|Year : 2017 | Volume
| Issue : 3 | Page : 412-418
Spindle cell lesions: A review on immunohistochemical markers
Surbhi, Rashmi Metgud, Smitha Naik, Shrikant Patel
Department of Oral and Maxillofacial Pathology and Microbiology, Pacific Dental College and Hospital, Udaipur, Rajasthan, India
|Date of Web Publication||31-Aug-2017|
Department of Oral and Maxillofacial Pathology and Microbiology, Pacific Dental College and Hospital, Debari, Udaipur - - 313 024, Rajasthan
Source of Support: None, Conflict of Interest: None
The intriguing array of spindle cell lesions occurring, especially in the head and neck region, poses a critical diagnostic challenge not only to the histopathologist but also ultimately to the clinicians for planning an appropriate treatment protocol. Overlapping spectrum of clinico-radiographic and microscopic features further compounds this problem. In such situations, the aid of ancillary techniques such as immunohistochemistry (IHC) is sought to clinch the diagnosis. This study aims to review the spindle cell neoplasms of the oral cavity with emphasis on IHC.
Keywords: Immunohistochemical markers, oral neoplasms, spindle cell lesions
|How to cite this article:|
Surbhi, Metgud R, Naik S, Patel S. Spindle cell lesions: A review on immunohistochemical markers. J Can Res Ther 2017;13:412-8
| > Introduction|| |
Spindle cell lesions of head and neck include a diverse group of clinically and biologically heterogeneous lesions. Some are malignant while many others are benign or simply reactive in nature. There is a diagnostic challenge to the oral pathologists to differentiate dizzying array of spindle cell lesions from other similar microscopic simulates ranging all the way from reactive to malignant and very aggressive. More recently, a simple working type classification was proposed By the author Shamim 2013 for the spindle cell neoplasms of the oral cavity on the basis of predominance of spindle cells in the histopathology of the lesions of the oral cavity. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on immunohistochemical markers. Including neural, myofibroblastic, muscle, fibroblastic, vascular, epithelial, odontogenic, and miscellaneous tumors.
| > Neural Tumors|| |
These neoplasms of neurogenic origin arise from the cells of neuroectodermal origin.
This category includes neurofibroma, neurilemmoma (schwannoma), palisaded encapsulated neuroma (PEN), traumatic neuroma (amputation neuroma), and malignant peripheral nerve sheath tumor (MPNST).
Neurofibroma is a benign peripheral nerve sheath tumor comprising variable mixture of Schwann cells, perineurial-like cells, and fibroblasts. Immunohistochemically, the tumor cells show a scattered positive reaction for S-100 protein. Variable staining for CD34 is also seen. Antibodies to epithelial membrane antigen (EMA), CD57, and collagen IV are of secondary value. The benign nature of these lesions is signified by the negative or weakly positive staining of tumor cells for P53 and Ki-67. Francisco Oliveira et al. in 2013 analyzed 8 cases of oral neurofibromas immunohistochemically and observed positive staining for S-100 protein in seven specimens, EMA, and CD34 immunoexpression was negative and positive in all the samples, respectively.
Neurilemmoma is a benign tumor that originates from perineural Schwann cells of the nerve sheath. Immunohistochemically, the tumor cells show a diffuse, positive reaction for S-100 protein. According to Chrysomali et al., the tumor cells with Antoni A show greater intensity scores compared to Antoni B tumor pattern. EMA was seen only in the capsule staining perineural cells and laminin-stained basement membrane around tumor cells. Fibronectin and collagens I and III were expressed, especially in the capsule. They also show positivity for vimentin, Leu-7 antigen, and glial fibrillary acidic protein (GFAP).
Palisaded encapsulated neuroma is a benign and hyperplastic lesion consisting of Schwann cells. Immunohistochemical analyses demonstrate strong positive tumor cell staining for S-100 protein and vimentin characteristic of Schwann cell differentiation and negative for GFAP and alpha-smooth muscle actin (α-SMA). The capsule may stain with EMA. EMA, glucose transporter type 1, claudin 1 positive cells around the lobules, and epithelioid and vascular variants have been reported. Moreover, the positive axon staining of PENs may be useful in differentiating PENs from schwannomas.
