Fine Needle Aspiration Cytology of Nodular Fasciitis of the Breast Takahiko Sakuma, M.D., Ph.D,1* Koji Matsuo, M.D.,2 Shinya Koike, M.D., Ph.D.,3 and Kouichiro Tagami, M.D.,
We report a case of nodular fasciitis (NF) of the breast, which was cytologically diagnosed as a spindle cell proliferation with undetermined malignant potential. Owing to small size of the lesion (5.9 3 3.7 3 4.1 mm), only fine needle aspiration (FNA) cytology was performed under ultrasound guidance. The FNA smears were cellular, rich in single/clustered spindle cells but mammary ductal epithelial/myoepithelial cells were absent. These cytologic findings suggested spindle cell growth of mesenchymal origin. Pattern-less arrangement of spindle cells, heterogeneous composition of the stromal matrix, lack of nuclear/ cellular atypia, occasional mitosis but no aberrant mitotic figures, and lymphocyte infiltration indicated reactive rather than neoplastic nature of the lesion. Nonetheless, lumpectomy was conducted because the possibility of neoplasm was not completely ruled out. The histologic diagnosis of the resected nodule was NF. FNA specimens were reviewed thoroughly in an attempt to define the key cytomorphologic features of NF that are important for the correct diagnosis. Differential diagnoses from the lesions that show similar cytologic pictures are discussed in detail. Although NF arising from the breast is rare, cytopathologists should be aware of its clinical and cytopathologic characteristics. Knowledge of the possibility of NF in the breast and its cytologic findings may help cytopathologists to discern its reactive, not neoplastic, characteristics of the lesion. If the referring surgeon is alerted NF as a possibility along with other differential diagnoses, close observation would become a management option. In-depth discussion of cytologic features and a review of the pertinent literature are also included. Diagn. Cytopathol. 2015;43:222–229. VC 2014 Wiley Periodicals, Inc. Key Words: breast; deep benign fibrous histiocytoma; fine needle aspiration; inflammatory myoblastic tumor; nodular fasciitis
Ph.D.
3
unknown, NF is believed as a reactive rather than neoplastic lesion.1 Young adults (20–40 years) are often affected, but pediatric and geriatric cases have also been reported.2 It usually arises from upper extremities, trunk, head, and neck. However, other anatomic sites such as external ear,3 female genital tract,4 ocular region,5 oral cavity,6 and parotid gland2,7 are as well involved, though rarely. Sporadic cases of breast NF have also been documented.2,8–18 Its clinical presentation as a rapidly growing tumor sometimes gives a false impression as a malignant neoplasm. However, NF does not metastasize and spontaneous regression has been reported.10,19 Cytopathologic diagnosis is crucial for the management of NF because imaging studies are not helpful to radiologically discriminate whether malignant or benign.11,13 NF sometimes becomes the target of fine needle aspiration (FNA) cytologic examination. However, cytologic findings of NF have been described sporadically.10,12,18–26 NF of the breast is uncommon,2,8–18 and hence its cytologic characteristics have been reported only in a few reports.10,12,18 It is essential to accurately interpret the key cytologic findings suggestive of benignity to avoid surgical over-treatment. Here, we present a case of breast NF describing the cytologic characteristics in detail. Cytologic and histologic pictures were carefully compared and cytologic features vital for the accurate diagnosis of NF are emphasized. Relevant differential diagnoses with similar cytologic findings are also discussed.
Nodular fasciitis (NF) is a benign, proliferative disorder of fibroblast/myofibroblast. Although its etiology remains
Case Report
1 Department of Laboratory Medicine, Atsumi Hospital, Tahara, Aichi, Japan 2 Matsuo Clinic, Toyohashi, Aichi, Japan 3 Department of Surgery, Atsumi Hospital, Tahara, Aichi, Japan *Correspondence to: Takahiko Sakuma, M.D., Ph.D., Department of Laboratory Medicine, 1-1 Akaishi, Kanbe, Tahara, Aichi 441-3415, Japan. E-mail: [email protected] Received 20 September 2013; Accepted 9 May 2014 DOI: 10.1002/dc.23176 Published online 26 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
A 31-year-old woman presented with a painless breast lump in the right breast (upper lateral quadrant), which was depicted as a 5.9 3 3.7 3 4.1 mm nodule with ultrasonography (US) (data not shown). As a young female, mammography demonstrated generally dense breast, and this small nodule was not revealed. There was no history of trauma to the breast. FNA slides were cellular in which abundant spindle cells appeared both as single cells (Fig. C-1a) and as clusters (Figs. C-1b and c). Isolated spindle cells had ovoid/
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Diagnostic Cytopathology DOI 10.1002/dc
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Fig. C-1. FNA smears. a: Spindle cells were with oval to kidney-shaped nuclei scattered randomly in the hemorrhagic background (Papanicolaou, 4003). b: Dense aggregate of spindle cells with lymphocyte infiltration (Papanicolaou, 4003). c: Loose cluster of spindle cells with lymphocyte. It should be noted that the arrangement of spindle cells is disorganized and sparse compared with (b). It should also be noted that the stromal matrix is myxomatous (Papanicolaou, 4003). d: Histiocytes (arrowhead), mucus microfragments (double arrowheads), and plentiful fine granular material seen in the FNA smear background (Papanicolaou, 4003). e: Adipose tissue fragment permeated with lymphocytes (Papanicolaou, 4003).
