Med Mol Morphol DOI 10.1007/s00795-013-0062-8
CASE REPORT
Solitary myofibroma of the mandible: an immunohistochemical and ultrastructural study with a review of the literature Takafumi Satomi • Michihide Kohno • Ai Enomoto • Harutsugu Abukawa Ko Fujikawa • Toshiyuki Koizumi • Daichi Chikazu • Jun Matsubayashi • Toshitaka Nagao
•
Received: 19 August 2013 / Accepted: 18 October 2013 Ó The Japanese Society for Clinical Molecular Morphology 2013
Abstract A solitary myofibroma (MF) is an unusual spindle cell neoplasm that usually arises in the soft tissue, skin, or bone of the head and neck region in infancy. We report an extremely rare case of MF of the mandible in an 18-year-old Japanese woman together with the conventional histologic, immunohistochemical, and electron microscopic findings. The tumor was well circumscribed and composed of fibroblast-like or myofibroblast-like spindle cells. On immunohistochemical evaluation the tumor cells were positive for vimentin, a-smooth muscle actin, HHF-35, and calponin, but negative for neurogenic antigens and markers for vascular endothelial cells. The Ki67 labeling index was 10 % and the p53 labeling index was 10 %. Ultrastructural examination revealed smooth muscle cell differentiation. The patient was treated by surgical resection and underwent follow-up without any signs of recurrence. MF presents a wide range of differential diagnosis, including benign and malignant neoplasms. Therefore, accurate diagnosis may avoid an unnecessarily aggressive therapy. Keywords Solitary myofibroma Mandible Immunohistochemical study Ultrastructural study
T. Satomi (&) M. Kohno A. Enomoto H. Abukawa K. Fujikawa T. Koizumi D. Chikazu Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan e-mail: [email protected] J. Matsubayashi T. Nagao Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
Introduction Myofibroma (MF) is a rare benign neoplasm of mesenchymal origin composed of myofibroblasts which is frequently observed in the soft tissue of the head and neck region in early childhood [1]. It was first described by Williams and Schrum [2] in 1951 as congenital fibrosarcoma. In 1954, this entity was described by Stout [3] as a form of congenital multicentric fibroblastic proliferation that he referred to as ‘‘congenital generalized fibromatosis.’’ In 1981, Chung and Enzinger [4] renamed it ‘‘infantile myofibromatosis.’’ They reported that 88 % of the tumors occurred in patients under the age of 2 years. They divided it into the solitary type and the multiple type. On the other hand, the adult counterpart of this lesion was reported by Daimaru et al. [5] in 1989, renamed as ‘‘myofibromatosis’’. However, Jones et al. [6] in accordance with Smith et al. [7] prefer the term MF when describing a solitary neoplasm of this type. In young children multiple lesions are often present and it is known as infantile myofibromatosis [4]. The solitary form is more common than the multiple form and tends to occur in adults [8]. MF in the oral cavity has been reported in the mandible [1, 9], tongue [10], buccal mucosa [11], and only a few cases reported from the gingiva [12]. Clinically, MF presents as a single swelling when it occurs on the gingiva. With more common lesions such as fibrous epulis, pyogenic granuloma, and peripheral odontogenic fibroma, MF is usually considered in the differential diagnosis. Morphologically, MF is generally characterized by spindle cell proliferation showing a biphasic growth pattern [13] and the final diagnosis is made by immunohistochemical and electron microscopic studies [14]. This report describes an MF of the lingual gingiva of the right posterior mandible in an 18-year-old woman and is
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reported together with the conventional histologic, immunohistochemical, and electron microscopic findings, together with a review of the literature.
Case report Clinical course An 18-year-old Japanese woman was referred to our department of Tokyo Medical University Hospital with a painless swelling of the lingual gingiva of the right second molar of the mandible that had been present for 1 month. The lesion had gradually increased in size. Medical and familial histories were noncontributory. There was no history of trauma or spontaneous bleeding associated with the lesion. Clinical examination revealed a hard mass 3 cm in diameter with ulceration arising from the lingual gingiva of the right second molar to the right retromolar pad in the mandible (Fig. 1). The right lower second molar showed abnormal mobility. The regional lymph nodes were not enlarged. Radiographic examination revealed a unilocular radiolucent area surrounding the root of the right lower second molar (Fig. 2). Computed tomography revealed a well-demarcated, unilocular low-density area approximately 3 9 2 cm in the right posterior mandible with partial resorption of the lingual cortical bone (Fig. 3). An incisional biopsy showed the benign neoplasm to be composed of spindle cells, such as in inflammatory myofibroblastic tumor, and complete surgical resection along with a peripheral osteotomy was planned. Under general anesthesia, nasotracheal intubation was done. The tumor was resected with a surgical margin of normal tissue of 5 mm. The inferior alveolar nerve was not damaged during
Fig. 1 Clinical appearance of myofibroma. Well circumscribed nodular soft tissue mass in the right posterior lingual gingiva of the mandible causing second molar displacement
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the resection. Thorough conservative (rim) marginal resection of the mandible was carried out; a PGA mesh sheet (NeoveilÒ; Gunze Limited, Kyoto, Japan) was placed on the wound surface of the surgical defect which was then covered with fibrin glue (BolhealÒ; Chemo-sero-therapeutic Research Institute, Kumamoto, Japan). Postoperative recovery was uneventful. A 10-month follow-up period showed no signs of recurrence.
