed of mononuclear cells interspersed with numerous osteoclast-like giant cells, resembling giant cell tumor of bone (GCT-B), with apocrine DCIS in proximity to the tumor. The mononuclear and giant
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cells were immunoreactive for CD68 and negative for cytokeratins. Granulomatous
diseases, carcinomas with giant cells, and giant cell-type sarcomas were excluded by histological and immunophenotypic features. Lack of H3F3A mutation eliminated the
possibility of GCT-B metastasis to the breast. These findings were consistent with GCT-
-p
ST of the breast. To our knowledge, this is the ninth reported case of breast GCT-ST, but the first case that accompanied DCIS or involved H3F3A mutation status investigation.
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For correct diagnosis of this rare tumor, it is important for pathologists to raise the possibility of GCT-ST when encountering giant cell-rich breast lesions and to exclude other
differential
diagnoses
by
combining
the
results
of
histological,
lP
immunohistochemical, and genetic analyses.
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Key words: Primary breast tumor; Giant cell tumor of soft tissue; Giant cell tumor of bone; H3F3A mutation; Histone H3.3; Cystic breast mass
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Introduction
Giant cell tumor of soft tissue (GCT-ST) is an uncommon neoplasm usually occurring
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in the superficial and deep soft tissues of the extremities [1]. This tumor type is categorized by tumors with low malignant potential and a propensity for local recurrence, while rarely metastasizing [2]. GCT-ST is composed of mononuclear stromal cells interspersed with numerous osteoclastic giant cells, and is identical in histological appearance to giant cell tumor of bone (GCT-B), which usually arises in the epiphysis of long bones. However, recent studies have suggested that GCT-ST and GCT-B are different entities, because unlike GCT-ST [3], most GCT-B harbor H3F3A (histone H3.3) 2
mutations at codon G34 [4]. Approximately 90% of GCT-B harbor H3F3A G34W mutation, but minor groups have the G34L, G34M, G34R, or G34V mutations [4-7]. GCT-ST arising in the breast is extremely rare; only eight cases have been reported in literature [8-15]. Because of its rarity as a breast tumor, GCT-ST is often difficult to correctly diagnose. In this case report, we present a unique case of breast GCT-ST coincident with ductal carcinoma in situ (DCIS), diagnosed with histological, immunohistochemical, and H3F3A mutation analyses, and include a review of the
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literature and suggestions to aid future diagnosis.
Clinical Summary
A 59-year-old Japanese woman presented with pain in her left breast. She had a history of hysterectomy for uterine leiomyoma. On physical examination, a 2.5-cm, nontender,
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rubbery mass was palpable between the outer and upper quadrant close to the nipple. The mass was slightly fixed to the skin, but the overlying skin was unremarkable. There was
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no discharge from the nipple or palpable axillary lymph node.
Mammography showed a microlobulated mass located in the retroareolar region (Fig. 1a and 1b). Ultrasonography revealed a 17x17x13-mm mixed solid and cystic mass (Fig.
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1c). Magnetic resonance imaging detected a 18x15x15-mm, mixed solid and cystic irregular mass surrounded with a 44x33x31-mm non-mass enhancement (Fig. 1d).
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Intracystic tumor, papilloma or carcinoma, was suspected from these images. Histological analysis of the needle biopsy specimen revealed DCIS, along with an aggregation of multinucleated giant cells in the breast stroma. Thus, the tumor was
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suspected to be an intracystic carcinoma, and the patient underwent total mastectomy and sentinel lymph node biopsy. The sentinel node was negative for tumor. The patient was
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not given any adjuvant therapies, and was followed up with no sign of recurrence after eight months post-surgery.
Pathological Findings Macroscopic and microscopic findings Macroscopic examination revealed a 30x19x16-mm, well-demarcated, unencapsulated mass with hemorrhagic cystic spaces (Fig. 2a). Microscopically, this tumor was 3
composed of closely-packed round to short-spindled mononuclear cells and evenly interspersed with numerous osteoclast-like multinucleated giant cells (Fig. 2b). The mononuclear cells had basophilic cytoplasm and round to oval nuclei with small nucleoli. The nuclear atypia was moderate, and the mitotic figure was rare in number. The multinucleated giant cells had irregular cell borders and contained 5–30 oval nuclei. The giant cells showed an absence of mitotic figures or pleomorphic morphology. The tumor was observed spreading into the surrounding adipose tissue, vessels and normal breast ducts (Fig. 2c). Apocrine DCIS, 11x5 mm in size, involving sclerosing adenosis was
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identified in close proximity to the main tumor (Fig. 2d).
Immunohistochemical findings
The mononuclear and multinucleated giant cells were immunoreactive for CD68, but
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the giant cells were more diffusely and strongly stained than the mononuclear cells (Table
1, Fig. 2f). The mononuclear cells were also immunoreactive for S100 and CD14, and focally immunoreactive for smooth muscle actin and SATB2. The mononuclear and giant
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cells were negative for cytokeratins (AE1/3 and CAM5.2, Fig. 2g) and p63. On the other hand, the apocrine DCIS cells were immunoreactive for cytokeratins (Fig. 2g) and
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androgen receptor, and negative for CD68, S100 and smooth muscle actin. The DCIS, mononuclear and multinucleated giant cells were all negative for estrogen receptor,
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progesterone receptor and human epidermal growth factor receptor-2.