Traumatic neuroma is a reactive proliferation of neural tissue after transection or other damage of a nerve bundle. Immunohistochemically, S-100 being the single best antibody, whereas antibodies to EMA, CD57, and collagen IV are of secondary value. In a case reported by Jham et al., 2014, the lesional tissue was stained with Ki-67 to confirm its low proliferative index and benign nature.
MPNSTs are rare high-grade sarcomas arising from peripheral nerves or cells of the peripheral nerve sheath. In immunohistochemistry (IHC), focal S-100 protein is positive in 50–90% of MPNSTs; neuron-specific enolase is confirmatory for the neurogenic origin and positivity of Leu-7; vimentin and myelin basic protein also are helpful for diagnosis of the MPNSTs., In a case reported by Jahanshah Salehinejad et al., 2013, they observed negative immunoreactivity for HMB-45.
| > Myofibroblastic Tumors|| |
Myofibroblastic tumors include tumors of myofibroblasts (i.e., cells with both smooth muscle and fibroblastic features). This category includes myofibroma, inflammatory myofibroblastic tumor (IMT), and low-grade myofibrosarcoma.
Myofibroma is a rare spindle cell neoplasm that consists of myofibroblasts. Immunohistochemically, the tumor cells will be positive for vimentin and α actin smooth muscle antibodies and negative for keratin, S-100, and EMA antibodies. An immunohistochemical panel consisting of antibodies to vimentin, S-100p, desmin, HHF-35, and SMA must be achieved [Table 1].
IMT encompasses a spectrum of myofibroblastic proliferation along with varying amount of inflammatory infiltrate including mature lymphocytes, histiocytes, plasma cells, eosinophils, and collagen. The IHC is usually utilized to confirm the myofibroblastic phenotype of the tumor spindle cells which are typically reactive to vimentin (99%), SMA (92%), muscle-specific actin (89%), and desmin (69%). Spindle cells may be focally positive to epithelial markers such as cytokeratin, EMA (36%), and CD68 (25%). Other features, such as the presence of ganglion-like cells, atypia, p53 expression, and aneuploidy may identify patients with IMT and those at high malignant risk. Frequently, cytogenetic abnormalities (approximately 50% of IMTs) result in the overexpression of the ALK protein kinase. Gallego et al., 2013, have also demonstrated faint positivity of Ki-67 immunohistochemically. However, a case reported by Rahman et al., 2014, observed Ki-67 was negative for nuclear stain.
Low-grade myofibrosarcoma is a rare entity in the oral cavity. Immunohistochemically, myofibroblastic sarcoma is immunopositive for vimentin, SMA, muscle-specific actin, calponin, and fibronectin, rarely immunopositive for desmin and immunonegative for laminin and type IV collagen. Furthermore, low-grade myofibroblastic sarcoma is no immunoreactive for S-100, EMA, cytokeratin, or CD34.
| > Muscle Tumors|| |
Muscle tumors include tumors of muscle tissue origin. This category includes leiomyoma, vascular leiomyoma, leiomyosarcoma, rhabdomyoma, and rhabdomyosarcoma (RMS).
Leiomyoma is benign tumor of smooth muscle that most commonly occurs in the uterus, gastrointestinal tract, and skin. The immunophenotype of the neoplastic cells is α-SMA (+), vimentin (+), desmin (+), CD34 (−) (although the endothelium of the vascular spaces is CD34+), and S-100 protein (−). Masson trichrome and Van Gieson's stains are specific for muscle cells and collagen fibers whereas Mallory's phosphotungstic acid hematoxylin may aid to differentiate leiomyoma from other spindle cell tumors.