elongated nuclei with inconspicuous nucleoli and pale, evenly dispersed chromatin. The nuclear membrane was thin and smooth, and the nucleoli were inconspicuous. Nuclear/cytoplasmic ratio was low, and cellular/nuclear pleomorphism was minimal. The cytoplasm of spindle cells was fine and indistinct. In another area of the specimens, erythrocytes, lymphocytes, histiocytes, lipid drop-
let, mucus microfragments, and fine granular material were seen in the background (Fig. C-1d). Epithelial cells/ myoepithelial cells (naked bipolar nuclei) were absent in all the specimens. Adipose tissue fragments infiltrated with lymphocytes were also observed (Fig. C-1e). In some spindle cell aggregates, spindle cells were closely packed (Fig. C-1b), whereas in others the spindle Diagnostic Cytopathology, Vol. 43, No 3
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Fig. C-2. Histology of the resected nodule. a: Spindle cells compactly arranged in a pattern-less pattern. It should be noted that lymphocyte infiltration and extravasated red blood cells (hematoxylin–eosin, 4003). b: In another area of the nodule, spindle cells were loosely grouped as feathery pattern in a myxomatous stromal matrix (hematoxylin–eosin, 4003). c: Lymphocytes permeated into the adipose tissue adjacent to the nodule (hematoxylin– eosin, 4003).
cells were less compactly grouped in a myxomatous stromal matrix (Fig. C-1c). In the compact spindle cell aggregates, no specific cell pattern such as fasciculation/ herringbone appearance was seen. In the less crowded clusters, spindle cells were arranged in a feathery configuration (Fig. C-1c). Mitosis was sparsely noticed (data not shown) but none was aberrant. Lymphocytes infiltrated into the cell clusters (Figs. C-1b and c) and fat cell clusters (Fig. C-1e). As no ductal epithelial cells/myoepithelial cells were observed in spite of cellular smears, the lesion was thought of stromal origin. However, whether the lesion was reactive or neoplastic could not be determined with certainty with cytology alone. Core needle biopsy was not performed because of small size of the lesion. As the possibility of low-grade malignancy was not completely ruled out with cytology, the tumor was excised as lumpectomy. Macroscopically, the resected tumor was a grayish, hard nodule measuring 6 3 4 mm. Histologically, the tumor was encapsulated by thin fibrous connective tissue in part and was composed of spindle cells arranged in a disorganized manner. Spindle cells were densely packed (Fig. C-2a) or occasionally loosely in myxomatous stroma (Fig. C-2b). The nodule was mildly infiltrated with lym224
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phocytes (Figs. C-2a and b), and the lymphocytes permeation spread into the adjacent adipose tissue (Fig. C-2c). Extravasated red blood cells were occasionally seen within the lesion (Fig. C-2a). No giant cells were noted. The most likely histological diagnosis with hematoxylin– eosin stain was NF. Immunohistochemical profile was compatible with NF: positive for a-smooth muscle actin, desmin, CD34, Factor XIIIa, and negative for CD68 and anaplastic lymphoma kinase. The postoperative course has been unremarkable for 11 months.
Discussion Spindle cell lesion of the breast is rare, accounting only 0.13–0.87% of FNA cytologic specimens.27,28 Various lesions of diverse histogenesis, both malignant and benign, are included in this category such as myoepithelial lesions with spindle cell morphology, phyllodes tumor (PT, particularly higher grade), sarcomatoid/metaplastic carcinoma, primary breast sarcomas, metastases from extra-mammary malignancies, and other miscellaneous lesions.29 Therefore, cytopathologic diagnosis of breast spindle cell lesion requires close inspection of the specimens and careful consideration of many differential diagnoses.
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF BREAST NODULAR FASCIITIS
Myoepithelial lesions with spindle cell morphology consist of myoepithelioma and adenomyoepithelioma (AME). The cytologic findings of pure myoepithelial lesions of the breast have been described only in two cases.30,31 The spindle cells appeared singly or as cell aggregates, and the latter sometimes showed lobular arrangement. The spindle cells had well-defined and orangeophilic cytoplasm and longitudinal intracytoplasmic filaments.30 The spindle cells, arranged in a fascicular pattern, had centrally located, cigar-shaped nuclei.31 These features are useful in the differential diagnoses. Breast AME displays a wide variety of cytologic findings.32–49 The smears are moderately to highly cellular. As a biphasic tumor, epithelial elements are present in the slides32–49 though epithelial cells may be fewer in case of malignant AME.37 The epithelial cells sometimes harbor apocrine features.38,42,43 The myoepithelial cells are abundantly present in the background as naked bipolar nuclei, and they show variable look such as spindle, epithelioid, clear cell, and plasmatoid appearance. The myoepithelial cells often have intranuclear inclusion,35–38,46,48 and its vacuolated cytoplasm may exhibit a “soap-bubble” appearance.36,43 The presence of epithelial cells, especially associated with apocrine metaplasia, and myoepithelial cells with fascicular arrangement, intranuclear cytoplasmic inclusions, and vacuolated cytoplasm are useful in the discrimination of NF from myoepithelial lesions. The cytologic findings of AME are sometimes confusing with PT.39,42 PT is another dimorphic breast tumor that may present spindle cytomorphology.50,51 Being a fibroepithelial lesion, both stromal and epithelial cells are usually present in the cytologic FNA specimens of PT, and the epithelial cells are easily recognized as a monolayer, tubular, or branched clusters.50–54 However, in malignant PT, epithelial cells decrease in number50–52 or disappear.51 Stromal overgrowth of malignant PT results in spindle cell-predominant specimens, which need to be differentiated from other spindle cell lesions. Nevertheless, malignant PT often shows the features of high-grade tumor such as often marked hyper-cellularity,50–52 stromal pleomorphism,50–52 and mitosis,51,52 which favor a neoplastic, rather than reactive diagnosis. Metaplastic carcinoma includes low-grade adenosquamous carcinoma, squamous cell carcinoma, spindle cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, and mixed metaplastic carcinomas.55 Metaplastic carcinoma, especially spindle cell carcinoma, should also be raised as a differential of NF. In the analyses of 19 FNA cytology of breast metaplastic carcinoma,56 four cases were monophasic pure spindle carcinoma and 6 out of 11 biphasic tumors showed spindle cell components. Pure spindle carcinomas showed moderate to marked atypia, whereas spindle cells in the mixed components were associated with mild to moderate