Materials and methods The surgical specimen was immediately fixed in 10 % formalin and processed for paraffin embedding, sectioned into 3- to 4-lm sections, and stained with standard hematoxylin and eosin. For immunohistochemical study, the avidin–biotin-peroxidase complex method was used. The
Fig. 2 Panoramic radiograph showing unilocular radiolucency surrounding the root of the right second molar of the mandible
Fig. 3 Axial view of a CT showing a unilocular low-density area with partial resorption of the cortical bone indicated (arrow)
Med Mol Morphol Table 1 Summary of immunohistochemical results of the present myofibroma case Antigen
Clone
Dilution
Source
Positivity
Intensity
Vimentin
V9
Calponin
CALP
1:2000
DAKO
???
Strong
1:100
DAKO
?
Actin
HHF35
1:100
Moderate
DAKO
?
Weak Strong
a-Smooth muscle actin
1A4
1:100
DAKO
???
Pan cytokeratin
AE1/AE3
1:200
DAKO
–
Cytokeratin 7/18
CAM5.2
1:10
DAKO
–
Desmin
D33
1:50
DAKO
–
S-100
SI 00
1:2000
DAKO
–
CD34
QBEndIO
1:100
DAKO
–
CD68
PG-M1
1:100
DAKO
–
Epithelial membrane antigen ALK-1
E29 ALK-1
1:100 1:50
DAKO DAKO
– –
Caldesmon
h-CD
1:100
DAKO
–
Ki-67
Mib-1
1:50
DAKO
? (10 %)
Weak
p53
p53
1:50
DAKO
? (10 %)
Weak
commercially purchased primary antibodies used in the present study are summarized in Table 1. In addition, immunohistochemical methods for assessment of the protein expression of the tumor proliferative index Ki-67 (MIB-1) were followed. To determine the positivity of the immunostaining, we utilized the following classification system: -(0–5 % positive cells), ?(5–25 % positive cells), ??(25–50 % positive cells), ???(50–100 % positive cells). The intensity of the immunostaining was classified as weak, moderate, and strong. Negative controls for the staining were stained specimens with prior omission of the primary antibody. For electron microscopy, fresh tissue was immersed in 2.5 % glutaraldehyde at 4 °C for 4 h, post-fixed in 1 % osmium tetroxide for 2 h, dehydrated in graded ethanol solutions (30 % 10 min, 50 % 10 min, 70 % 10 min, 100 % 10 min), and embedded in Epon (Chemical polymerization at 70 °C for 4 days). Ultrathin sections were cut using a microtome, stained with uranyl acetate-lead citrate, and observed under a Hitachi H-7500 transmission electron microscope (Hitachi Ltd., Tokyo, Japan).
Results Macroscopic findings On gross examination, the surgical specimen consisted of a well-circumscribed 2.6 9 2.5 cm solid mass of white to pink-tan tissue. The cut surface revealed relatively homogeneous and smooth, unevenly yellowish-white, and peripherally firm tissue (Fig. 4).
Fig. 4 a Surgical specimen: Tumor was a well-circumscribed 2.6 9 2.5 cm solid mass of white to pink-tan tissue. b Cut surface: the cut surface revealed relatively homogeneous and smooth, unevenly yellowish-white, and peripherally firm tissue
Microscopic findings The tumor was a well circumscribed, although not encapsulated, mass. The characteristic biphasic growth pattern was obscure. The mostly well-circumscribed nodular lesion was composed of a proliferation of fibroblast- or myofibroblast-like spindle cells having fusiform nuclei and eosinophilic cytoplasm arranged in interlacing fascicles or whorls with mildly fibrocollagenous or myxoid stroma, alternating with cellular areas containing many dilated and thin-walled blood vessels, displaying a hemangiopericytomatous appearance, mainly at the periphery of the lesion and an inflammatory infiltrate probably due to the surface ulceration. Mitotic figures were
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Fig. 5 Histopathologic features (hematoxylin and eosin stain). a The lesion is composed of a proliferation of spindle cells in interlacing fascicles or whorls, alternating with cellular areas containing thinwalled blood vessels, displaying a hemangiopericytomatous appearance (original magnification 940). b The spindle cells have fusiform nuclei and eosinophilic cytoplasm with a mildly fibrocollagenous stroma (original magnification 9200). Immunohistochemical stain.
c Tumor cells showing strong positivity for a-smooth muscle actin (original magnification 9200). d Most of the tumor cells were weakly positive for HHF-35 (original magnification 9200). e Tumor cells were also positive for calponin (original magnification 9200). f Ki-67 (MIB-1) labeling index is approximately 10 % (original magnification 9200)
sometimes encountered. No abnormal mitotic figures, cellular pleomorphism, or areas of necrosis were seen (Fig. 5a, b).
muscle actin, HHF-35, and calponin. These tumor cells were weakly Ki-67 positive (MIB-1 labeling index was 10 %) and the p53 labeling index was 10 %, whereas staining for cytokeratin, S-100, EMA, desmin, caldesmon, CD34, ALK-1, and ß-catenin was negative (Fig. 5c, d, e, f). The above histopathologic and immunohistochemical findings were consistent with the features of
Immunohistochemical findings Immunohistochemical analysis revealed that the spindleshaped cells were positive for vimentin, a-smooth
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Fig. 6 a Electron micrograph of myofibroblast-like cells. Spindleshaped cells with long nuclei are observed. Note myofilaments (arrowhead), actin fiber arrangement (arrow) and RER (asterisk).
b Electron micrograph of fibroblasts. Cells are rich in RER with surrounding collagen fibers. Note basal membrane (arrow) and pinocytotic vesicles (asterisk)
MF. All performed immunohistochemical studies are summarized in Table 1.