Leiomyosarcoma is a malignant neoplasm of smooth muscle origin, which accounts for 7% of all soft tissue sarcomas. Masson's trichrome staining and immunohistochemical analysis usually reveal the presence of desmin, vimentin, muscle-specific actin, h-caldesmon, and SMA and negative for S-100 protein, cytokeratin, and desmin.,, In addition, P53 expression has been associated with higher recurrence rate and shorter survival.
Benign neoplasms of skeletal muscle are called rhabdomyomas. The adult rhabdomyoma has revealed variable immunoreactivity for vimentin, S-100, SMA, myoglobin, and myogenin actin., HHF-35 is a specific and sensitive marker for tumors of muscle origin.
RMS is a malignant tumor originating from striated muscle cells. Intense staining for myoglobin, desmin, and specific muscle actin is proportional to the rhabdomyoblast differentiation degree. Positive reaction for desmin indicated muscular differentiation. Desmin could not distinguish between skeletal and smooth muscle differentiation. The MyoD family includes four proteins myogenin, MyoD1, myf-5, and MRF-4. Antibodies to myogenin and MyoD1 have high sensitivity and specificity for skeletal muscle differentiation. They are positive in about 90% of the RMS.
| > Fibroblastic Tumors|| |
Fibroblastic tumors include tumors of fibroblasts. This category includes solitary fibrous tumor, fibromatoses, nodular fasciitis, desmoplastic fibroma, and fibrosarcoma.
Solitary fibrous tumor is an uncommon benign lesion of mesenchymal origin, less commonly associated with head and neck, accounting for around 6% of the cases. It shows reactivity to CD34, bcl-2, vimentin, and CD99. CD34 is the only consistently expressed and sensitive marker but is negative to keratin, EMA, S-100, desmin, SMA, and muscle-specific actin.,
Fibromatosis is proliferations of highly differentiated fibrous tissue. In the oral cavity, fibromatosis is presenting as aggressive type. No specific immunohistochemical markers are available. In a case reported by Reddy et al., 2014, spindle cells immunohistochemically showed focal cytoplasmic positivity with SMA, diffuse nuclear positivity with beta-catenin and negativity for desmin.
Nodular fasciitis is a benign reactive proliferation of fibroblasts that is thought to be a response of tissue to injury. All exhibit some degree of positive reaction to vimentin staining from weak to strong. Immunohistochemical analysis will reveal positivity of the spindle cells for the antibodies against SMA and muscle-specific actin (HHF-35) but not desmin and cytokeratin, implying that their origin was myofibroblasts.
The desmoplastic fibroma of bone is an uncommon tumor of fibroblastic origin. The fibroblastic cells are intensely positive for vimentin. A few cells may show a positive immunoreactivity for Muscle specific actin and α-SMA.
Fibrosarcoma is a malignant tumor of fibroblasts. The positive immunostaining for vimentin, together with negativity for muscular immunomarkers (desmin, SMA, HHF-35), human osteoblasts (osteocalcin), macrophages (CD-68), leukocyte common antigen, neural tissue (S-100, neuron specific enolase), melanoma (HMB-45), neutrophils (CD-31), hematopoietic cells (CD-34), epithelial tissue (cytokeratin, EMA), and CD-99 helps in diagnosing the fibrosarcoma.
| > Vascular Tumors|| |
Vascular tumors include tumors of vascular tissue origin. This category includes hemangiopericytoma, Kaposi sarcoma, and spindle cell hemangioma.
Hemangiopericytoma is a rare neoplasm that is presumably derived from pericytes, i.e. cells whose processes encircle the endothelial cells of capillaries. It has localized CD34 immunoreactivity, vimentin (100%), SMA (72%), muscle-specific actin (65%).
Kaposi's sarcoma is an angioproliferative tumor rarely found in the oral cavity. The vascular nature of this tumor can be confirmed by immunostaining for CD31 and CD34. Immunohistochemical detection of HHV-8 LNA-1 and D2-40 are useful tools to differentiate Kaposi sarcoma from other vascular tumors.
