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Year : 2017  |  Volume : 60  |  Issue : 3  |  Page : 350-354
Clinicopathologic features of four rare types of chordomas, confirmed by brachyury immunostaining

1 Department of Surgical Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

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Date of Web Publication22-Sep-2017


Background: A wide clinicopathologic spectrum of a chordoma exists. Brachyury constitutes as its most useful diagnostic immunohistochemical (IHC) marker. Methods: During a 7-year-period, 4 unusual histopathologic types of chordomas were identified. Immunohistochemistry was performed by polymer technique. Results: Clinicopathologic features of the 4 cases are as follows: Cases 1 and 2: Two tumors occurred in the sacrococcygeal and lumbosacral regions of a 42-year-old male and a 34-year-old female, respectively. Histopathologic examination showed areas of classical chordoma; juxtaposed to a high-grade, spindle cell sarcoma. By IHC, cytokeratin (CK), epithelial membrane antigen (EMA), S-100 protein, and brachyury were found to be distinctly positive in the differentiated chordomatous areas. Both these cases were diagnosed as dedifferentiated chordomas. The first patient, postresection and adjuvant radiation therapy (RT), died after 14 months of therapy. Case 3: A 58-year-old male presented with pain in his sacral region and urinary incontinence. Imaging disclosed a sacral mass. Histopathologic examination showed physaliphorous cells intimately admixed with, markedly pleomorphic cells, scattered mitotic figures, and focal tumor necrosis. By IHC, the tumor cells were positive for CK, AE1/AE3, S-100 protein, brachyury, and INI1/SMARCB1. The diagnosis of a poorly differentiated chordoma was offered. Despite surgical resection and adjuvant RT, the patient died within 18 months. Case 4: A 58-year-old male presented with a soft tissue lesion in his left leg. Histopathologic examination showed physaliphorous cells, embedded in a myxohyaline stroma. By IHC, the tumor cells were positive for EMA, S-100 protein, brachyury, and INI1. Diagnosis of an extra-axial, soft tissue chordoma was offered. Conclusions: These four unusual chordomas, confirmed by brachyury immunoexpression, constitute as one of the first such documentation from our country, revealing a wide clinicopathologic spectrum of chordomas. Dedifferentiated and poorly differentiated chordomas are associated with an aggressive clinical course. Further diagnostic implications are discussed herewith.

Keywords: Brachyury, chordoma, dedifferentiated chordoma, extra-axial chordoma, poorly differentiated chordoma

How to cite this article:
Rekhi B, Banerjee D, Ramadwar M, Bajpai J, Jambhekar NA. Clinicopathologic features of four rare types of chordomas, confirmed by brachyury immunostaining. Indian J Pathol Microbiol 2017;60:350-4

How to cite this URL:
Rekhi B, Banerjee D, Ramadwar M, Bajpai J, Jambhekar NA. Clinicopathologic features of four rare types of chordomas, confirmed by brachyury immunostaining. Indian J Pathol Microbiol [serial online] 2017 [cited 2021 Jul 24];60:350-4. Available from: https://www.ijpmonline.org/text.asp?2017/60/3/350/215380

   Introduction Top

Chordoma is a relatively uncommon, malignant tumor, showing notochordal differentiation. It occurs predominantly in the axial skeleton, typically in the sacrococcyx and in the spheno-occipital region.[1] Rare cases of extra-axial chordomas have been reported in the soft tissues, and in the appendicular bones.[2],[3],[4] An exact diagnosis of a chordoma is crucial, considering this tumor is characterized by recurrences and metastasis. It is also crucial to differentiate it from its various diagnostic mimics, in view of significant therapeutic implications.[1]

As radiologic features are nonspecific, especially of the uncommon forms, a definite diagnosis requires histopathologic examination, that shows characteristic features, including physaliphorous cells, in most cases.[1] Most common histopathologic types of a chordoma include classical and chondroid subtypes.[1] Rarely, poorly differentiated and dedifferentiated chordomas have been reported, that can be diagnostically challenging, especially in small biopsies, wherein the characteristic physaliphorous cells might not be easily identified, and only the poorly differentiated or dedifferentiated components are sampled.[1],[5],[6] Dedifferentiated chordomas are associated with a relatively aggressive clinical course.[1],[7],[8],[9],[10] Immunohistochemical (IHC) stains, especially brachyury, a highly specific marker of notochordal differentiation, are useful in confirming the diagnosis of a chordoma and in differentiating this tumor from its diagnostic mimics.[1],[11],[12]

Herein, we describe four rare forms of chordoma, confirmed by positive brachyury immunostaining.