H3F3A mutation analysis
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The mononuclear and multinucleated giant cells were both negative for anti-histone H3.3 G34W immunostaining (Table 1, Fig. 2h). Direct sequencing of the polymerase chain reaction-amplified DNA from the macrodissected tumor samples showed a wild-
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type H3F3A G34 codon (no G34W/L/M/R/V mutasion) (Fig. 3).
Discussion
We present a unique case of breast GCT-ST coincident with apocrine DCIS. To our knowledge, this is the ninth case of breast GCT-ST, but the first case co-occurring with
4
DCIS or in which the absence of the H3F3A mutation was investigated to exclude GCTB metastasizing to the breast. In our case, the presence of DCIS made the diagnosis of GCT-ST more complicated. Although the giant cell-rich lesion and apocrine DCIS were located adjacent to each other in the specimens, these were considered two different tumors. Histology revealed no transitional morphology between the giant cell-rich lesion and DCIS, epithelial differentiation in the giant cell-rich lesion, nor the invasive component in DCIS. Immunohistochemistry showed different protein expressions: the giant cell-rich lesion
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was positive for CD68 and S100 and DCIS was negative, while DCIS was positive for cytokeratins and androgen receptor and the giant cell-rich lesion was negative.
The following giant cell-rich lesions should be excluded before making a diagnosis of
GCT-ST of the breast [11]: (1) granulomatous diseases of the breast (e.g. fat necrosis,
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foreign body granuloma, granulomatous lobular mastitis), (2) breast carcinomas with giant cells (e.g. carcinoma with osteoclast-like giant cells, pleomorphic carcinoma), (3) giant cell-type breast sarcomas (e.g. undifferentiated pleomorphic sarcoma, extraskeletal
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osteosarcoma), and (4) GCT-B metastasizing to the breast (no reported case in the literature). The possibility of extraskeletal osteosarcoma should be raised because small
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amounts of osteoid in GCT-ST have been reported in the literature [1]. In our case, all the above-mentioned differential diagnoses were excluded by combining the results of histological, immunohistochemical, and genetic examinations.
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Granulomatous diseases of the breast can be ruled out by the patient’s history and histology. Fat necrosis and foreign body granuloma result from prior breast events (e.g.
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trauma, injection of silicone). Histologically, fat necrosis, foreign body granuloma, and granulomatous lobular mastitis are granulomatous reactions to necrotic fat, foreign materials, and mammary lobules, respectively. These granulomas are composed of
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epithelioid and multinucleated histiocytes, foreign body and/or Langhans giant cells, while GCT-ST is composed of osteoclast-like tumor giant cells and mononuclear stromal cells.
Breast carcinomas with giant cells can be ruled out by the lack of obvious epithelial differentiation in histological appearance and the lack of staining for epithelial markers in GCT-ST. The absence of marked nuclear pleomorphism, atypia, and atypical mitoses in GCT-ST can exclude the possibility of giant cell-type breast sarcomas. Although GCT5
ST and GCT-B are histologically indistinguishable, the absence of an underlying primary bone tumor and no H3F3A mutation at the G34 codon can eliminate the possibility of GCT-B metastasizing to the breast [3]. In addition, low expression of p63, SATB2 or RANKL in immunohistochemistry can possibly be helpful to distinguish GCT-ST from GCT-B [16]. In our case, no/low expression of p63 and SATB2 supported the diagnosis of GCT-
ST. It is challenging but important to preoperatively diagnose breast GCT-ST correctly to avoid over/undertreatments. Only one patient (case #7) reported in literature was
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preoperatively diagnosed with GCT-ST [14]. Recognition of GCT-ST as a breast tumor is essential for making the correct preoperative diagnosis. In our case, multinucleated
giant cells were observed in the needle biopsy specimen, but GCT-ST was not included
in the differential diagnosis due to lack of recognition. Breast mass with cystic lesions
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may be a diagnostic clue for GCT-ST identification as the cystic space can be attributed
to intratumoral hemorrhage [11, 14]. Half of the cases in literature (case #2, 4, 6 and 7), and our case, clinically and/or radiologically presented masses containing cystic lesions.
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Thus, for rendering correct preoperative diagnosis, it is important to raise the possibility of GCT-ST when multinucleated giant cells are observed on biopsy specimens,
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particularly sampled from a cystic breast mass with intratumoral hemorrhage. Spreading of giant cell-rich components in mammary ducts might be a unique histological finding of breast GCT-ST. In the present case, the mononuclear and
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multinucleated giant cells of GCT-ST formed solid nests in several mammary ducts. This histological finding was validated by cytokeratin and p63 staining, which were positive
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for myoepithelium and negative for GCT-ST; and CD68 staining, which was positive for GCT-ST and negative for myoepithelium. It is noted that pathologists do not misdiagnose
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these intraductal lesions as intraductal carcinoma.
Conclusions
We present a unique case of breast GCT-ST coincident with DCIS, which was
diagnosed with histological, immunohistochemical, and H3F3A mutation analysis. For the correct diagnosis of this rare tumor, it is important for pathologists to consider the possibility of GCT-ST when they encounter giant cell-rich breast lesions and to employ a combination of histological, immunohistochemical, and genetic analyses to exclude 6
other differential diagnoses (i.e. granulomatous diseases, carcinomas, sarcomas, and metastatic GCT-B).
Patient Consent Obtained.
Conflict of Interest Statement
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None of the authors have any conflicts of interest to declare.