study by Sugatani et al. [14] 62.5 % of oral MFs in patients younger than 16 years occurred in the mandible. Other locations included the tongue, buccal mucosa, lip, vestibule, and attached gingiva [18]. Therefore, MFs involving the mandible are relatively common in children; however, there are few reports of MFs in adults [6, 22]. Our case of a solitary MF occurring in the lingual gingiva of the mandible of an 18-year-old woman is unusual. We summarized in Table 2 the clinical data in the English literature (PubMed) of the 14 reported cases (including our case) of oral MFs in patients older than 16 years, originating from the mandible including the gingiva, retromolar region, and intraosseous sites. In Table 2, the mean age of patients with solitary MFs in the mandible is 36.1 years (range 18–70 years) in patients older than 16 years. Solitary MF of the mandible, excluding the intraosseous lesions, seems to be extremely rare, and to the best of our knowledge, only 9 cases have been reported [6, 9, 23–29]. The MF etiology remains unknown. It has been suggested that the tumor is inherited as an autosomal dominant or autosomal recessive trait, although very low familial incidence has been reported [30]. The typical clinical presentation is a painless mass that may display rapid growth and ulceration, thus raising alarm [19, 31]. The nonspecific clinical presentation and the relative rarity make the differential diagnosis wide, including benign and malignant mesenchymal lesions which may be of fibrous, muscle, neural, or vascular tissue in origin [6, 19, 25, 32]. Abramowicz et al. [1] reported in a retrospective analysis that there are 2 distinct clinical types of solitary MF of the jaws. There is an aggressive exophytic type and a nonaggressive intraosseous type. The aggressive type is characterized as an exophytic soft tissue mass in the dentoalveolar region often covering the teeth, with tooth mobility and surface ulceration. Our case is an aggressive exophytic type; the tumor had been associated with tooth
Electron microscopic findings Electron microscopy has been reported in only a few cases [14–16]. The cells were described as spindle-shaped and round with long cellular processes and extracellular collagen fibrils. Spindle-shaped cells were primarily distributed within a collagenous matrix. The nuclei were oval to spindle in shape with occasional irregular indented contours. The cytoplasm contained fine microfilaments along with large amounts of rough endoplasmic reticulum (RER) and pinocytotic vesicles. Microfilaments and pinocytotic vesicles were noted along the cell membrane. An interrupted basal membrane was visible at the periphery of these cells. A dense patch representing actin fibers attached to a portion of the cell membrane, a focal dense area indicating microfilament bundles, and a high-density area spreading from the center to the peripheral region were seen (Fig. 6a, b).
Discussion MF occurs mostly in the head and neck region, the skin of the trunk, and subcutaneous tissue, but rarely within bone [10, 17, 18]. Solitary MFs are often diagnosed during infancy and childhood and have a male predilection [14, 18–20]. Chung and Enzinger [4] reported that nearly 90 % of the 61 cases they reviewed were diagnosed in patients younger than 2 years of age. The most affected sites are the soft tissue of the head and neck; however, internal organs and bones can also be involved [21]. Three studies in 1995 and in 2000 identified the mandible as the most frequent oral site (16 [44 %] of 36 [20], 15 [42.6 %] of 35 [14], and 30 [38.0 %] of 79 [19]). In a
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Med Mol Morphol Table 2 Reported cases of myofibroma of the mandible in patients older than 16 years Report
Year
No.
Age (years)
Sex
Site
Size (cm)
Beham et al. [23]
1993
1
60
M
Gingiva
0.5
NA
Jones et al. [6]
1994
1
70
F
Gingiva
0.8 9 0.5
NA
2
35
F
Vestibule (mandible)
0.7
NA
3
19
M
Vestibule (mandible)
2.5
NA
1
21
M
Retromolar (mandible)
2 9 1.5
6 months
Ugar et al. [29]
1999
Montromery et al. [25]
2000
Follow-up (months)
1
29
M
Retromolar (mandible)
1.8
16 months
2
46
F
Retromolar (mandible)
2.2
48 months
3
50
M
Gingiva (mandible)
2.2
NA
Oliver et al. [26]
2003
1
34
F
Mandibular angle (intraosseous)
NA
NA
Sedghizadeh et al. [28]
2004
1
20
M
Mandibular left body and angle (intraosseous)
NA
NA
Ramadorai et al. [27] Lyons et al. [24]
2010 2012
1 1
32 28
F M
Mandibular left body (intraosseous) Mandibular right body
4.2 9 2 NA
NA NA
Brierley et al. [9]
2013
1
43
F
Anterior mandible (intraosseous)
NA
NA
Present report
2013
1
18
F
Gingiva (mandible)
2.6 9 2.5
10 months
NA not available
mobility and surface ulceration and lingual cortical bone resorption could be seen. MFs are usually well circumscribed and display a biphasic pattern consisting of fascicles of spindle-shaped cells admixed with areas that demonstrate a hemangiopericytoma-like pattern. The fascicles are composed of elongated smooth muscle-like cells with thin cytoplasmic extensions containing tapered to blunt-ended nuclei. Other portions of the lesion demonstrate cells with ovoid nuclei. These fibroblast-like cells tend to surround the staghornshaped blood vessels, which are characteristic of the hemangiopericytoma-like areas. The tumor cells may display occasional mitotic activity, but abnormal mitotic figures are not seen. The supporting stroma varies from myxoid in appearance to focal areas of hyalinization. No necrosis is evident [1, 10, 12–14, 18, 19, 21, 32]. MF was commonly misdiagnosed previously, particularly as a malignant or a locally aggressive lesion [9, 19, 25]. Misdiagnosis has included many of these tumors, with an initial histopathological misdiagnosis occurring in 26 % of biopsies [33]. Wavy and blunt-ended nuclei seen in neurofibroma and leiomyoma/leiomyosarcoma, respectively, were not observed in the present cases [22, 34, 35]. Leiomyomas and leiomyosarcomas can be distinguished because they lack the zoning phenomenon that is easily recognized in the MFs. In addition, leiomyosarcomas possess considerably more cellular pleomorphism and a higher mitotic rate. Besides, smooth-muscle tumors are extremely rare in the oral cavity [34, 35]. Fibrosarcomas are uncommon tumors of the oral cavity [36]. They are mostly seen in the retroperitoneum or deep tissues of the extremities. They often contain areas of hemorrhage and necrosis, which are not MF features.