   Materials and Methods Top

After computerized search of medical records from January 1, 2000, to December 31, 2014, two cases of dedifferentiated chordomas; a single case of a poorly differentiated chordoma and a single case of an extra-axial soft tissue chordoma (relatively recently diagnosed) were retrieved that were included in this study after a critical review by B.R with D.B.

IHC staining was performed using the polymer technique (Dako REAL Envision Detection System, Glostrup, Denmark) including peroxidase/3-3-diaminobenzidine tetrahydrochloride. Details of various antibody markers have been enlisted in [Table 1].
Table 1: Various immunohistochemical antibody markers used in the present study

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   Results Top

Clinicopathologic features of the four cases have been summarized in [Table 2].
Table 2: Clinicopathologic features of four rare types of chordomas

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Case 1

A 42-year-old male presented with pain in his lower back. Radiologic imaging disclosed a sacrococcygeal tumor. He underwent a biopsy, followed by surgical excision, elsewhere. Two stained slides and a paraffin block from the tumor were submitted to us for review.

Histopathologic examination showed distinct tumor areas composed of cells arranged in sheets and cords with abundant clear/vacuolated (physaliphorous cells) to pale, eosinophilic cytoplasm and small dark nuclei, within a myxoid stroma, reminiscent of a classical chordoma. Adjacent areas were composed of spindle-shaped sarcomatous cells with interspersed mitotic figures and areas of necrosis, reminiscent of a high-grade sarcoma. By IHC, tumor cells in the chordomatous component were positive for cytokeratin (CK), epithelial membrane antigen (EMA), S-100 protein and brachyury, whereas the tumor cells constituting the high-grade sarcomatous areas were negative for all these antibody markers. Diagnosis of a dedifferentiated chordoma was offered [Figure 1]a and [Figure 1]b and [Figure 2]a,[Figure 2]b,[Figure 2]c,[Figure 2]d. Marginal status of the surgical excision was unavailable. Postexcision, the patient received adjuvant radiation therapy (RT) but died of the disease after 14 months.
Figure 1: Case 1 - Dedifferentiated chordoma. Microscopic features. (a) Tumor area of differentiated chordoma (asterix) composed of cells with clear/vacuolated cytoplasm, juxtaposed to sarcomatous areas, comprising spindle-shaped sarcomatous cells (H and E, ×200). (b) Higher magnification showing distinct tumor areas of sarcomatous and chordomatous differentiation, latter characterized by cells with vacuolated/”bubbly” cytoplasm (physaliphorous cells) (asterix) (H and E, ×400)

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Figure 2: Case 1 - Immunohistochemical results. (a) Diffuse AE1AE3 positivity in the areas of chordomatous differentiation (DAB ×200). (b) Epithelial membrane antigen positivity in the areas of chordomatous differentiation (DAB, ×200). (c) S-100 protein positivity in the areas of chordomatous differentiation (DAB, ×200). (d) Brachyury positivity in the areas of chordomatous differentiation (DAB, ×200)

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Case 2

A 34-year-old female presented with gradually increasing lower back pain for 1 year, associated with constipation since few months ago. There was no associated history of painful neuropathy. On clinical examination, a vague, tender lump and was noted over her lumbosacral region.

Magnetic resonance imaging (MRI) showed a well-defined, heterogeneous, space occupying lesion, measuring 10 cm × 9 cm × 8 cm in the presacral spaces, arising from the lower three spaces.

Computed tomogram and positron emission tomogram, performed 6 months back did not reveal pulmonary metastatic lesions.