atypia. In pure spindle carcinoma, cellular/nuclear atypia of the spindle cells is a useful clue for the discrimination from NF, which is a benign process. Although the atypia of the spindle cells seen in the mixed metaplastic carcinoma was mild to moderate, the presence of poorly differentiated carcinoma fragments or necrosis strongly suggests malignancy. These cytologic findings can be utilized for the differential diagnosis from NF. In our case, lack of epithelial/myoepithelial cells suggests that the lesion was of mesenchymal origin, excluding the possibility of biphasic lesions such as PT and (adeno)myoepithelial lesions. Void of cellular/nuclear atypia indicates that the lesion is unlikely malignant. For the differential diagnoses of spindle cell lesions of the breast, a simplified histologic diagnostic diagram is proposed in which margins, growth pattern, cellularity, and cellular composition of the lesion are utilized.29 Unfortunately, histologic architecture is sometimes indistinct in cytologic specimens. Instead, cellular/nuclear atypia, cellular components, and background should be comprehensively taken into account for arriving at the proper cytologic diagnosis. Classifications of the cytologic findings of spindle cell-/mesenchymal component-rich FNA specimens of the breast into four categories (reactive, benign neoplastic, low-grade, and high-grade malignant neoplastic lesions) are proposed.28 Miscellaneous lesions are included in each category. Reactive conditions consisted of diabetic mastopathy, granulation tissue, and granulomatous mastitis, and benign neoplastic diseases contained mammary hamartoma, dermatofibroma, fibromatosis, granular cell tumor, angiolipoma, and cellular fibroadenoma, respectively. NF was not examined. Accordingly, cytologic pictures vary considerably. However, in malignant lesions, whether low-grade or highgrade, nuclear/cellular atypia is usually discernible. On the other hand, discriminating reactive from benign neoplastic lesions is not straightforward. No single cytologic feature is reliable for the differentiation. Nonetheless, by carefully eliminating the findings, suggesting neoplastic proliferation, it may be possible to deduce the reactive nature of the lesion. Within the “benign neoplastic” category, the monophasic mesenchymal spindle cell lesion that requires differential diagnosis with NF is fibromatosis. The FNA cytologic findings of mammary fibromatosis have been reported. The spindle cells of breast fibromatosis are bland,57–61 uniform in size and shape,59,60 and usually appear isolated.57,58,61 The background is rich in collagenous stoma,57,58 and abundant collagen makes the spindle cells arranged in dissociated or haphazard manner.57,58,60,61 These bland but uniform spindle cells growth associated with stromal matrix production indicate benign neoplastic proliferation. Diagnostic Cytopathology, Vol. 43, No 3
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Deep benign fibrous histiocytoma (FH), and inflammatory myofibroblastic tumor (IMT) were also raised as major differential diagnoses. As NF usually arises as a subcutaneous nodule in the upper extremities and trunk,2 dermatologists may well be aware of this entity. However, when NF occurs in other unusual sites such as auricular region,3 oral cavity,6 parotid gland,2,7 peri-orbit,5 and vulva,4 it may be clinically mistaken as a soft tissue tumor. Although sporadic reports of breast NF have also been reported,2,8–18 most breast surgeons may not be familiar with it and might fail to remind NF as a differential diagnosis. Similarly, it may be difficult for cytopathologists to conceive NF as one of the possible diagnoses from the breast FNA specimens. In our case, imaging studies suggested that the lesion probably arose from the breast tissue. However, FNA specimens yielded cellular smears composed of isolated (Fig. C-1a) and aggregated spindle cells (Figs. C-1b and c) admixed of tiny fat tissue fragments (Fig. C-1e) but lacking ductal epithelial/myoepithelial cells. As the FNA procedure was successful (target hit was confirmed by the US guidance), the absence of epithelial/myoepithelial cells was not attributable to inadequate sampling. In spite of intense growth of spindle cells, nuclear/cellular atypia was not observed (Figs. C-1a–c and e). The arrangement of the spindle cell in the clusters was not uniform. In the dense aggregates (Fig. C-1b), fasciculation/herringbone appearance was not evident despite strong spindle cell growth. In the loose clusters (Fig. C-1c), spindle cells were arranged randomly without specific pattern, and the stroma was composed of myxomatous matrix. Lymphocytes infiltrated into the spindle cell aggregates (Figs. C1b and c) and also into adipose cell clusters (Fig. C-1e). In the background, lymphocytes were seen plentifully (Figs. C-1a and c). The background also endowed with copious fine granular substance (Fig. C-1d) as reported previously.10,12 These cytomorphologic findings were compatible with NF.10,12,18 The above cytologic characteristics were also reproduced in the histology slides. Bland spindle cell proliferated as pattern-less pattern with extravasated red blood cells and lymphocyte infiltration (Fig. C-2a). Occasionally, spindle cells grew loosely in a myxomatous background (Fig. C-2b). Adipose cell clusters permeated with lymphocytes (Fig. C-1e) in the FNA smears corresponded with the histologic picture in which the lymphocyte in the NF spread into adjacent adipose tissue (Fig. C-2c). The cytologic findings of NF are summarized in some case series.20,25 The cytologic smears are predominantly composed of spindle cells. In one series, the cellularity was generally moderate to high.25 In another series, the cellularity was variable: marked (38.5%), moderate (46.2%), and hypocellular (15.4%), respectively.20 Although inflammatory cell infiltration is listed as an 226