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Inflammation and extravasated red blood cells, characteristic of fasciitis nodular and inflammatory myofibroblastic tumors, were not prominent features in the reported cases [22, 37, 38]. Nodular fasciitis is a fibroblastic growth that has been reported in the oral cavity. However, nodular fasciitis does not exhibit the hemangiopericytoma-like pattern. Moreover, the hallmark features of nodular fasciitis (myxoid stroma, extravasated red blood cells, and lymphocytic infiltrate) are not present in MFs. Differentiation from solitary fibrous tumor may also be difficult because of the hemangiopericytoid appearance shared by both lesions; nevertheless, the biphasic pattern present in the present cases is not observed in solitary fibrous tumor, described as a patternless proliferation of spindle cells, alternating hypercellular areas and hypocellular areas rich in dense keloid-type collagen [22, 38]. Benign fibrous histiocytoma is a fairly common lesion of the head and neck region and may also present with hemangiopericytoma-like areas [39], but it is better characterized by a biphasic cell population of fibroblast-like spindle cells and histiocyte-like rounded cells arranged in a storiform pattern [20, 38]. They are usually associated with inflammatory infiltrate, numerous multinucleated giant cells of a foreign body, or the Touton type that are lacking in MFs, and foamy cells [20, 32, 38]. They also lack the zoning phenomenon present in MF. Hemangiopericytomas can resemble the central areas of MFs but lack the mature peripheral areas. They also are uniformly negative when stained with smooth musclespecific antibodies. Hemangiopericytoma is a soft tissue sarcoma that originates in the pericytes on the walls of capillaries and must be distinguished from MF to avoid improper treatment [9, 14].
Med Mol Morphol
Immunohistochemical staining is useful to identify the nature of neoplastic cells and to reach an accurate diagnosis. An immunohistochemical panel consisting of antibodies to vimentin, S-100, desmin, HHF-35, and SMA must be performed [12, 13, 18, 21, 22, 32]. HHF-35, a muscle actin-specific monoclonal antibody, has also been used as a marker for soft tissue tumors with muscle differentiation, for which it displayed a higher degree of sensitivity than desmin antibodies. HHF-35 reacts with skeletal muscle cells and cardiac muscle cells, but is not reactive with endothelial, neural, or connective tissue cells [40]. Some authors have used this marker recently for MF diagnosis [12]. Smooth muscle actin (SMA) expression is the most-used marker for myofibroblast identification. Foss et al. [19] reported on an immunohistochemical analysis of 39 cases of oral MF that showed 100 % positivity for SMA. In our case, positive staining for SMA was obtained, confirming the myofibroblastic origin of the tumor. Immunohistochemical analysis of Ki-67 (MIB-1) positive cells in various types of tumors has been confirmed to be useful for assessing the growth potential. [41] Several investigators reported that in smooth muscle tumors the MIB-1 labeling index was related to the biologic aggressiveness and level of malignancy, and they proposed its diagnostic and prognostic usefulness. Previous electron microscopy of MF has identified the presence of myofibroblasts [7, 14] and mature fibroblasts [14]. Matthews et al. [16], however, reported that there was no evidence of intracellular microfilaments exhibiting focal densities, characteristic of myofibroblasts. In our case, 3 cell types were recognized, and myofibroblast-like cells had focal dense areas representing microfilaments, dense patches, irregularly demarcated long oval nuclei, pinocytotic vesicles, and a basement lamina around the cells. Myofibroblast-like cells occupied a few areas and intermediate cells comprised most of the tumor. Complete surgical resection is the best treatment for solitary adult MF. The prognosis of this rare tumor is excellent after conservative surgical curettage or resection [14]. Local recurrence has been reported in 7–31 % of excised cases [42]; however, those recurrences are thought to be mostly attributable to the multicentric tumor feature or insufficient resection. In agreement with previous reports, there was no evidence of recurrence after over 2 years of follow-up [10]. As MFs are unencapsulated tumors, treatment should include complete surgical resection along with a border of clinically normal bone. A 5-mm margin is appropriate. In conclusion, MF is a mesenchymal benign neoplasm with myofibroblastic differentiation that may present clinical and histopathologic features that overlap with benign and malignant spindle cell tumors. Immunohistochemical
staining is a valuable, precise, and reliable method for establishing a definitive diagnosis of this tumor. Awareness and recognition of this benign tumor is important to establish the correct diagnosis and avoid the morbidity resulting from unnecessarily aggressive therapy. Acknowledgments The authors would like to thank Assistant Professor Dr. Atsuji Matsuyama and Chief Professor Dr. Masanori Hisaoka, Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan, for providing histological information. The authors are grateful to Associate Professor Edward Barroga of the Department of International Medical Communications of Tokyo Medical University for the editorial review of the English manuscript. Conflict of interest
None declared.