Acknowledgments
We thank Dr. Toru Motoi (Department of Pathology, Tokyo Metropolitan Cancer and
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Infectious Diseases Center Komagome Hospital) for his helpful advice on how to revise
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JFCR) for helping the mutation analysis.
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the manuscript, and Ms. Kimie Nomura (Division of Pathology, the Cancer Institute,
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References [1] J.G. Guccion, F.M. Enzinger, Malignant giant cell tumor of soft parts. An analysis of 32 cases. Cancer 29 (1972) 1518-1529. [2] C.D.M. Fletcher, J.A. Bridge, P. Hogendoorn, F. Mertens, WHO Classification of Tumours of Soft Tissue and Bone. Fourth Edition, IARC Press, Lyon, 2013. [3] J.C. Lee, C.W. Liang, C.D. Fletcher, Giant cell tumor of soft tissue is genetically distinct from its bone counterpart. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 30 (2017) 728-733.
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[4] S. Behjati, P.S. Tarpey, N. Presneau, S. Scheipl, N. Pillay, P. Van Loo, D.C. Wedge,
S.L. Cooke, G. Gundem, H. Davies, S. Nik-Zainal, S. Martin, S. McLaren, V. Goodie, B.
Robinson, A. Butler, J.W. Teague, D. Halai, B. Khatri, O. Myklebost, D. Baumhoer, G.
Jundt, R. Hamoudi, R. Tirabosco, M.F. Amary, P.A. Futreal, M.R. Stratton, P.J. Campbell,
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A.M. Flanagan, Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 45 (2013) 1479-1482.
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[5] N. Presneau, D. Baumhoer, S. Behjati, N. Pillay, P. Tarpey, P.J. Campbell, G. Jundt, R. Hamoudi, D.C. Wedge, P.V. Loo, A.B. Hassan, B. Khatri, H. Ye, R. Tirabosco, M.F. Amary, A.M. Flanagan, Diagnostic value of H3F3A mutations in giant cell tumour of
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bone compared to osteoclast-rich mimics. The journal of pathology. Clinical research 1 (2015) 113-123.
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[6] T. Kervarrec, C. Collin, F. Larousserie, C. Bouvier, S. Aubert, A. Gomez-Brouchet, B. Marie, E. Miquelestorena-Standley, L.R. Le Nail, P. Avril, J. Christophe Pages, G. de Pinieux, H3F3 mutation status of giant cell tumors of the bone, chondroblastomas and
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their mimics: a combined high resolution melting and pyrosequencing approach. Modern pathology : an official journal of the United States and Canadian Academy of Pathology,
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Inc 30 (2017) 393-406.
[7] H. Yamamoto, T. Iwasaki, Y. Yamada, Y. Matsumoto, H. Otsuka, M. Yoshimoto, K. Kohashi, K. Taguchi, R. Yokoyama, Y. Nakashima, Y. Oda, Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. Human pathology 73 (2018) 41-50. [8] J.G. Lucas, H.M. Sharma, R.V. O'Toole, Unusual giant cell tumor arising in a male breast. Human pathology 12 (1981) 840-844. 8
[9] M. Fukunaga, Giant cell tumor of the breast. Virchows Archiv : an international journal of pathology 441 (2002) 93-95. [10] S. Shousha, H.D. Sinnett, Chest wall tumors presenting as breast lumps. The breast journal 10 (2004) 150-153. [11] S.A. May, M.T. Deavers, E. Resetkova, D. Johnson, C.T. Albarracin, Giant cell tumor of soft tissue arising in breast. Ann Diagn Pathol 11 (2007) 345-349. [12] L. Romics, Jr., E.A. Mallon, R. Reid, C.M. Cordiner, J.C. Doughty, Osteoclast-like giant cell tumor arising in the soft tissue of the breast: report of a case. Surgery today 39
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(2009) 48-51. [13] B.L. Gaspar, S. Sharma, R. Singh, R.K. Vasishta, Primary giant cell tumor of the female breast: a diagnostic red herring with therapeutic implications. APMIS 125 (2017) 32-37.
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[14] A. Sawa, T. Ikeda, E. Ichioka, Y. Tsushima, A. Iguchi-Manaka, H. Bando, Y. Kondo, H. Hara, Preoperative diagnosis of a giant cell tumor of soft tissue arising from the breast
by ultrasound-guided core needle biopsy. Journal of medical ultrasonics (2001) 46 (2019)
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257-261.
[15] M. Terada, N. Gondo, M. Sawaki, M. Hattori, A. Yoshimura, H. Kotani, Y. Adachi,
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M. Iwase, A. Kataoka, K. Sugino, M. Mori, N. Horisawa, Y. Ozaki, H. Iwata, A case of giant cell tumor of the breast, clinically suspected as malignant breast tumor. Surgical case reports 5 (2019) 77.
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[16] I. Mancini, A. Righi, M. Gambarotti, P. Picci, A.P. Dei Tos, S.D. Billings, L. Simi, A. Franchi, Phenotypic and molecular differences between giant-cell tumour of soft tissue
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and its bone counterpart. Histopathology 71 (2017) 453-460.