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important cytologic finding of NF,12,20,25 inflammatory cells were absent in the FNA smears of three NF cases.26 The cytomorphologic features of breast NF were similar to those arising from other organs.10,12,18 These inconsistent cytologic findings are the most characteristic features of NF, representing its reactive nature. The evolutional stage of the lesion may also affect the cytologic pictures. In the early stage, infiltration of inflammatory cells may be abundant and the stroma is myxomatous. As the lesion matures, inflammatory cells may gradually disappear and the stroma becomes fibrotic. Clinical history can be an important aid in the interpretation of the specimens. In regard to the differential diagnoses, deep benign FH is similar to NF clinically in that both diseases occur frequently in the ages of 20–40 years. However, FH grows slowly, whereas NF proliferates rapidly. In the two reports of breast FH,62,63 spindle cell growth in FH was associated with more distinct fascicular/storiform cell arrangement than NF. FH shows short and intersecting fascicles of spindle cells with a loose crisscross pattern or an inconspicuous storiform arrangement occasionally associated with multinucleated giant cells (either foreign body or Touton type). Cytologic features of FH, including that arising from the breast,63 have been described.64 Spindle cell-rich FNA smears of FH show more distinct arrangement such as in sheets, papillary fronds, and storiform pattern64 than in NF. Foam cells, siderophages, roundish or polygonal histiocytic cells, and occasionally Touton-type multinucleated giant cells are seen.63,64 These cytologic findings can be utilized for the differential diagnosis. Another differential diagnosis includes IMT. IMT primarily arises from the viscera and soft tissue in children/ young adults as a slowly growing mass. Sporadic cases of breast IMT have been presented.65–76 Among these, cytologic findings of breast IMT are described in some reports.65,66,74 Proliferation of cells in the oval, spindleto-stellate form appearing occasionally as whorls is the overall cytologic feature of IMT, and the cellular density in the clusters is more homogenous than in NF. Cells with round to oval nuclei, dense cytoplasm, and tapered ends are characteristic features.76 Longitudinal nuclear grooves are often recognized.65 Plasma cell infiltration is another characteristic of IMT.74,76 In contrast to NF, which is a reactive lesion, both deep benign FH and IMT are neoplasms, though benign. The clues to arrive at the cytologic diagnosis of NF are to recognize the findings suggestive of reactive nature. If the possibility of NF is indicated as one of the differential diagnoses with a less invasive examination method such as FNA, close follow-up may become an option. When a cessation of the tumor growth or spontaneous shrinkage is observed within this observation period, it strongly suggests that the lesion is benign, a reactive one.
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF BREAST NODULAR FASCIITIS
Other breast spindle cell tumors that should be differentiated from NF are fibrosarcoma including dermatofibrosarcoma protuberans (DFSP) and leiomyosarcoma. Although DFSP is a cutaneous tumor, a single case presenting as a breast mass is reported.77 Its FNA smear showed cellular fragments composed of bland spindle cells with storiform pattern. Compared with NF, the arrangement of spindle cells in DFSP is more homogenous and inflammatory cells were absent.77 Leiomyosarcoma of the breast is a very unusual tumor, and its FNA cytologic findings have been reported only in several cases.78–81 Their FNA specimens were cellular, composed of both round and spindle-shaped cells with elongated, oval, or blunt-ended (cigarette shaped) nuclei. Its malignant characteristics are easily recognized with nuclear pleomorphism and hyperchromasia.
Conclusions In summary, cytologic diagnosis of a case of breast NF is presented. The cytologic findings were common to NF arising elsewhere in the body.10,12,18,20,25 Of these, recognizing the heterogeneity of the stroma (myxomatous/ fibrous) and the spindle cell proliferation configuration (dense aggregate/loose and feathery patterned, both without specific arrangement) seems to be important for the cytologic diagnosis of NF. Background hemorrhage, fine granular material, lymphocytes, and mucus microfragments are corroborative features. The knowledge of the possibility of NF in the breast and its cytologic findings would help NF to be raised as a differential diagnosis. Although NF is a benign, reactive disease, it is a notorious mimic of soft tissue malignancy. Clinical information such as the onset, time course is vital in making the cytologic diagnosis of NF. Close contact with breast surgeons would greatly help cytopathologists to reach an accurate cytologic diagnosis of NF and to avoid unnecessary surgical treatment.
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60. L opez-Ferrer P, Jimenez-Heffeman JA, Vicandi B, Ortega L, Viguer JM. Fine-needle aspiration cytology of mammary fibromatosis: Report of two cases. Diagn Cytopathol 1997;17:363–368. 61. Zanella M, Falconieri G, Della Libera D. The value of fine needle aspiration cytology in breast fibromatosis: Study of two new cases and review of the literature. Breast J 1999;5:264–268. 62. Friedman HD, Gonchoroff NJ, Jones DB, Tatum AH. Pleomorphic fibrohistiocytoma of the breast: A potential pitfall in breast biopsy interpretation. Virchows Arch 1994;425:199–203. 63. Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration of primary and recurrent benign fibrous histiocytoma: Classic, aneurysmal, and myxoid variants. Diagn Cytopathol 2004;31:387–391. 64. Bharatnur SS, Naik CN, Swethadri GK, Fernandes H, Shekhar JC, Marla NJ. Fine needle aspiration cytology of benign fibrous histiocytoma of bone: A case report. Acta Cytol 2010;54:89–91. 65. Ordi J, Riverola A, Sole M, et al. Fine needle aspiration of myofibroblastoma of the breast in a man. A report of two cases. Acta Cytol 1992;36:194–198. 66. Amin MB, Gottlieb CA, Fitzmaurice M, Gaba AR, Lee MW, Zarbo RJ. Fine-needle aspiration cytologic study of myofibroblastoma of the breast. Immunohistochemical and ultrastructural findings. Am J Clin Pathol 1993;99:593–597. 67. Pettinato G, Manivel JC, Insabato L, De Chiara A, Petrella G. Plasma cell granuloma (inflammatory pseudotumor) of the breast. Am J Clin Pathol 1988;90:627–632. 68. Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859–872. 69. Chetty R, Govender D. Inflammatory pseudotumor of the breast. Pathology 1997;29:270–271. 70. Yip CH, Wong KT, Samuel D. Bilateral plasma cell granuloma (inflammatory pseudotumour) of the breast. Aust N Z J Surg 1997; 67:300–302.