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CASE REPORT
Solitary myofibroma of the mandible: an immunohistochemical and ultrastructural study with a review of the literature Takafumi Satomi • Michihide Kohno • Ai Enomoto • Harutsugu Abukawa Ko Fujikawa • Toshiyuki Koizumi • Daichi Chikazu • Jun Matsubayashi • Toshitaka Nagao
•
Received: 19 August 2013 / Accepted: 18 October 2013 Ó The Japanese Society for Clinical Molecular Morphology 2013
Abstract A solitary myofibroma (MF) is an unusual spindle cell neoplasm that usually arises in the soft tissue, skin, or bone of the head and neck region in infancy. We report an extremely rare case of MF of the mandible in an 18-year-old Japanese woman together with the conventional histologic, immunohistochemical, and electron microscopic findings. The tumor was well circumscribed and composed of fibroblast-like or myofibroblast-like spindle cells. On immunohistochemical evaluation the tumor cells were positive for vimentin, a-smooth muscle actin, HHF-35, and calponin, but negative for neurogenic antigens and markers for vascular endothelial cells. The Ki67 labeling index was 10 % and the p53 labeling index was 10 %. Ultrastructural examination revealed smooth muscle cell differentiation. The patient was treated by surgical resection and underwent follow-up without any signs of recurrence. MF presents a wide range of differential diagnosis, including benign and malignant neoplasms. Therefore, accurate diagnosis may avoid an unnecessarily aggressive therapy. Keywords Solitary myofibroma Mandible Immunohistochemical study Ultrastructural study
T. Satomi (&) M. Kohno A. Enomoto H. Abukawa K. Fujikawa T. Koizumi D. Chikazu Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan e-mail: [email protected] J. Matsubayashi T. Nagao Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
Introduction Myofibroma (MF) is a rare benign neoplasm of mesenchymal origin composed of myofibroblasts which is frequently observed in the soft tissue of the head and neck region in early childhood [1]. It was first described by Williams and Schrum [2] in 1951 as congenital fibrosarcoma. In 1954, this entity was described by Stout [3] as a form of congenital multicentric fibroblastic proliferation that he referred to as ‘‘congenital generalized fibromatosis.’’ In 1981, Chung and Enzinger [4] renamed it ‘‘infantile myofibromatosis.’’ They reported that 88 % of the tumors occurred in patients under the age of 2 years. They divided it into the solitary type and the multiple type. On the other hand, the adult counterpart of this lesion was reported by Daimaru et al. [5] in 1989, renamed as ‘‘myofibromatosis’’. However, Jones et al. [6] in accordance with Smith et al. [7] prefer the term MF when describing a solitary neoplasm of this type. In young children multiple lesions are often present and it is known as infantile myofibromatosis [4]. The solitary form is more common than the multiple form and tends to occur in adults [8]. MF in the oral cavity has been reported in the mandible [1, 9], tongue [10], buccal mucosa [11], and only a few cases reported from the gingiva [12]. Clinically, MF presents as a single swelling when it occurs on the gingiva. With more common lesions such as fibrous epulis, pyogenic granuloma, and peripheral odontogenic fibroma, MF is usually considered in the differential diagnosis. Morphologically, MF is generally characterized by spindle cell proliferation showing a biphasic growth pattern [13] and the final diagnosis is made by immunohistochemical and electron microscopic studies [14]. This report describes an MF of the lingual gingiva of the right posterior mandible in an 18-year-old woman and is
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reported together with the conventional histologic, immunohistochemical, and electron microscopic findings, together with a review of the literature.
Case report Clinical course An 18-year-old Japanese woman was referred to our department of Tokyo Medical University Hospital with a painless swelling of the lingual gingiva of the right second molar of the mandible that had been present for 1 month. The lesion had gradually increased in size. Medical and familial histories were noncontributory. There was no history of trauma or spontaneous bleeding associated with the lesion. Clinical examination revealed a hard mass 3 cm in diameter with ulceration arising from the lingual gingiva of the right second molar to the right retromolar pad in the mandible (Fig. 1). The right lower second molar showed abnormal mobility. The regional lymph nodes were not enlarged. Radiographic examination revealed a unilocular radiolucent area surrounding the root of the right lower second molar (Fig. 2). Computed tomography revealed a well-demarcated, unilocular low-density area approximately 3 9 2 cm in the right posterior mandible with partial resorption of the lingual cortical bone (Fig. 3). An incisional biopsy showed the benign neoplasm to be composed of spindle cells, such as in inflammatory myofibroblastic tumor, and complete surgical resection along with a peripheral osteotomy was planned. Under general anesthesia, nasotracheal intubation was done. The tumor was resected with a surgical margin of normal tissue of 5 mm. The inferior alveolar nerve was not damaged during
Fig. 1 Clinical appearance of myofibroma. Well circumscribed nodular soft tissue mass in the right posterior lingual gingiva of the mandible causing second molar displacement
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the resection. Thorough conservative (rim) marginal resection of the mandible was carried out; a PGA mesh sheet (NeoveilÒ; Gunze Limited, Kyoto, Japan) was placed on the wound surface of the surgical defect which was then covered with fibrin glue (BolhealÒ; Chemo-sero-therapeutic Research Institute, Kumamoto, Japan). Postoperative recovery was uneventful. A 10-month follow-up period showed no signs of recurrence.