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Tables Table 1. Antibodies for immunostaining and results for the present case
Dako Becton Dickinson Dako Dako Abcam Dako Santa Cruz Abcam Ventana Ventana Ventana Dako Dako RevMAb
1/200 RTU 1/20 1/1000 1/1000 1/100 1/1000 1/200 1/100 RTU RTU RTU 1/50 1/200 1/400
Giant cells
Mononuclear cells
DCIS
(-) (-) (+) (-) (-) (-) (-) (-) 0% 0% (0) 0% (-) (-)
(-) (-) (+) (+) (+) (+, focal) (+, focal) (-) 0% 0% (0) 15% (-) (-)
(+) (+) (-) (-) (-) (-) (-) (-) 0% 0% (1+) 7% (+) (-)
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AE1, AE3 CAM5.2 KP1 Polyclonal SP192 1A4 SATBA4B10 4A4 SP1 1E2 4B5 MIB1 AR441 RM263
Dilution
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Cytokeratin Cytokeratin CD68 S100 CD14 Smooth muscle actin SATB2 p63 Estrogen receptor Progesterone receptor HER2 Ki67 Androgen receptor Histone H3.3 G34W
Source
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Clone
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Antibody
Immunoreactivity GCT-ST
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GCT-ST, giant cell tumor of soft tissue; DCIS, ductal carcinoma in situ; HER2, human epidermal growth factor-2; RTU, ready to use
10
f
Table 2. Clinicopathological findings of the reported cases of GCT-ST of the breast Immunoreactivity
Treatment
Follow-up/ Outcome
1
8
72M 13
Mass
NA
Total mastectomy
6 months, no NA recurrence
2
9
68F
2.5
Cystic mass
Intracystic papilloma
3
10
59F
3.7
Mass
Soft tumor
Suspected organizing hematoma
Total mastectomy
10 months, die CD68, CD68, of lung vimentin, α1- vimentin, metastasis antitripsin (35%)
NA
Excision
NA
Phyllodes tumor
Wide excision
1 year, recurrence
no CD68, vimentin, S100
GCT-ST
Total mastectomy
5 years, recurrence
no
Total mastectomy
1year, recurrence
no
Total mastectomy
8 months, no CD68 recurrence
60F
3
Cystic mass
5
12
50F
2.5
Mass
13
36F
7
Cystic mass
7
14
45F
5
Mass with lesion
8
15
74F
2.5
9
Our 49F case
3.0
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6
pr
e-
Pr
11
cystic
Total mastectomy
tissue Wide excision
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4
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Case Ref. Age/ Size Clinical/radiological Preoperative No. No. Sex (cm) presentation diagnosis
Suspected Mass spreading to malignant nipple tumor Solid and cystic Intracystic mass carcinoma
Giant cells
2 years, recurrence
no CD68, vimentin
2 years, recurrence
no
CD68
CD68
Mononuclear cells NA Vimentin, SMA, calponin, S100, PgR CD68 SMA, Ki67
NA CD68, SMA, EMA, vimentin, Ki67 (55%)
CD68
CD68
CD68
CD68 CD68, S100, SMA, Ki67 (15%)
GCT-ST, giant cell tumor of soft tissue; NA, not available; DCIS, ductal carcinoma in situ; SMA, smooth muscle actin; PgR, progesterone receptor; EMA, epithelial membrane antigen 11
Figure legends Figure 1. Radiological images of the giant cell tumor of soft tissue (GCT-ST) arising in the breast. Mediolateral oblique and craniocaudal views of the mammography (a, b), ultrasonography (c), axial section of contrast enhancement T1-weighted magnetic
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resonance imaging (d).
Figure 2. Pathological images of the giant cell tumor of soft tissue (GCT-ST) and
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apocrine ductal carcinoma in situ (DCIS) of the breast. Macroscopic photograph of the tumor (a). Hematoxylin-and-eosin-stained images of the tumor (magnification 100x):
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GCT-ST (b), spread of GCT-ST in the mammary duct (c), and DCIS (d). Immunohistochemical images of GCT-ST (left) and DCIS (right) corresponding to the
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hematoxylin-and-eosin-stained image (e, magnification 200x): CD68 (f), cytoketatin AE1/3 (g) and histone H3.3 G34W (h).