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77. Zee SY, Wang Q, Jones CM, Abadi MA. Fine needle aspiration cytology of dermatofibrosarcoma protuberans presenting as a breast mass. A case report. Acta Cytol 2002;46:741–743.
72. Sastre-Garau X, Couturier J, Derre J, Aurias A, Klijanienko J, Lagace R. Inflammatory myofibroblastic tumour (inflammatory pseudotumour) of the breast. Clinicopathological and genetic analysis of a case with evidence for clonality. J Pathol 2002;196:97–102.
78. Parham DM, Robertson AJ, Hussein KA, Davidson AI. Leiomyosarcoma of the breast; cytological and histological features, with a review of the literature. Cytopathology 1992;3:245–252.
73. Haj M, Weiss M, Loberant N, Cohen I. Inflammatory pseudotumor of the breast: Case report and literature review. Breast J 2003;9:423–425. 74. Zardawi IM, Clark D, Williamsz G. Inflammatory myofibroblastic tumor of the breast. A case report. Acta Cytol 2003;47:1077–1081. 75. Ilvan S, Celik V, Paksoy M, Cetinaslan I, Calay Z. Inflammatory myofibroblastic tumor (inflammatory pseudotumor) of the breast. APMIS 2005;113:66–69. 76. Stoll LM, Li QK. Cytology of fine-needle aspiration of inflammatory myofibroblastic tumor. Diagn Cytopathol 2011;39:663–672.
79. Jun Wei X, Hiotis K, Garcia R, Hummel Levine P. Leiomyosarcoma of the breast: A difficult diagnosis on fine-needle aspiration biopsy. Diagn Cytopathol 2003;29:172–178. 80. Gupta RK, Kenwright D, Naran S, Lallu S, Fauck R. Fine needle aspiration cytodiagnosis of leiomyosarcoma of the breast. A case report. Acta Cytol 2000;44:1101–1105. 81. Jayaram G, Jayalakshmi P, Yip CH. Leiomyosarcoma of the breast: Report of a case with fine needle aspiration cytologic, histologic and immunohistochemical features. Acta Cytol 2005;49: 656–660.
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We report a case of nodular fasciitis (NF) of the breast, which was cytologically diagnosed as a spindle cell proliferation with undetermined malignant potential. Owing to small size of the lesion (5.9 3 3.7 3 4.1 mm), only fine needle aspiration (FNA) cytology was performed under ultrasound guidance. The FNA smears were cellular, rich in single/clustered spindle cells but mammary ductal epithelial/myoepithelial cells were absent. These cytologic findings suggested spindle cell growth of mesenchymal origin. Pattern-less arrangement of spindle cells, heterogeneous composition of the stromal matrix, lack of nuclear/ cellular atypia, occasional mitosis but no aberrant mitotic figures, and lymphocyte infiltration indicated reactive rather than neoplastic nature of the lesion. Nonetheless, lumpectomy was conducted because the possibility of neoplasm was not completely ruled out. The histologic diagnosis of the resected nodule was NF. FNA specimens were reviewed thoroughly in an attempt to define the key cytomorphologic features of NF that are important for the correct diagnosis. Differential diagnoses from the lesions that show similar cytologic pictures are discussed in detail. Although NF arising from the breast is rare, cytopathologists should be aware of its clinical and cytopathologic characteristics. Knowledge of the possibility of NF in the breast and its cytologic findings may help cytopathologists to discern its reactive, not neoplastic, characteristics of the lesion. If the referring surgeon is alerted NF as a possibility along with other differential diagnoses, close observation would become a management option. In-depth discussion of cytologic features and a review of the pertinent literature are also included. Diagn. Cytopathol. 2015;43:222–229. VC 2014 Wiley Periodicals, Inc. Key Words: breast; deep benign fibrous histiocytoma; fine needle aspiration; inflammatory myoblastic tumor; nodular fasciitis
Ph.D.
3
unknown, NF is believed as a reactive rather than neoplastic lesion.1 Young adults (20–40 years) are often affected, but pediatric and geriatric cases have also been reported.2 It usually arises from upper extremities, trunk, head, and neck. However, other anatomic sites such as external ear,3 female genital tract,4 ocular region,5 oral cavity,6 and parotid gland2,7 are as well involved, though rarely. Sporadic cases of breast NF have also been documented.2,8–18 Its clinical presentation as a rapidly growing tumor sometimes gives a false impression as a malignant neoplasm. However, NF does not metastasize and spontaneous regression has been reported.10,19 Cytopathologic diagnosis is crucial for the management of NF because imaging studies are not helpful to radiologically discriminate whether malignant or benign.11,13 NF sometimes becomes the target of fine needle aspiration (FNA) cytologic examination. However, cytologic findings of NF have been described sporadically.10,12,18–26 NF of the breast is uncommon,2,8–18 and hence its cytologic characteristics have been reported only in a few reports.10,12,18 It is essential to accurately interpret the key cytologic findings suggestive of benignity to avoid surgical over-treatment. Here, we present a case of breast NF describing the cytologic characteristics in detail. Cytologic and histologic pictures were carefully compared and cytologic features vital for the accurate diagnosis of NF are emphasized. Relevant differential diagnoses with similar cytologic findings are also discussed.