Spindle cell hemangioma is an uncommon benign vascular tumor of the oral cavity. Only the cells lining the vascular spaces and the epithelioid cells stain for endothelial markers (CD31 and CD34). Most spindle cells stain only for vimentin and a smaller percent for actin/desmin.,
| > Epithelial Tumors|| |
Epithelial tumors include tumors of epithelial tissue origin. This category includes spindle cell carcinoma, pleomorphic adenoma, and malignant melanoma.
In spindle cell carcinoma, the most sensitive and reliable epithelial markers to be used for demonstration of the epithelial phenotype are keratin (AE1/AE3) and EMA. AE1/AE3 and EMA, on the spindle cell component, can be useful in the differential diagnosis of spindle cell carcinoma (SpCC) with other sarcomatous lesions.
Approximately two-third of the cases of SpCC react with antibodies directed against cytokeratin, and an equivalent number show vimentin immunoreactivity. Some cases also will be positive for Carcinoembryonic antigen (CEA). The spindle-cell component expressed diffuse SMA. Immunoreactivity for Ki-67 was detected in up to 40% in the sarcomatous region and 60% in the carcinomatous region. An additional epithelial marker, p63, was positively detected in cases of SpCC. Silvestri et al. have presented that immunologically sarcomatoid elements are always strongly positive for vimentin, but cytokeratin reactivity of spindle cells are variable and may be completely absent. The vimentin positivity reflects that bizarre fibroblast-like cells are carcinoma cells with true mesenchymal metaplasia.
Pleomorphic adenoma is a benign epithelial neoplasm demonstrating both epithelial and modified myoepithelial differentiation with diversified histologic features. The tumor expresses CK7, CK14, CEA, SMA, MSA, SMMHC, calponin, p63, S-100, vimentin, Wilms tumor 1, and GFAP. Currently, the most reliable marker for the neoplastic myoepithelium is calponin. PLAG1 protein is a sensitive and specific marker for pleomorphic adenoma and can be useful to differentiate pleomorphic adenoma from adenoid cystic carcinoma, mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma, and acinic cell carcinoma.
Oral malignant melanoma is a rare, aggressive neoplasm of melanocytic origin representing 0.2–8% of all melanomas. Immunohistochemically, the typical melanoma is reactive for vimentin, S-100 protein, HMB-45, Melan-A, tyrosinase, and microphthalmia transcription factor. Positivity for S-100 protein, seen both in nucleus and cytoplasm, although nonspecific, is of greater practical importance because it is negative in most of other tumors that enter into the differential diagnosis. HMB-45 is a much more specific marker than S-100 and is confirmatory, reliably specific in 93% of melanocytic malignancies., S-100 protein is frequently used to highlight the spindled, more neural-appearing melanocytes, whereas HMB-45 is used to identify the round cells. As for the other markers, Ki-67 is commonly used as an adjunct in distinguishing benign nevi from melanoma. Some of the more recently studied proliferation markers include HDM2 and the Growth arrest DNA damage proteins to show that they may have real promise as prognostic markers.
| > Odontogenic Tumors|| |
Odontogenic tumors include tumors of odontogenic origin. This category includes ameloblastic fibroma, ameloblastic fibrosarcoma (AF), central odontogenic fibroma, and desmoplastic ameloblastoma.
Ameloblastic fibroma is a rare odontogenic tumor constituting neoplastic epithelial and mesenchymal tissues. Odontogenic epithelial cells are fully positive for cytokeratin detected by antibody KL-1. On the other hand, only immature dental papilla-like mesenchymal tissue are positive for tenascin, positive vimentin staining can be observed. Proliferating indices, such as AgNOR, proliferating cell nuclear antigen, and Ki-67 can be used to suggest the malignant development.,
AF is a rare malignant odontogenic tumor characterized by a benign epithelial component within a malignant fibrous stroma. Yamamoto et al., in their study, showed the presence of keratin in the columnar and polyhedral cells of the epithelial component and vimentin in the ectomesenchymal component verifying the biphasic nature of this tumor. Moreover, Williams et al. demonstrated alterations of the p53 and c-KIT genes in the sarcomatous component of an anaplastic AFS that transformed from a recurrent AF. Positive reactions for MIB-1 were observed in the nuclei of tumor cells in both the epithelial and ectomesenchymal components.