12
ro of -p re lP na ur Jo Figure 3. H3F3A mutation analysis of the giant cell tumor of soft tissue (GCT-ST) of the breast. A screen shot of the electropherogram demonstrating no mutation in H3F3A G34 codon (black underbar). 13
14
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ur
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PII:
S0344-0338(19)32069-2
DOI:
https://doi.org/10.1016/j.prp.2019.152750
Reference:
PRP 152750
To appear in:
Pathology - Research and Practice
Received Date:
23 September 2019
Revised Date:
14 November 2019
Accepted Date:
17 November 2019
Please cite this article as: Luangxay T, Osako T, Yonekura R, Sugiura Y, Kikuchi M, Gomi N, Ueno T, Ohno S, Machinami R, Takeuchi K, Akiyama F, Giant cell tumor of soft tissue of the breast: case report with H3F3A mutation analysis and review of the literature, Pathology Research and Practice (2019), doi: https://doi.org/10.1016/j.prp.2019.152750
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Case report
Giant cell tumor of soft tissue of the breast: case report with H3F3A mutation analysis and review of the literature Thitsamay Luangxay, MD, PhD 1,2,3, Tomo Osako, MD, PhD
1,4
, Rika Yonekura, MD,
PhD 5, Yoshiya Sugiura, MD 4, Mari Kikuchi, MD, PhD 6, Naoya Gomi, MD, PhD 6, Takayuki Ueno, MD, PhD 5, Shinji Ohno, MD, PhD 5, Rikuo Machinami, MD, PhD
1,7
,
1
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Kengo Takeuchi, MD, PhD 1,4,8, Futoshi Akiyama, MD, PhD 1
Division of Pathology, Cancer Institute of Japanese Foundation for Cancer Research,
Tokyo, Japan
Department of Comprehensive Pathology, Graduate School of Medical and Dental
-p
2
Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Department of Pathology, Cancer Center, Mittaphab Hospital, Vientiane, Lao PDR
4
Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer
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3
5
Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer
Research, Tokyo, Japan
Diagnostic Imaging Center, Cancer Institute Hospital of Japanese Foundation for Cancer
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6
lP
Research, Tokyo, Japan
Research, Tokyo, Japan
Department of Pathology, Kawakita General Hospital, Tokyo, Japan
8
Pathology Project for Molecular Targets, Cancer Institute of Japanese Foundation for
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7
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Cancer Research, Tokyo, Japan
Correspondence: Tomo Osako, MD, PhD Division of Pathology, Cancer Institute of Japanese Foundation for Cancer Research, 38-31, Ariake, Koto-ku, Tokyo 135-8550, Japan E-mail: [email protected], Tel: +81-3-3570-0559, Fax: +81-3-3570-0558
1
Abstract Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. We report a unique case of breast GCT-ST coincident with ductal carcinoma in situ (DCIS), diagnosed with histological, immunohistochemical, and H3F3A (Histone H3.3) mutation analyses. A 59-year-old woman preoperatively diagnosed with DCIS underwent total mastectomy for a cystic mass. Histology revealed a tumor composed of mononuclear cells interspersed with numerous osteoclast-like giant cells, resembling giant cell tumor of bone (GCT-B), with apocrine DCIS in proximity to the tumor. The mononuclear and giant
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cells were immunoreactive for CD68 and negative for cytokeratins. Granulomatous
diseases, carcinomas with giant cells, and giant cell-type sarcomas were excluded by histological and immunophenotypic features. Lack of H3F3A mutation eliminated the
possibility of GCT-B metastasis to the breast. These findings were consistent with GCT-
-p
ST of the breast. To our knowledge, this is the ninth reported case of breast GCT-ST, but the first case that accompanied DCIS or involved H3F3A mutation status investigation.
re
For correct diagnosis of this rare tumor, it is important for pathologists to raise the possibility of GCT-ST when encountering giant cell-rich breast lesions and to exclude other
differential
diagnoses
by
combining
the
results
of
histological,
lP
immunohistochemical, and genetic analyses.
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Key words: Primary breast tumor; Giant cell tumor of soft tissue; Giant cell tumor of bone; H3F3A mutation; Histone H3.3; Cystic breast mass
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Introduction
Giant cell tumor of soft tissue (GCT-ST) is an uncommon neoplasm usually occurring
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in the superficial and deep soft tissues of the extremities [1]. This tumor type is categorized by tumors with low malignant potential and a propensity for local recurrence, while rarely metastasizing [2]. GCT-ST is composed of mononuclear stromal cells interspersed with numerous osteoclastic giant cells, and is identical in histological appearance to giant cell tumor of bone (GCT-B), which usually arises in the epiphysis of long bones. However, recent studies have suggested that GCT-ST and GCT-B are different entities, because unlike GCT-ST [3], most GCT-B harbor H3F3A (histone H3.3) 2
mutations at codon G34 [4]. Approximately 90% of GCT-B harbor H3F3A G34W mutation, but minor groups have the G34L, G34M, G34R, or G34V mutations [4-7]. GCT-ST arising in the breast is extremely rare; only eight cases have been reported in literature [8-15]. Because of its rarity as a breast tumor, GCT-ST is often difficult to correctly diagnose. In this case report, we present a unique case of breast GCT-ST coincident with ductal carcinoma in situ (DCIS), diagnosed with histological, immunohistochemical, and H3F3A mutation analyses, and include a review of the
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literature and suggestions to aid future diagnosis.
Clinical Summary
A 59-year-old Japanese woman presented with pain in her left breast. She had a history of hysterectomy for uterine leiomyoma. On physical examination, a 2.5-cm, nontender,
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rubbery mass was palpable between the outer and upper quadrant close to the nipple. The mass was slightly fixed to the skin, but the overlying skin was unremarkable. There was
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no discharge from the nipple or palpable axillary lymph node.
Mammography showed a microlobulated mass located in the retroareolar region (Fig. 1a and 1b). Ultrasonography revealed a 17x17x13-mm mixed solid and cystic mass (Fig.
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1c). Magnetic resonance imaging detected a 18x15x15-mm, mixed solid and cystic irregular mass surrounded with a 44x33x31-mm non-mass enhancement (Fig. 1d).
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Intracystic tumor, papilloma or carcinoma, was suspected from these images. Histological analysis of the needle biopsy specimen revealed DCIS, along with an aggregation of multinucleated giant cells in the breast stroma. Thus, the tumor was
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suspected to be an intracystic carcinoma, and the patient underwent total mastectomy and sentinel lymph node biopsy. The sentinel node was negative for tumor. The patient was
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not given any adjuvant therapies, and was followed up with no sign of recurrence after eight months post-surgery.