Materials and methods The surgical specimen was immediately fixed in 10 % formalin and processed for paraffin embedding, sectioned into 3- to 4-lm sections, and stained with standard hematoxylin and eosin. For immunohistochemical study, the avidin–biotin-peroxidase complex method was used. The
Fig. 2 Panoramic radiograph showing unilocular radiolucency surrounding the root of the right second molar of the mandible
Fig. 3 Axial view of a CT showing a unilocular low-density area with partial resorption of the cortical bone indicated (arrow)
Med Mol Morphol Table 1 Summary of immunohistochemical results of the present myofibroma case Antigen
Clone
Dilution
Source
Positivity
Intensity
Vimentin
V9
Calponin
CALP
1:2000
DAKO
???
Strong
1:100
DAKO
?
Actin
HHF35
1:100
Moderate
DAKO
?
Weak Strong
a-Smooth muscle actin
1A4
1:100
DAKO
???
Pan cytokeratin
AE1/AE3
1:200
DAKO
–
Cytokeratin 7/18
CAM5.2
1:10
DAKO
–
Desmin
D33
1:50
DAKO
–
S-100
SI 00
1:2000
DAKO
–
CD34
QBEndIO
1:100
DAKO
–
CD68
PG-M1
1:100
DAKO
–
Epithelial membrane antigen ALK-1
E29 ALK-1
1:100 1:50
DAKO DAKO
– –
Caldesmon
h-CD
1:100
DAKO
–
Ki-67
Mib-1
1:50
DAKO
? (10 %)
Weak
p53
p53
1:50
DAKO
? (10 %)
Weak
commercially purchased primary antibodies used in the present study are summarized in Table 1. In addition, immunohistochemical methods for assessment of the protein expression of the tumor proliferative index Ki-67 (MIB-1) were followed. To determine the positivity of the immunostaining, we utilized the following classification system: -(0–5 % positive cells), ?(5–25 % positive cells), ??(25–50 % positive cells), ???(50–100 % positive cells). The intensity of the immunostaining was classified as weak, moderate, and strong. Negative controls for the staining were stained specimens with prior omission of the primary antibody. For electron microscopy, fresh tissue was immersed in 2.5 % glutaraldehyde at 4 °C for 4 h, post-fixed in 1 % osmium tetroxide for 2 h, dehydrated in graded ethanol solutions (30 % 10 min, 50 % 10 min, 70 % 10 min, 100 % 10 min), and embedded in Epon (Chemical polymerization at 70 °C for 4 days). Ultrathin sections were cut using a microtome, stained with uranyl acetate-lead citrate, and observed under a Hitachi H-7500 transmission electron microscope (Hitachi Ltd., Tokyo, Japan).
Results Macroscopic findings On gross examination, the surgical specimen consisted of a well-circumscribed 2.6 9 2.5 cm solid mass of white to pink-tan tissue. The cut surface revealed relatively homogeneous and smooth, unevenly yellowish-white, and peripherally firm tissue (Fig. 4).
Fig. 4 a Surgical specimen: Tumor was a well-circumscribed 2.6 9 2.5 cm solid mass of white to pink-tan tissue. b Cut surface: the cut surface revealed relatively homogeneous and smooth, unevenly yellowish-white, and peripherally firm tissue
Microscopic findings The tumor was a well circumscribed, although not encapsulated, mass. The characteristic biphasic growth pattern was obscure. The mostly well-circumscribed nodular lesion was composed of a proliferation of fibroblast- or myofibroblast-like spindle cells having fusiform nuclei and eosinophilic cytoplasm arranged in interlacing fascicles or whorls with mildly fibrocollagenous or myxoid stroma, alternating with cellular areas containing many dilated and thin-walled blood vessels, displaying a hemangiopericytomatous appearance, mainly at the periphery of the lesion and an inflammatory infiltrate probably due to the surface ulceration. Mitotic figures were
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Fig. 5 Histopathologic features (hematoxylin and eosin stain). a The lesion is composed of a proliferation of spindle cells in interlacing fascicles or whorls, alternating with cellular areas containing thinwalled blood vessels, displaying a hemangiopericytomatous appearance (original magnification 940). b The spindle cells have fusiform nuclei and eosinophilic cytoplasm with a mildly fibrocollagenous stroma (original magnification 9200). Immunohistochemical stain.
c Tumor cells showing strong positivity for a-smooth muscle actin (original magnification 9200). d Most of the tumor cells were weakly positive for HHF-35 (original magnification 9200). e Tumor cells were also positive for calponin (original magnification 9200). f Ki-67 (MIB-1) labeling index is approximately 10 % (original magnification 9200)
sometimes encountered. No abnormal mitotic figures, cellular pleomorphism, or areas of necrosis were seen (Fig. 5a, b).
muscle actin, HHF-35, and calponin. These tumor cells were weakly Ki-67 positive (MIB-1 labeling index was 10 %) and the p53 labeling index was 10 %, whereas staining for cytokeratin, S-100, EMA, desmin, caldesmon, CD34, ALK-1, and ß-catenin was negative (Fig. 5c, d, e, f). The above histopathologic and immunohistochemical findings were consistent with the features of
Immunohistochemical findings Immunohistochemical analysis revealed that the spindleshaped cells were positive for vimentin, a-smooth
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Fig. 6 a Electron micrograph of myofibroblast-like cells. Spindleshaped cells with long nuclei are observed. Note myofilaments (arrowhead), actin fiber arrangement (arrow) and RER (asterisk).
b Electron micrograph of fibroblasts. Cells are rich in RER with surrounding collagen fibers. Note basal membrane (arrow) and pinocytotic vesicles (asterisk)
MF. All performed immunohistochemical studies are summarized in Table 1.