Nodular fasciitis (NF) is a benign, proliferative disorder of fibroblast/myofibroblast. Although its etiology remains
Case Report
1 Department of Laboratory Medicine, Atsumi Hospital, Tahara, Aichi, Japan 2 Matsuo Clinic, Toyohashi, Aichi, Japan 3 Department of Surgery, Atsumi Hospital, Tahara, Aichi, Japan *Correspondence to: Takahiko Sakuma, M.D., Ph.D., Department of Laboratory Medicine, 1-1 Akaishi, Kanbe, Tahara, Aichi 441-3415, Japan. E-mail: [email protected] Received 20 September 2013; Accepted 9 May 2014 DOI: 10.1002/dc.23176 Published online 26 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
A 31-year-old woman presented with a painless breast lump in the right breast (upper lateral quadrant), which was depicted as a 5.9 3 3.7 3 4.1 mm nodule with ultrasonography (US) (data not shown). As a young female, mammography demonstrated generally dense breast, and this small nodule was not revealed. There was no history of trauma to the breast. FNA slides were cellular in which abundant spindle cells appeared both as single cells (Fig. C-1a) and as clusters (Figs. C-1b and c). Isolated spindle cells had ovoid/
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C 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF BREAST NODULAR FASCIITIS
Fig. C-1. FNA smears. a: Spindle cells were with oval to kidney-shaped nuclei scattered randomly in the hemorrhagic background (Papanicolaou, 4003). b: Dense aggregate of spindle cells with lymphocyte infiltration (Papanicolaou, 4003). c: Loose cluster of spindle cells with lymphocyte. It should be noted that the arrangement of spindle cells is disorganized and sparse compared with (b). It should also be noted that the stromal matrix is myxomatous (Papanicolaou, 4003). d: Histiocytes (arrowhead), mucus microfragments (double arrowheads), and plentiful fine granular material seen in the FNA smear background (Papanicolaou, 4003). e: Adipose tissue fragment permeated with lymphocytes (Papanicolaou, 4003).
elongated nuclei with inconspicuous nucleoli and pale, evenly dispersed chromatin. The nuclear membrane was thin and smooth, and the nucleoli were inconspicuous. Nuclear/cytoplasmic ratio was low, and cellular/nuclear pleomorphism was minimal. The cytoplasm of spindle cells was fine and indistinct. In another area of the specimens, erythrocytes, lymphocytes, histiocytes, lipid drop-
let, mucus microfragments, and fine granular material were seen in the background (Fig. C-1d). Epithelial cells/ myoepithelial cells (naked bipolar nuclei) were absent in all the specimens. Adipose tissue fragments infiltrated with lymphocytes were also observed (Fig. C-1e). In some spindle cell aggregates, spindle cells were closely packed (Fig. C-1b), whereas in others the spindle Diagnostic Cytopathology, Vol. 43, No 3
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Fig. C-2. Histology of the resected nodule. a: Spindle cells compactly arranged in a pattern-less pattern. It should be noted that lymphocyte infiltration and extravasated red blood cells (hematoxylin–eosin, 4003). b: In another area of the nodule, spindle cells were loosely grouped as feathery pattern in a myxomatous stromal matrix (hematoxylin–eosin, 4003). c: Lymphocytes permeated into the adipose tissue adjacent to the nodule (hematoxylin– eosin, 4003).
cells were less compactly grouped in a myxomatous stromal matrix (Fig. C-1c). In the compact spindle cell aggregates, no specific cell pattern such as fasciculation/ herringbone appearance was seen. In the less crowded clusters, spindle cells were arranged in a feathery configuration (Fig. C-1c). Mitosis was sparsely noticed (data not shown) but none was aberrant. Lymphocytes infiltrated into the cell clusters (Figs. C-1b and c) and fat cell clusters (Fig. C-1e). As no ductal epithelial cells/myoepithelial cells were observed in spite of cellular smears, the lesion was thought of stromal origin. However, whether the lesion was reactive or neoplastic could not be determined with certainty with cytology alone. Core needle biopsy was not performed because of small size of the lesion. As the possibility of low-grade malignancy was not completely ruled out with cytology, the tumor was excised as lumpectomy. Macroscopically, the resected tumor was a grayish, hard nodule measuring 6 3 4 mm. Histologically, the tumor was encapsulated by thin fibrous connective tissue in part and was composed of spindle cells arranged in a disorganized manner. Spindle cells were densely packed (Fig. C-2a) or occasionally loosely in myxomatous stroma (Fig. C-2b). The nodule was mildly infiltrated with lym224
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phocytes (Figs. C-2a and b), and the lymphocytes permeation spread into the adjacent adipose tissue (Fig. C-2c). Extravasated red blood cells were occasionally seen within the lesion (Fig. C-2a). No giant cells were noted. The most likely histological diagnosis with hematoxylin– eosin stain was NF. Immunohistochemical profile was compatible with NF: positive for a-smooth muscle actin, desmin, CD34, Factor XIIIa, and negative for CD68 and anaplastic lymphoma kinase. The postoperative course has been unremarkable for 11 months.
Discussion Spindle cell lesion of the breast is rare, accounting only 0.13–0.87% of FNA cytologic specimens.27,28 Various lesions of diverse histogenesis, both malignant and benign, are included in this category such as myoepithelial lesions with spindle cell morphology, phyllodes tumor (PT, particularly higher grade), sarcomatoid/metaplastic carcinoma, primary breast sarcomas, metastases from extra-mammary malignancies, and other miscellaneous lesions.29 Therefore, cytopathologic diagnosis of breast spindle cell lesion requires close inspection of the specimens and careful consideration of many differential diagnoses.