Percutaneous biopsy showed distinct tumor areas reminiscent of a chordoma, juxtaposed to a high-grade spindle cell sarcoma. By IHC, the tumor cells of the chordomatous component were diffusely positive for EMA, S-100 protein, and brachyury, in contrast to the sarcomatous component. The diagnosis of a dedifferentiated chordoma was offered.

The patient was induced on neoadjuvant chemotherapy, osteosarcoma 2012 protocol, wherein she developed febrile neutropenia. Three months after her diagnosis, she was also offered RT. Subsequently, she was planned for a sacrectomy. During her last follow-up, 16 months, since her complaints, she was alive-with-disease.

Case 3

A 58-year-old male presented with pain in his sacral region and in his both lower limbs of 2 months duration, along with constipation and bladder incontinence.

MRI showed a heterogeneously enhancing soft tissue mass measuring 9.6 cm × 6.6 cm × 5.5 cm, predominantly extra-osseous, intrapelvic, along with intraspinal extension, involving the lower sacral vertebrae, and extending into the right articular surface of the sacrum.

A biopsy, followed by sacrectomy, along with rectal segment excision was performed. Grossly, on cutting open, a gray-white tumor was identified, measuring 9 cm × 6.5 cm × 4.2 cm, with areas of hemorrhage and necrosis.

Histopathologic examination showed an infiltrating tumor comprising cells with eosinophilic to clear cytoplasm (physaliphorous cells), along with several cells exhibiting moderate to marked nuclear pleomorphism; tumor giant cells, few spindle-shaped cells, mitotic figures, including atypical forms, and focal necrosis [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d.
Figure 3: Case 3 - Poorly differentiated chordoma. (a) Magnetic resonance imaging showing a heterogeneous tumor mass, involving the sacral bone. (b) Sacrectomy specimen. Gross findings. Cut surface showing a grey-white tumor with focal necrosis. (c-d) Microscopic features. (c) Tumor composed of cells with clear to eosinophilic cytoplasm, exhibiting moderate to marked nuclear atypia and focal areas of tumor necrosis (arrow head) (H and E, ×200). (d) Interspersed, markedly pleomorphic/anaplastic tumor cells, including tumor giant cells. Inset showing an atypical mitosis (H and E, ×400)

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By IHC, the tumor cells were diffusely positive for CK, AE1/AE3, S-100 protein, brachyury, and INI1/SMARCB1. Diagnosis of a poorly differentiated chordoma was offered. The tumor was seen involving one of the bony cut margins [Figure 4]a,[Figure 4]b,[Figure 4]c,[Figure 4]d.
Figure 4: Case 3 - Immunohistochemical features. (a) Diffuse cytokeratin positivity (DAB, ×400). (b) Diffuse epithelial membrane antigen positivity (DAB, ×200). (c) Diffuse S-100 protein positivity (DAB, ×400). (d) Diffuse brachyury positivity, including within pleomorphic tumor cells (DAB, ×400)

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Postoperative, external beam radiotherapy was offered, over a duration of 3 months. However, the patient died of disease after 20 months.

Case 4

A 58-year-old male patient presented with a soft tissue lesion in his left leg.

Histopathologic examination showed a nodular tumor, composed of cells arranged in cords, nests, and pseudoglandular patterns, containing moderate to abundant eosinophilic to vacuolated cytoplasm and hyperchromatic nuclei within a myxohyaline stroma. By IHC, the tumor cells were positive for EMA, S-100 protein, brachyury, and INI1 [Figure 5]a,[Figure 5]b,[Figure 5]c,[Figure 5]d,[Figure 5]e,[Figure 5]f. The diagnosis of an extra-axial chordoma was offered. Unfortunately, the patient was lost to follow-up.
Figure 5: Case 4 - Extra-axial chordoma. Microscopic features. (a) Tumor composed of cells arranged in cords and pseudoglandular pattern (H and E, ×200). (b) Higher magnification showing cells with eosinophilic to vacuolated/clear cytoplasm (H and E, ×400). Immunohistochemical features. (c) Epithelial membrane antigen positivity within the tumor cells (DAB, ×400) (d) Diffuse. S-100 protein positivity (DAB, ×400). (e) Diffuse brachyury positivity (DAB, ×400). (f) Diffusely retained INI1/SMACB1 expression (DAB, ×400)

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   Discussion Top

Chordomas comprise 3% of primary bone tumors.[13] The present study describes four extremely rare types or forms of a chordoma.