Pathological Findings Macroscopic and microscopic findings Macroscopic examination revealed a 30x19x16-mm, well-demarcated, unencapsulated mass with hemorrhagic cystic spaces (Fig. 2a). Microscopically, this tumor was 3
composed of closely-packed round to short-spindled mononuclear cells and evenly interspersed with numerous osteoclast-like multinucleated giant cells (Fig. 2b). The mononuclear cells had basophilic cytoplasm and round to oval nuclei with small nucleoli. The nuclear atypia was moderate, and the mitotic figure was rare in number. The multinucleated giant cells had irregular cell borders and contained 5–30 oval nuclei. The giant cells showed an absence of mitotic figures or pleomorphic morphology. The tumor was observed spreading into the surrounding adipose tissue, vessels and normal breast ducts (Fig. 2c). Apocrine DCIS, 11x5 mm in size, involving sclerosing adenosis was
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identified in close proximity to the main tumor (Fig. 2d).
Immunohistochemical findings
The mononuclear and multinucleated giant cells were immunoreactive for CD68, but
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the giant cells were more diffusely and strongly stained than the mononuclear cells (Table
1, Fig. 2f). The mononuclear cells were also immunoreactive for S100 and CD14, and focally immunoreactive for smooth muscle actin and SATB2. The mononuclear and giant
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cells were negative for cytokeratins (AE1/3 and CAM5.2, Fig. 2g) and p63. On the other hand, the apocrine DCIS cells were immunoreactive for cytokeratins (Fig. 2g) and
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androgen receptor, and negative for CD68, S100 and smooth muscle actin. The DCIS, mononuclear and multinucleated giant cells were all negative for estrogen receptor,
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progesterone receptor and human epidermal growth factor receptor-2.
H3F3A mutation analysis
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The mononuclear and multinucleated giant cells were both negative for anti-histone H3.3 G34W immunostaining (Table 1, Fig. 2h). Direct sequencing of the polymerase chain reaction-amplified DNA from the macrodissected tumor samples showed a wild-
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type H3F3A G34 codon (no G34W/L/M/R/V mutasion) (Fig. 3).
Discussion
We present a unique case of breast GCT-ST coincident with apocrine DCIS. To our knowledge, this is the ninth case of breast GCT-ST, but the first case co-occurring with
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DCIS or in which the absence of the H3F3A mutation was investigated to exclude GCTB metastasizing to the breast. In our case, the presence of DCIS made the diagnosis of GCT-ST more complicated. Although the giant cell-rich lesion and apocrine DCIS were located adjacent to each other in the specimens, these were considered two different tumors. Histology revealed no transitional morphology between the giant cell-rich lesion and DCIS, epithelial differentiation in the giant cell-rich lesion, nor the invasive component in DCIS. Immunohistochemistry showed different protein expressions: the giant cell-rich lesion
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was positive for CD68 and S100 and DCIS was negative, while DCIS was positive for cytokeratins and androgen receptor and the giant cell-rich lesion was negative.
The following giant cell-rich lesions should be excluded before making a diagnosis of
GCT-ST of the breast [11]: (1) granulomatous diseases of the breast (e.g. fat necrosis,
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foreign body granuloma, granulomatous lobular mastitis), (2) breast carcinomas with giant cells (e.g. carcinoma with osteoclast-like giant cells, pleomorphic carcinoma), (3) giant cell-type breast sarcomas (e.g. undifferentiated pleomorphic sarcoma, extraskeletal
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osteosarcoma), and (4) GCT-B metastasizing to the breast (no reported case in the literature). The possibility of extraskeletal osteosarcoma should be raised because small
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amounts of osteoid in GCT-ST have been reported in the literature [1]. In our case, all the above-mentioned differential diagnoses were excluded by combining the results of histological, immunohistochemical, and genetic examinations.
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Granulomatous diseases of the breast can be ruled out by the patient’s history and histology. Fat necrosis and foreign body granuloma result from prior breast events (e.g.
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trauma, injection of silicone). Histologically, fat necrosis, foreign body granuloma, and granulomatous lobular mastitis are granulomatous reactions to necrotic fat, foreign materials, and mammary lobules, respectively. These granulomas are composed of
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epithelioid and multinucleated histiocytes, foreign body and/or Langhans giant cells, while GCT-ST is composed of osteoclast-like tumor giant cells and mononuclear stromal cells.
Breast carcinomas with giant cells can be ruled out by the lack of obvious epithelial differentiation in histological appearance and the lack of staining for epithelial markers in GCT-ST. The absence of marked nuclear pleomorphism, atypia, and atypical mitoses in GCT-ST can exclude the possibility of giant cell-type breast sarcomas. Although GCT5
ST and GCT-B are histologically indistinguishable, the absence of an underlying primary bone tumor and no H3F3A mutation at the G34 codon can eliminate the possibility of GCT-B metastasizing to the breast [3]. In addition, low expression of p63, SATB2 or RANKL in immunohistochemistry can possibly be helpful to distinguish GCT-ST from GCT-B [16]. In our case, no/low expression of p63 and SATB2 supported the diagnosis of GCT-
ST. It is challenging but important to preoperatively diagnose breast GCT-ST correctly to avoid over/undertreatments. Only one patient (case #7) reported in literature was
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preoperatively diagnosed with GCT-ST [14]. Recognition of GCT-ST as a breast tumor is essential for making the correct preoperative diagnosis. In our case, multinucleated
giant cells were observed in the needle biopsy specimen, but GCT-ST was not included
in the differential diagnosis due to lack of recognition. Breast mass with cystic lesions
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may be a diagnostic clue for GCT-ST identification as the cystic space can be attributed
to intratumoral hemorrhage [11, 14]. Half of the cases in literature (case #2, 4, 6 and 7), and our case, clinically and/or radiologically presented masses containing cystic lesions.