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF BREAST NODULAR FASCIITIS
Myoepithelial lesions with spindle cell morphology consist of myoepithelioma and adenomyoepithelioma (AME). The cytologic findings of pure myoepithelial lesions of the breast have been described only in two cases.30,31 The spindle cells appeared singly or as cell aggregates, and the latter sometimes showed lobular arrangement. The spindle cells had well-defined and orangeophilic cytoplasm and longitudinal intracytoplasmic filaments.30 The spindle cells, arranged in a fascicular pattern, had centrally located, cigar-shaped nuclei.31 These features are useful in the differential diagnoses. Breast AME displays a wide variety of cytologic findings.32–49 The smears are moderately to highly cellular. As a biphasic tumor, epithelial elements are present in the slides32–49 though epithelial cells may be fewer in case of malignant AME.37 The epithelial cells sometimes harbor apocrine features.38,42,43 The myoepithelial cells are abundantly present in the background as naked bipolar nuclei, and they show variable look such as spindle, epithelioid, clear cell, and plasmatoid appearance. The myoepithelial cells often have intranuclear inclusion,35–38,46,48 and its vacuolated cytoplasm may exhibit a “soap-bubble” appearance.36,43 The presence of epithelial cells, especially associated with apocrine metaplasia, and myoepithelial cells with fascicular arrangement, intranuclear cytoplasmic inclusions, and vacuolated cytoplasm are useful in the discrimination of NF from myoepithelial lesions. The cytologic findings of AME are sometimes confusing with PT.39,42 PT is another dimorphic breast tumor that may present spindle cytomorphology.50,51 Being a fibroepithelial lesion, both stromal and epithelial cells are usually present in the cytologic FNA specimens of PT, and the epithelial cells are easily recognized as a monolayer, tubular, or branched clusters.50–54 However, in malignant PT, epithelial cells decrease in number50–52 or disappear.51 Stromal overgrowth of malignant PT results in spindle cell-predominant specimens, which need to be differentiated from other spindle cell lesions. Nevertheless, malignant PT often shows the features of high-grade tumor such as often marked hyper-cellularity,50–52 stromal pleomorphism,50–52 and mitosis,51,52 which favor a neoplastic, rather than reactive diagnosis. Metaplastic carcinoma includes low-grade adenosquamous carcinoma, squamous cell carcinoma, spindle cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, and mixed metaplastic carcinomas.55 Metaplastic carcinoma, especially spindle cell carcinoma, should also be raised as a differential of NF. In the analyses of 19 FNA cytology of breast metaplastic carcinoma,56 four cases were monophasic pure spindle carcinoma and 6 out of 11 biphasic tumors showed spindle cell components. Pure spindle carcinomas showed moderate to marked atypia, whereas spindle cells in the mixed components were associated with mild to moderate
atypia. In pure spindle carcinoma, cellular/nuclear atypia of the spindle cells is a useful clue for the discrimination from NF, which is a benign process. Although the atypia of the spindle cells seen in the mixed metaplastic carcinoma was mild to moderate, the presence of poorly differentiated carcinoma fragments or necrosis strongly suggests malignancy. These cytologic findings can be utilized for the differential diagnosis from NF. In our case, lack of epithelial/myoepithelial cells suggests that the lesion was of mesenchymal origin, excluding the possibility of biphasic lesions such as PT and (adeno)myoepithelial lesions. Void of cellular/nuclear atypia indicates that the lesion is unlikely malignant. For the differential diagnoses of spindle cell lesions of the breast, a simplified histologic diagnostic diagram is proposed in which margins, growth pattern, cellularity, and cellular composition of the lesion are utilized.29 Unfortunately, histologic architecture is sometimes indistinct in cytologic specimens. Instead, cellular/nuclear atypia, cellular components, and background should be comprehensively taken into account for arriving at the proper cytologic diagnosis. Classifications of the cytologic findings of spindle cell-/mesenchymal component-rich FNA specimens of the breast into four categories (reactive, benign neoplastic, low-grade, and high-grade malignant neoplastic lesions) are proposed.28 Miscellaneous lesions are included in each category. Reactive conditions consisted of diabetic mastopathy, granulation tissue, and granulomatous mastitis, and benign neoplastic diseases contained mammary hamartoma, dermatofibroma, fibromatosis, granular cell tumor, angiolipoma, and cellular fibroadenoma, respectively. NF was not examined. Accordingly, cytologic pictures vary considerably. However, in malignant lesions, whether low-grade or highgrade, nuclear/cellular atypia is usually discernible. On the other hand, discriminating reactive from benign neoplastic lesions is not straightforward. No single cytologic feature is reliable for the differentiation. Nonetheless, by carefully eliminating the findings, suggesting neoplastic proliferation, it may be possible to deduce the reactive nature of the lesion. Within the “benign neoplastic” category, the monophasic mesenchymal spindle cell lesion that requires differential diagnosis with NF is fibromatosis. The FNA cytologic findings of mammary fibromatosis have been reported. The spindle cells of breast fibromatosis are bland,57–61 uniform in size and shape,59,60 and usually appear isolated.57,58,61 The background is rich in collagenous stoma,57,58 and abundant collagen makes the spindle cells arranged in dissociated or haphazard manner.57,58,60,61 These bland but uniform spindle cells growth associated with stromal matrix production indicate benign neoplastic proliferation. Diagnostic Cytopathology, Vol. 43, No 3
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Deep benign fibrous histiocytoma (FH), and inflammatory myofibroblastic tumor (IMT) were also raised as major differential diagnoses. As NF usually arises as a subcutaneous nodule in the upper extremities and trunk,2 dermatologists may well be aware of this entity. However, when NF occurs in other unusual sites such as auricular region,3 oral cavity,6 parotid gland,2,7 peri-orbit,5 and vulva,4 it may be clinically mistaken as a soft tissue tumor. Although sporadic reports of breast NF have also been reported,2,8–18 most breast surgeons may not be familiar with it and might fail to remind NF as a differential diagnosis. Similarly, it may be difficult for cytopathologists to conceive NF as one of the possible diagnoses from the breast FNA specimens. In our case, imaging studies suggested that the lesion probably arose from the breast tissue. However, FNA specimens yielded cellular smears composed of isolated (Fig. C-1a) and aggregated spindle cells (Figs. C-1b and c) admixed of tiny fat