A dedifferentiated chordoma represents only 6%–9% of chordomas.[7],[8] In our earlier documented series of 51 chordomas, constituting as the largest study on chordomas from our country, there were only two dedifferentiated chordomas.[5] Kim et al.[10] documented two cases of dedifferentiated chordomas, predominantly involving the sacrum, similar to the first two cases in the present study. On histopathologic examination, differential diagnoses included a pleomorphic sarcoma, a metastatic sarcomatoid type of renal cell carcinoma, and a dedifferentiated liposarcoma. The presence of sharply demarcated, two distinct tumor components, along with co-expression of epithelial markers, S-100 protein and brachyury, mostly, distinctly in the differentiated chordomatous areas, in both the tumors, were helpful in ruling out these differential diagnoses. As previously observed, among various IHC markers, S-100 protein was also found to be focally positive in the sarcomatous areas, in the first case of a dedifferentiated chordoma.[9]

In the third case of a poorly differentiated chordoma, instead of sharply demarcated areas of chordomatous and sarcomatous differentiation, markedly pleomorphic cells were intimately admixed with relatively well-differentiated chordomatous areas, including physaliphorous cells. Most chordomas comprise tumor cells with minimal nuclear atypia, as previously described.[5] Immunohistochemically, epithelial markers, S-100 protein, and brachyury were diffusely expressed in the third case, in contrast to the first 2 cases of dedifferentiated chordomas. In an earlier study, Mobley et al.,[6] in addition, observed the lack of INI1/SMARCB1 expression in all 4 cases of poorly differentiated chordomas, unlike the present case of a poorly differentiated chordoma that showed retained INI1 immunostaining.

Lately, cases of an extra-axial chordoma/chordoma periphericium have been documented in the soft tissues, similar to the fourth case.[2] This tumor can be misdiagnosed as a metastatic mucinous carcinoma or as a parachordoma/mixed tumor/myoepithelial tumor. Whereas mucinous carcinomas express epithelial markers, myoepithelial tumors, in addition, express S-100 protein, similar to chordomas, including those occurring at extra-axial sites.[2],[3],[12],[14] Another differential diagnosis, considered in this particular case, was an extraskeletal myxoid chondrosarcoma that shares overlapping histopathologic and IHC features with an extra-axial chordoma. An extra-axial chordoma can be differentiated from these mimics with brachyury immunostaining, as was performed in the present study.[2],[3],[4],[5] Brachyury immunoexpression has been documented in >90% chordomas with a specificity of up to 100%, with regards to differential diagnoses of a chordoma.[3],[5] Furthermore, certain myoepithelial tumors/parachordomas display loss of INI1 immunostaining, unlike the fourth case of an extra-axial chordoma.[12]

The value of identifying these uncommon forms of chordomas has clinical relevance. Surgical excision is the treatment mainstay of a chordoma. RT may salvage some patients with tumor recurrence.[15] A conventional chordoma has an indolent clinical course, and it is a slow growing tumor.[1] Contrastingly, dedifferentiated and poorly differentiated chordomas are rare but represent aggressive forms, associated with rapidly progressive and or fatal clinical outcome, as noted in our first three cases.[1],[9],[10],[15] Probably, such tumors need to be treated more aggressively.[15] Invariably, the dedifferentiated components have a tendency to metastasize. A dedifferentiated chordoma can occur de novo or as a malignant transformation of a conventional chordoma during its recurrence or postradiotherapy.[9],[10],[16] Both the cases in the present study occurred de novo, as there was no history of prior resection of a classical chordoma or RT.