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Thus, for rendering correct preoperative diagnosis, it is important to raise the possibility of GCT-ST when multinucleated giant cells are observed on biopsy specimens,
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particularly sampled from a cystic breast mass with intratumoral hemorrhage. Spreading of giant cell-rich components in mammary ducts might be a unique histological finding of breast GCT-ST. In the present case, the mononuclear and
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multinucleated giant cells of GCT-ST formed solid nests in several mammary ducts. This histological finding was validated by cytokeratin and p63 staining, which were positive
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for myoepithelium and negative for GCT-ST; and CD68 staining, which was positive for GCT-ST and negative for myoepithelium. It is noted that pathologists do not misdiagnose
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these intraductal lesions as intraductal carcinoma.
Conclusions
We present a unique case of breast GCT-ST coincident with DCIS, which was
diagnosed with histological, immunohistochemical, and H3F3A mutation analysis. For the correct diagnosis of this rare tumor, it is important for pathologists to consider the possibility of GCT-ST when they encounter giant cell-rich breast lesions and to employ a combination of histological, immunohistochemical, and genetic analyses to exclude 6
other differential diagnoses (i.e. granulomatous diseases, carcinomas, sarcomas, and metastatic GCT-B).
Patient Consent Obtained.
Conflict of Interest Statement
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None of the authors have any conflicts of interest to declare.
Acknowledgments
We thank Dr. Toru Motoi (Department of Pathology, Tokyo Metropolitan Cancer and
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Infectious Diseases Center Komagome Hospital) for his helpful advice on how to revise
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JFCR) for helping the mutation analysis.
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the manuscript, and Ms. Kimie Nomura (Division of Pathology, the Cancer Institute,
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References [1] J.G. Guccion, F.M. Enzinger, Malignant giant cell tumor of soft parts. An analysis of 32 cases. Cancer 29 (1972) 1518-1529. [2] C.D.M. Fletcher, J.A. Bridge, P. Hogendoorn, F. Mertens, WHO Classification of Tumours of Soft Tissue and Bone. Fourth Edition, IARC Press, Lyon, 2013. [3] J.C. Lee, C.W. Liang, C.D. Fletcher, Giant cell tumor of soft tissue is genetically distinct from its bone counterpart. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 30 (2017) 728-733.
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[4] S. Behjati, P.S. Tarpey, N. Presneau, S. Scheipl, N. Pillay, P. Van Loo, D.C. Wedge,
S.L. Cooke, G. Gundem, H. Davies, S. Nik-Zainal, S. Martin, S. McLaren, V. Goodie, B.
Robinson, A. Butler, J.W. Teague, D. Halai, B. Khatri, O. Myklebost, D. Baumhoer, G.
Jundt, R. Hamoudi, R. Tirabosco, M.F. Amary, P.A. Futreal, M.R. Stratton, P.J. Campbell,
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A.M. Flanagan, Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 45 (2013) 1479-1482.
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[5] N. Presneau, D. Baumhoer, S. Behjati, N. Pillay, P. Tarpey, P.J. Campbell, G. Jundt, R. Hamoudi, D.C. Wedge, P.V. Loo, A.B. Hassan, B. Khatri, H. Ye, R. Tirabosco, M.F. Amary, A.M. Flanagan, Diagnostic value of H3F3A mutations in giant cell tumour of
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bone compared to osteoclast-rich mimics. The journal of pathology. Clinical research 1 (2015) 113-123.
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[6] T. Kervarrec, C. Collin, F. Larousserie, C. Bouvier, S. Aubert, A. Gomez-Brouchet, B. Marie, E. Miquelestorena-Standley, L.R. Le Nail, P. Avril, J. Christophe Pages, G. de Pinieux, H3F3 mutation status of giant cell tumors of the bone, chondroblastomas and
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their mimics: a combined high resolution melting and pyrosequencing approach. Modern pathology : an official journal of the United States and Canadian Academy of Pathology,
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Inc 30 (2017) 393-406.
[7] H. Yamamoto, T. Iwasaki, Y. Yamada, Y. Matsumoto, H. Otsuka, M. Yoshimoto, K. Kohashi, K. Taguchi, R. Yokoyama, Y. Nakashima, Y. Oda, Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. Human pathology 73 (2018) 41-50. [8] J.G. Lucas, H.M. Sharma, R.V. O'Toole, Unusual giant cell tumor arising in a male breast. Human pathology 12 (1981) 840-844. 8
[9] M. Fukunaga, Giant cell tumor of the breast. Virchows Archiv : an international journal of pathology 441 (2002) 93-95. [10] S. Shousha, H.D. Sinnett, Chest wall tumors presenting as breast lumps. The breast journal 10 (2004) 150-153. [11] S.A. May, M.T. Deavers, E. Resetkova, D. Johnson, C.T. Albarracin, Giant cell tumor of soft tissue arising in breast. Ann Diagn Pathol 11 (2007) 345-349. [12] L. Romics, Jr., E.A. Mallon, R. Reid, C.M. Cordiner, J.C. Doughty, Osteoclast-like giant cell tumor arising in the soft tissue of the breast: report of a case. Surgery today 39
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(2009) 48-51. [13] B.L. Gaspar, S. Sharma, R. Singh, R.K. Vasishta, Primary giant cell tumor of the female breast: a diagnostic red herring with therapeutic implications. APMIS 125 (2017) 32-37.