study by Sugatani et al. [14] 62.5 % of oral MFs in patients younger than 16 years occurred in the mandible. Other locations included the tongue, buccal mucosa, lip, vestibule, and attached gingiva [18]. Therefore, MFs involving the mandible are relatively common in children; however, there are few reports of MFs in adults [6, 22]. Our case of a solitary MF occurring in the lingual gingiva of the mandible of an 18-year-old woman is unusual. We summarized in Table 2 the clinical data in the English literature (PubMed) of the 14 reported cases (including our case) of oral MFs in patients older than 16 years, originating from the mandible including the gingiva, retromolar region, and intraosseous sites. In Table 2, the mean age of patients with solitary MFs in the mandible is 36.1 years (range 18–70 years) in patients older than 16 years. Solitary MF of the mandible, excluding the intraosseous lesions, seems to be extremely rare, and to the best of our knowledge, only 9 cases have been reported [6, 9, 23–29]. The MF etiology remains unknown. It has been suggested that the tumor is inherited as an autosomal dominant or autosomal recessive trait, although very low familial incidence has been reported [30]. The typical clinical presentation is a painless mass that may display rapid growth and ulceration, thus raising alarm [19, 31]. The nonspecific clinical presentation and the relative rarity make the differential diagnosis wide, including benign and malignant mesenchymal lesions which may be of fibrous, muscle, neural, or vascular tissue in origin [6, 19, 25, 32]. Abramowicz et al. [1] reported in a retrospective analysis that there are 2 distinct clinical types of solitary MF of the jaws. There is an aggressive exophytic type and a nonaggressive intraosseous type. The aggressive type is characterized as an exophytic soft tissue mass in the dentoalveolar region often covering the teeth, with tooth mobility and surface ulceration. Our case is an aggressive exophytic type; the tumor had been associated with tooth
Electron microscopic findings Electron microscopy has been reported in only a few cases [14–16]. The cells were described as spindle-shaped and round with long cellular processes and extracellular collagen fibrils. Spindle-shaped cells were primarily distributed within a collagenous matrix. The nuclei were oval to spindle in shape with occasional irregular indented contours. The cytoplasm contained fine microfilaments along with large amounts of rough endoplasmic reticulum (RER) and pinocytotic vesicles. Microfilaments and pinocytotic vesicles were noted along the cell membrane. An interrupted basal membrane was visible at the periphery of these cells. A dense patch representing actin fibers attached to a portion of the cell membrane, a focal dense area indicating microfilament bundles, and a high-density area spreading from the center to the peripheral region were seen (Fig. 6a, b).
Discussion MF occurs mostly in the head and neck region, the skin of the trunk, and subcutaneous tissue, but rarely within bone [10, 17, 18]. Solitary MFs are often diagnosed during infancy and childhood and have a male predilection [14, 18–20]. Chung and Enzinger [4] reported that nearly 90 % of the 61 cases they reviewed were diagnosed in patients younger than 2 years of age. The most affected sites are the soft tissue of the head and neck; however, internal organs and bones can also be involved [21]. Three studies in 1995 and in 2000 identified the mandible as the most frequent oral site (16 [44 %] of 36 [20], 15 [42.6 %] of 35 [14], and 30 [38.0 %] of 79 [19]). In a
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Med Mol Morphol Table 2 Reported cases of myofibroma of the mandible in patients older than 16 years Report
Year
No.
Age (years)
Sex
Site
Size (cm)
Beham et al. [23]
1993
1
60
M
Gingiva
0.5
NA
Jones et al. [6]
1994
1
70
F
Gingiva
0.8 9 0.5
NA
2
35
F
Vestibule (mandible)
0.7
NA
3
19
M
Vestibule (mandible)
2.5
NA
1
21
M
Retromolar (mandible)
2 9 1.5
6 months
Ugar et al. [29]
1999
Montromery et al. [25]
2000
Follow-up (months)
1
29
M
Retromolar (mandible)
1.8
16 months
2
46
F
Retromolar (mandible)
2.2
48 months
3
50
M
Gingiva (mandible)
2.2
NA
Oliver et al. [26]
2003
1
34
F
Mandibular angle (intraosseous)
NA
NA
Sedghizadeh et al. [28]
2004
1
20
M
Mandibular left body and angle (intraosseous)
NA
NA
Ramadorai et al. [27] Lyons et al. [24]
2010 2012
1 1
32 28
F M
Mandibular left body (intraosseous) Mandibular right body
4.2 9 2 NA
NA NA
Brierley et al. [9]
2013
1
43
F
Anterior mandible (intraosseous)
NA
NA
Present report
2013
1
18
F
Gingiva (mandible)
2.6 9 2.5
10 months
NA not available
mobility and surface ulceration and lingual cortical bone resorption could be seen. MFs are usually well circumscribed and display a biphasic pattern consisting of fascicles of spindle-shaped cells admixed with areas that demonstrate a hemangiopericytoma-like pattern. The fascicles are composed of elongated smooth muscle-like cells with thin cytoplasmic extensions containing tapered to blunt-ended nuclei. Other portions of the lesion demonstrate cells with ovoid nuclei. These fibroblast-like cells tend to surround the staghornshaped blood vessels, which are characteristic of the hemangiopericytoma-like areas. The tumor cells may display occasional mitotic activity, but abnormal mitotic figures are not seen. The supporting stroma varies from myxoid in appearance to focal areas of hyalinization. No necrosis is evident [1, 10, 12–14, 18, 19, 21, 32]. MF was commonly misdiagnosed previously, particularly as a malignant or a locally aggressive lesion [9, 19, 25]. Misdiagnosis has included many of these tumors, with an initial histopathological misdiagnosis occurring in 26 % of biopsies [33]. Wavy and blunt-ended nuclei seen in neurofibroma and leiomyoma/leiomyosarcoma, respectively, were not observed in the present cases [22, 34, 35]. Leiomyomas and leiomyosarcomas can be distinguished because they lack the zoning phenomenon that is easily recognized in the MFs. In addition, leiomyosarcomas possess considerably more cellular pleomorphism and a higher mitotic rate. Besides, smooth-muscle tumors are extremely rare in the oral cavity [34, 35]. Fibrosarcomas are uncommon tumors of the oral cavity [36]. They are mostly seen in the retroperitoneum or deep tissues of the extremities. They often contain areas of hemorrhage and necrosis, which are not MF features.