Central odontogenic fibroma is a rare benign odontogenic mesenchymal tumor of jaw bones. Stellate and spindle-shaped connective tissue cells show immunoreactive for vimentin. The epithelial islands are positive for CK, AE1/AE3, CK5, CK 14, CK19, and 34BE12. Langerhan's cells are demonstrated within the epithelial islands which are immunoreactive for S-100 protein and CD1a. The antitype IV collagen is positive in areas of eosinophilic globules which are seen within the odontogenic islands.
Desmoplastic ameloblastoma show variable expression of S-100 protein and desmin, marked immunoexpression of transforming growth factor-alpha, high expression of caspase-3 and Fas, decreased expression of CK19 and high expression of p63. The desmoplastic stroma has been reported to show a strong positive reaction for collagen type VI.
| > Miscellaneous Tumors|| |
Miscellaneous tumors comprise of unclassified category tumors. This category includes benign fibrous histiocytoma, malignant fibrous histiocytoma (MFH), synovial sarcoma, ossifying fibromyxoid tumor, giant cell angiofibroma, and blue nevus.
Benign fibrous histiocytomas are a diverse group of tumors that exhibit both fibroblastic and histiocytic differentiation. Tumor cells show positivity for vimentin, CD68, -1-antitrypsin, -1-antichymotrypsin and negative for SMA, S-100 protein, EMA, cytokeratin, desmin, and CD34.
The MFH is a sarcoma with both fibroblastic and histiocytic features.
Lawson et al. studied 10 ultrastructurally-defined cases of MFH and found that all labeled for vimentin. In addition, six cases showed expression of desmin and neurofilaments. In 1989, Hirose et al. examined the expression of intermediate filaments in 34 cases of MFH and found 30/34 to be vimentin positive, 12/34 to be desmin positive, 2/34 to be neurofilament positive, and 1/34 to be cytokeratin positive. Kamatani et al. reported strong and diffuse immunohistochemically positivity for CD34 and vimentin within the cytoplasm of the tumor cells. They noticed positive expression for S-100 protein. Even some of the acinar cells were immunopositive for S-100 protein, although the peripheral cells of acinar structures were simultaneously actin-immunopositive, suggesting their myoepithelial differentiation.
Synovial sarcoma is a mesenchymal spindle cell tumor with variable epithelial differentiation. Immunohistochemically, TLE1 is a sensitive and specific marker and can be helpful to distinguish from other histological mimics. The spindle cells show strong and uniform expression of vimentin with occasional positivity of cytokeratin, particularly in biphasic variant. In all, 90% cases demonstrate strong cytokeratin positivity. Other epithelial markers such as CK7, CK19, and EMA are also positive.
Ossifying fibromyxoid tumor is a rare mesenchymal neoplasm initially reported by Enzinger et al. in 1989. IHC reveals positivity for S-100 protein in approximately 80% cases and desmin in 50–60% cases along with positivity for SMA in about 50%.
Giant cell angiofibroma is a well-circumscribed, normally encapsulated, distinctive orbital soft-tissue tumor with only 3 cases reported as painless solitary nodule in buccal mucosa., IHC reveals mononucleated and multinucleated giant cells are diffusely positive for vimentin, CD34 and weakly positive for bcl-2.,
Blue nevus is an uncommon, benign proliferation of dermal melanocytes, usually deep within subepithelial connective tissue. Immunohistochemically, the spindle-shaped cells of blue nevi will express both S-100 and HMB-45.
Tabulated forms of all the IHC markers are enlisted in [Table 2].
|Table 2: Systemic review of immunohistochemical markers for spindle cell lesions|
Click here to view
| > Conclusion|| |
Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. With attention to the clinical scenario, it is very difficult to diagnose these neoplasms from routine hematoxylin and eosin sections of histopathology, and judicious use of immunostains have to be carried out to arrive at the correct diagnosis.
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[Table 1], [Table 2]