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[14] A. Sawa, T. Ikeda, E. Ichioka, Y. Tsushima, A. Iguchi-Manaka, H. Bando, Y. Kondo, H. Hara, Preoperative diagnosis of a giant cell tumor of soft tissue arising from the breast
by ultrasound-guided core needle biopsy. Journal of medical ultrasonics (2001) 46 (2019)
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[15] M. Terada, N. Gondo, M. Sawaki, M. Hattori, A. Yoshimura, H. Kotani, Y. Adachi,
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M. Iwase, A. Kataoka, K. Sugino, M. Mori, N. Horisawa, Y. Ozaki, H. Iwata, A case of giant cell tumor of the breast, clinically suspected as malignant breast tumor. Surgical case reports 5 (2019) 77.
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[16] I. Mancini, A. Righi, M. Gambarotti, P. Picci, A.P. Dei Tos, S.D. Billings, L. Simi, A. Franchi, Phenotypic and molecular differences between giant-cell tumour of soft tissue
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and its bone counterpart. Histopathology 71 (2017) 453-460.
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Tables Table 1. Antibodies for immunostaining and results for the present case
Dako Becton Dickinson Dako Dako Abcam Dako Santa Cruz Abcam Ventana Ventana Ventana Dako Dako RevMAb
1/200 RTU 1/20 1/1000 1/1000 1/100 1/1000 1/200 1/100 RTU RTU RTU 1/50 1/200 1/400
Giant cells
Mononuclear cells
DCIS
(-) (-) (+) (-) (-) (-) (-) (-) 0% 0% (0) 0% (-) (-)
(-) (-) (+) (+) (+) (+, focal) (+, focal) (-) 0% 0% (0) 15% (-) (-)
(+) (+) (-) (-) (-) (-) (-) (-) 0% 0% (1+) 7% (+) (-)
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AE1, AE3 CAM5.2 KP1 Polyclonal SP192 1A4 SATBA4B10 4A4 SP1 1E2 4B5 MIB1 AR441 RM263
Dilution
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Cytokeratin Cytokeratin CD68 S100 CD14 Smooth muscle actin SATB2 p63 Estrogen receptor Progesterone receptor HER2 Ki67 Androgen receptor Histone H3.3 G34W
Source
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Clone
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Antibody
Immunoreactivity GCT-ST
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GCT-ST, giant cell tumor of soft tissue; DCIS, ductal carcinoma in situ; HER2, human epidermal growth factor-2; RTU, ready to use
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Table 2. Clinicopathological findings of the reported cases of GCT-ST of the breast Immunoreactivity
Treatment
Follow-up/ Outcome
1
8
72M 13
Mass
NA
Total mastectomy
6 months, no NA recurrence
2
9
68F
2.5
Cystic mass
Intracystic papilloma
3
10
59F
3.7
Mass
Soft tumor
Suspected organizing hematoma
Total mastectomy
10 months, die CD68, CD68, of lung vimentin, α1- vimentin, metastasis antitripsin (35%)
NA
Excision
NA
Phyllodes tumor
Wide excision
1 year, recurrence
no CD68, vimentin, S100
GCT-ST
Total mastectomy
5 years, recurrence
no
Total mastectomy
1year, recurrence
no
Total mastectomy
8 months, no CD68 recurrence
60F
3
Cystic mass
5
12
50F
2.5
Mass
13
36F
7
Cystic mass
7
14
45F
5
Mass with lesion
8
15
74F
2.5
9
Our 49F case
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6
pr
e-
Pr
11
cystic
Total mastectomy
tissue Wide excision
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Case Ref. Age/ Size Clinical/radiological Preoperative No. No. Sex (cm) presentation diagnosis
Suspected Mass spreading to malignant nipple tumor Solid and cystic Intracystic mass carcinoma
Giant cells
2 years, recurrence
no CD68, vimentin
2 years, recurrence
no
CD68
CD68
Mononuclear cells NA Vimentin, SMA, calponin, S100, PgR CD68 SMA, Ki67
NA CD68, SMA, EMA, vimentin, Ki67 (55%)
CD68
CD68
CD68
CD68 CD68, S100, SMA, Ki67 (15%)
GCT-ST, giant cell tumor of soft tissue; NA, not available; DCIS, ductal carcinoma in situ; SMA, smooth muscle actin; PgR, progesterone receptor; EMA, epithelial membrane antigen 11
Figure legends Figure 1. Radiological images of the giant cell tumor of soft tissue (GCT-ST) arising in the breast. Mediolateral oblique and craniocaudal views of the mammography (a, b), ultrasonography (c), axial section of contrast enhancement T1-weighted magnetic
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resonance imaging (d).
Figure 2. Pathological images of the giant cell tumor of soft tissue (GCT-ST) and
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apocrine ductal carcinoma in situ (DCIS) of the breast. Macroscopic photograph of the tumor (a). Hematoxylin-and-eosin-stained images of the tumor (magnification 100x):
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GCT-ST (b), spread of GCT-ST in the mammary duct (c), and DCIS (d). Immunohistochemical images of GCT-ST (left) and DCIS (right) corresponding to the
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hematoxylin-and-eosin-stained image (e, magnification 200x): CD68 (f), cytoketatin AE1/3 (g) and histone H3.3 G34W (h).
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ro of -p re lP na ur Jo Figure 3. H3F3A mutation analysis of the giant cell tumor of soft tissue (GCT-ST) of the breast. A screen shot of the electropherogram demonstrating no mutation in H3F3A G34 codon (black underbar). 13
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