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Inflammation and extravasated red blood cells, characteristic of fasciitis nodular and inflammatory myofibroblastic tumors, were not prominent features in the reported cases [22, 37, 38]. Nodular fasciitis is a fibroblastic growth that has been reported in the oral cavity. However, nodular fasciitis does not exhibit the hemangiopericytoma-like pattern. Moreover, the hallmark features of nodular fasciitis (myxoid stroma, extravasated red blood cells, and lymphocytic infiltrate) are not present in MFs. Differentiation from solitary fibrous tumor may also be difficult because of the hemangiopericytoid appearance shared by both lesions; nevertheless, the biphasic pattern present in the present cases is not observed in solitary fibrous tumor, described as a patternless proliferation of spindle cells, alternating hypercellular areas and hypocellular areas rich in dense keloid-type collagen [22, 38]. Benign fibrous histiocytoma is a fairly common lesion of the head and neck region and may also present with hemangiopericytoma-like areas [39], but it is better characterized by a biphasic cell population of fibroblast-like spindle cells and histiocyte-like rounded cells arranged in a storiform pattern [20, 38]. They are usually associated with inflammatory infiltrate, numerous multinucleated giant cells of a foreign body, or the Touton type that are lacking in MFs, and foamy cells [20, 32, 38]. They also lack the zoning phenomenon present in MF. Hemangiopericytomas can resemble the central areas of MFs but lack the mature peripheral areas. They also are uniformly negative when stained with smooth musclespecific antibodies. Hemangiopericytoma is a soft tissue sarcoma that originates in the pericytes on the walls of capillaries and must be distinguished from MF to avoid improper treatment [9, 14].
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Immunohistochemical staining is useful to identify the nature of neoplastic cells and to reach an accurate diagnosis. An immunohistochemical panel consisting of antibodies to vimentin, S-100, desmin, HHF-35, and SMA must be performed [12, 13, 18, 21, 22, 32]. HHF-35, a muscle actin-specific monoclonal antibody, has also been used as a marker for soft tissue tumors with muscle differentiation, for which it displayed a higher degree of sensitivity than desmin antibodies. HHF-35 reacts with skeletal muscle cells and cardiac muscle cells, but is not reactive with endothelial, neural, or connective tissue cells [40]. Some authors have used this marker recently for MF diagnosis [12]. Smooth muscle actin (SMA) expression is the most-used marker for myofibroblast identification. Foss et al. [19] reported on an immunohistochemical analysis of 39 cases of oral MF that showed 100 % positivity for SMA. In our case, positive staining for SMA was obtained, confirming the myofibroblastic origin of the tumor. Immunohistochemical analysis of Ki-67 (MIB-1) positive cells in various types of tumors has been confirmed to be useful for assessing the growth potential. [41] Several investigators reported that in smooth muscle tumors the MIB-1 labeling index was related to the biologic aggressiveness and level of malignancy, and they proposed its diagnostic and prognostic usefulness. Previous electron microscopy of MF has identified the presence of myofibroblasts [7, 14] and mature fibroblasts [14]. Matthews et al. [16], however, reported that there was no evidence of intracellular microfilaments exhibiting focal densities, characteristic of myofibroblasts. In our case, 3 cell types were recognized, and myofibroblast-like cells had focal dense areas representing microfilaments, dense patches, irregularly demarcated long oval nuclei, pinocytotic vesicles, and a basement lamina around the cells. Myofibroblast-like cells occupied a few areas and intermediate cells comprised most of the tumor. Complete surgical resection is the best treatment for solitary adult MF. The prognosis of this rare tumor is excellent after conservative surgical curettage or resection [14]. Local recurrence has been reported in 7–31 % of excised cases [42]; however, those recurrences are thought to be mostly attributable to the multicentric tumor feature or insufficient resection. In agreement with previous reports, there was no evidence of recurrence after over 2 years of follow-up [10]. As MFs are unencapsulated tumors, treatment should include complete surgical resection along with a border of clinically normal bone. A 5-mm margin is appropriate. In conclusion, MF is a mesenchymal benign neoplasm with myofibroblastic differentiation that may present clinical and histopathologic features that overlap with benign and malignant spindle cell tumors. Immunohistochemical
staining is a valuable, precise, and reliable method for establishing a definitive diagnosis of this tumor. Awareness and recognition of this benign tumor is important to establish the correct diagnosis and avoid the morbidity resulting from unnecessarily aggressive therapy. Acknowledgments The authors would like to thank Assistant Professor Dr. Atsuji Matsuyama and Chief Professor Dr. Masanori Hisaoka, Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan, for providing histological information. The authors are grateful to Associate Professor Edward Barroga of the Department of International Medical Communications of Tokyo Medical University for the editorial review of the English manuscript. Conflict of interest
None declared.
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