An extra-axial chordoma can be treated by surgical resection with optional RT, unlike its diagnostic mimic, a metastatic mucinous adenocarcinoma that would require specific adjuvant chemotherapy. Therefore, its correct diagnosis is crucial.

   Conclusions Top

These four rare cases of chordomas, constituting as one of the first such documentation from our continent, reinforce the expanding clinicopathologic spectrum of this uncommon tumor. An index of suspicion, based on certain histopathologic features and application of necessary IHC markers, including brachyury are necessary for an accurate diagnosis. A correct diagnosis has therapeutic, as well as prognostic implications.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Flanagan A, Yamaguchi T. Notochordal tumours. In: Fletcher CD, Bridge JA, Hogendoorn PC, Mertens F, editors. World Health Organization Classification of Tumours of Soft Tissue and Bone. Lyon: IARC Press; 2013. p. 326-9.  Back to cited text no. 1
Lauer SR, Edgar MA, Gardner JM, Sebastian A, Weiss SW. Soft tissue chordomas: A clinicopathologic analysis of 11 cases. Am J Surg Pathol 2013;37:719-26.  Back to cited text no. 2
Tirabosco R, Mangham DC, Rosenberg AE, Vujovic S, Bousdras K, Pizzolitto S, et al. Brachyury expression in extra-axial skeletal and soft tissue chordomas: A marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol 2008;32:572-80.  Back to cited text no. 3
Rekhi B. Primary, large extra-axial chordoma in proximal tibia: A rare case report with literature review and diagnostic implications. APMIS 2016;124:238-42.  Back to cited text no. 4
Jambhekar NA, Rekhi B, Thorat K, Dikshit R, Agrawal M, Puri A, et al. Revisiting chordoma with brachyury, a “new age” marker: Analysis of a validation study on 51 cases. Arch Pathol Lab Med 2010;134:1181-7.  Back to cited text no. 5
Mobley BC, McKenney JK, Bangs CD, Callahan K, Yeom KW, Schneppenheim R, et al. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol 2010;120:745-53.  Back to cited text no. 6
Meis JM, Raymond AK, Evans HL, Charles RE, Giraldo AA. “Dedifferentiated” chordoma. A clinicopathologic and immunohistochemical study of three cases. Am J Surg Pathol 1987;11:516-25.  Back to cited text no. 7
Meis JM. Dedifferentiated chordoma. In: Rosen PP, Fechner RE, editors. Pathology Annual, Part 1. Vol. 26. California: Appleton and Lange; 1991. p. 37-62.  Back to cited text no. 8
Saito A, Hasegawa T, Shimoda T, Toda G, Hirohashi S, Tajima G, et al. Dedifferentiated chordoma: A case report. Jpn J Clin Oncol 1998;28:766-71.  Back to cited text no. 9
Kim SC, Cho W, Chang UK, Youn SM. Two cases of dedifferentiated chordoma in the sacrum. Korean J Spine 2015;12:230-4.  Back to cited text no. 10
Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 2006;209:157-65.  Back to cited text no. 11
Rekhi B, Sable M, Jambhekar NA. Histopathological, immunohistochemical and molecular spectrum of myoepithelial tumours of soft tissues. Virchows Arch 2012;461:687-97.  Back to cited text no. 12
Unni KK, editor. Chordoma. In: Dahlin's Bone Tumors: General Aspects and Data on 11,087 Cases. 5th ed. New York: Lippincott-Raven; 1996. p. 291-305.  Back to cited text no. 13
Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: A clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol 2003;27:1183-96.  Back to cited text no. 14
Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH, et al. Chordoma: The nonsarcoma primary bone tumor. Oncologist 2007;12:1344-50.  Back to cited text no. 15
Hanna SA, Tirabosco R, Amin A, Pollock RC, Skinner JA, Cannon SR, et al. Dedifferentiated chordoma: A report of four cases arising 'de novo'. J Bone Joint Surg Br 2008;90:652-6.  Back to cited text no. 16

Correspondence Address:
Bharat Rekhi
Department of Surgical Pathology, Room Number: 818, 8th Floor, Annex Building, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_409_16

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]

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