tissue fragments (Fig. C-1e) but lacking ductal epithelial/myoepithelial cells. As the FNA procedure was successful (target hit was confirmed by the US guidance), the absence of epithelial/myoepithelial cells was not attributable to inadequate sampling. In spite of intense growth of spindle cells, nuclear/cellular atypia was not observed (Figs. C-1a–c and e). The arrangement of the spindle cell in the clusters was not uniform. In the dense aggregates (Fig. C-1b), fasciculation/herringbone appearance was not evident despite strong spindle cell growth. In the loose clusters (Fig. C-1c), spindle cells were arranged randomly without specific pattern, and the stroma was composed of myxomatous matrix. Lymphocytes infiltrated into the spindle cell aggregates (Figs. C1b and c) and also into adipose cell clusters (Fig. C-1e). In the background, lymphocytes were seen plentifully (Figs. C-1a and c). The background also endowed with copious fine granular substance (Fig. C-1d) as reported previously.10,12 These cytomorphologic findings were compatible with NF.10,12,18 The above cytologic characteristics were also reproduced in the histology slides. Bland spindle cell proliferated as pattern-less pattern with extravasated red blood cells and lymphocyte infiltration (Fig. C-2a). Occasionally, spindle cells grew loosely in a myxomatous background (Fig. C-2b). Adipose cell clusters permeated with lymphocytes (Fig. C-1e) in the FNA smears corresponded with the histologic picture in which the lymphocyte in the NF spread into adjacent adipose tissue (Fig. C-2c). The cytologic findings of NF are summarized in some case series.20,25 The cytologic smears are predominantly composed of spindle cells. In one series, the cellularity was generally moderate to high.25 In another series, the cellularity was variable: marked (38.5%), moderate (46.2%), and hypocellular (15.4%), respectively.20 Although inflammatory cell infiltration is listed as an 226
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important cytologic finding of NF,12,20,25 inflammatory cells were absent in the FNA smears of three NF cases.26 The cytomorphologic features of breast NF were similar to those arising from other organs.10,12,18 These inconsistent cytologic findings are the most characteristic features of NF, representing its reactive nature. The evolutional stage of the lesion may also affect the cytologic pictures. In the early stage, infiltration of inflammatory cells may be abundant and the stroma is myxomatous. As the lesion matures, inflammatory cells may gradually disappear and the stroma becomes fibrotic. Clinical history can be an important aid in the interpretation of the specimens. In regard to the differential diagnoses, deep benign FH is similar to NF clinically in that both diseases occur frequently in the ages of 20–40 years. However, FH grows slowly, whereas NF proliferates rapidly. In the two reports of breast FH,62,63 spindle cell growth in FH was associated with more distinct fascicular/storiform cell arrangement than NF. FH shows short and intersecting fascicles of spindle cells with a loose crisscross pattern or an inconspicuous storiform arrangement occasionally associated with multinucleated giant cells (either foreign body or Touton type). Cytologic features of FH, including that arising from the breast,63 have been described.64 Spindle cell-rich FNA smears of FH show more distinct arrangement such as in sheets, papillary fronds, and storiform pattern64 than in NF. Foam cells, siderophages, roundish or polygonal histiocytic cells, and occasionally Touton-type multinucleated giant cells are seen.63,64 These cytologic findings can be utilized for the differential diagnosis. Another differential diagnosis includes IMT. IMT primarily arises from the viscera and soft tissue in children/ young adults as a slowly growing mass. Sporadic cases of breast IMT have been presented.65–76 Among these, cytologic findings of breast IMT are described in some reports.65,66,74 Proliferation of cells in the oval, spindleto-stellate form appearing occasionally as whorls is the overall cytologic feature of IMT, and the cellular density in the clusters is more homogenous than in NF. Cells with round to oval nuclei, dense cytoplasm, and tapered ends are characteristic features.76 Longitudinal nuclear grooves are often recognized.65 Plasma cell infiltration is another characteristic of IMT.74,76 In contrast to NF, which is a reactive lesion, both deep benign FH and IMT are neoplasms, though benign. The clues to arrive at the cytologic diagnosis of NF are to recognize the findings suggestive of reactive nature. If the possibility of NF is indicated as one of the differential diagnoses with a less invasive examination method such as FNA, close follow-up may become an option. When a cessation of the tumor growth or spontaneous shrinkage is observed within this observation period, it strongly suggests that the lesion is benign, a reactive one.
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF BREAST NODULAR FASCIITIS
Other breast spindle cell tumors that should be differentiated from NF are fibrosarcoma including dermatofibrosarcoma protuberans (DFSP) and leiomyosarcoma. Although DFSP is a cutaneous tumor, a single case presenting as a breast mass is reported.77 Its FNA smear showed cellular fragments composed of bland spindle cells with storiform pattern. Compared with NF, the arrangement of spindle cells in DFSP is more homogenous and inflammatory cells were absent.77 Leiomyosarcoma of the breast is a very unusual tumor, and its FNA cytologic findings have been reported only in several cases.78–81 Their FNA specimens were cellular, composed of both round and spindle-shaped cells with elongated, oval, or blunt-ended (cigarette shaped) nuclei. Its malignant characteristics are easily recognized with nuclear pleomorphism and hyperchromasia.
Conclusions In summary, cytologic diagnosis of a case of breast NF is presented. The cytologic findings were common to NF arising elsewhere in the body.10,12,18,20,25 Of these, recognizing the heterogeneity of the stroma (myxomatous/ fibrous) and the spindle cell proliferation configuration (dense aggregate/loose and feathery patterned, both without specific arrangement) seems to be important for the cytologic diagnosis of NF. Background hemorrhage, fine granular material, lymphocytes, and mucus microfragments are corroborative features. The knowledge of the possibility of NF in the breast and its cytologic findings would help NF to be raised as a differential diagnosis. Although NF is a benign, reactive disease, it is a notorious mimic of soft tissue malignancy. Clinical information such as the onset, time course is vital in making the cytologic diagnosis of NF. Close contact with breast surgeons would greatly help cytopathologists to reach an accurate cytologic diagnosis of NF and to avoid unnecessary surgical treatment.
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