A hyalinised tenosynovial giant cell tumour with absence of giant cells posing a diagnostic challenge.

Tenosynovial giant cell tumour (TGCT) is a soft tissue neoplasm that arises from the synovial lining of joints, bursae and tendon sheaths.1Gouin F. Noailles T. Localized and diffuse forms of tenosynovial giant cell tumor (formerly giant cell tumor of the tendon sheath and pigmented villonodular synovitis).Orthop Traumatol Surg Res. 2017; 103: S91-S97Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar TGCT is classified based on its clinical presentation and biological behaviour as localised (L-TGCT) or diffuse (D-TGCT), the former previously known as a giant cell tumour of the tendon sheath or localised nodular tenosynovitis, and the latter previously known as pigmented villonodular synovitis (PVNS).2de St Aubain Somerhausen N. van de Rijn M. Tenosynovial giant cell tumour.in: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC, Lyon2020: 133-136Google Scholar L-TGCT usually occurs between the ages of 30 and 50 years with a predilection for females. It tends to be extra-articular and mainly involves the digits (85% of cases), located near the tendon sheaths or interphalangeal joints. L-TGCT is a benign neoplasm that presents as a painless, slow-growing mass coming to clinical attention weeks to years after onset.3Nagaputra J.C. Sittampalam K. Tenosynovial giant cell tumor with extensive myxoid change: a rare variant of a common tumor.Hum Pathol Case Rep. 2018; 12: 56-59Crossref Scopus (1) Google Scholar In contrast, D-TGCT usually affects young adults less than 40 years of age with no gender predilection.4Giustini N. Bernthal N.M. Bukata S.V. Singh A.S. Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature.Clin Sarcoma Res. 2018; 8: 1-5Crossref PubMed Google Scholar It is predominantly intra-articular and mainly affects large joints such as the knee (75% of cases), hip and ankle.5Flandry F. Hughston J.C. Pigmented villonodular synovitis.J Bone Joint Surg Am. 1987; 69: 942-949Crossref PubMed Scopus (163) Google Scholar D-TGCT is locally aggressive and destructive given its infiltrative growth pattern and patients typically present with articular complaints including joint swelling, restricted range of movement or instability.6Dines J.S. DeBerardino T.M. Wells J.L. et al.Long-term follow-up of surgically treated localized pigmented villonodular synovitis of the knee.Arthroscopy. 2007; 23: 930-937Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Rarely, D-TGCT has been reported to undergo sarcomatous transformation with a high rate of local recurrence and distant metastasis.7Righi A. Gambarotti M. Sbaraglia M. et al.Metastasizing tenosynovial giant cell tumour, diffuse type/pigmented villonodular synovitis.Clin Sarcoma Res. 2015; 5: 2-5Crossref Google Scholar,8Rebuzzi S.E. Grassi M. Catalano F. et al.Multiple systemic treatment options in a patient with malignant tenosynovial giant cell tumour.Anticancer Drugs. 2020; 31: 80-84Crossref PubMed Scopus (5) Google Scholar A case of metastasising D-TGCT has also been documented.9Bertoni F. Unni K.K. Beabout J.W. Sim F.H. Malignant giant cell tumor of the tendon sheaths and joints (malignant pigmented villonodular synovitis).Am J Surg Pathol. 1997; 21: 153-163Crossref PubMed Scopus (175) Google Scholar The pathogenesis of TGCTs is thought to be a ‘landscape effect’ attributed to a minor population of neoplastic cells with aberrant expression of colony-stimulating factor 1 (CSF1) leading to the recruitment of CSF1-receptor-expressing macrophages and inflammatory cells which form the majority of the tumour milieu.10West R.B. Rubin B.P. Miller M.A. et al.A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.Proc Natl Acad Sci USA. 2006; 103: 690-695Crossref PubMed Scopus (381) Google Scholar The overexpression of CSF1 by neoplastic cells is due to a COL6A3::CSF1 gene fusion resulting from a t(1;2)(p13;q37) rearrangement, which occurs in approximately 60% of TGCT.10West R.B. Rubin B.P. Miller M.A. et al.A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.Proc Natl Acad Sci USA. 2006; 103: 690-695Crossref PubMed Scopus (381) Google Scholar,11Nagase M. Araki A. Ishikawa N. et al.Tenosynovial giant cell tumor, localized type with extensive chondroid metaplasia: a case report with immunohistochemical and molecular genetic analysis.Int J Surg Pathol. 2020; 28: 447-453Crossref PubMed Scopus (3) Google Scholar Histologically, TGCTs consist of neoplastic large epithelioid mononuclear cells with eccentric nuclei and abundant eosinophilic cytoplasm, small histiocytoid cells, multinucleated osteoclast-like giant cells, foamy histiocytes, lymphocytes and variable stromal hyalinisation and haemosiderin deposition.3Nagaputra J.C. Sittampalam K. Tenosynovial giant cell tumor with extensive myxoid change: a rare variant of a common tumor.Hum Pathol Case Rep. 2018; 12: 56-59Crossref Scopus (1) Google Scholar Immunohistochemically, the large neoplastic cells are positive for clusterin and D2-40 and focally positive for desmin which highlights their dendritic processes, while the small histiocytoid cells are diffusely positive for CD68 and CD163.2de St Aubain Somerhausen N. van de Rijn M. Tenosynovial giant cell tumour.in: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC, Lyon2020: 133-136Google Scholar,3Nagaputra J.C. Sittampalam K. Tenosynovial giant cell tumor with extensive myxoid change: a rare variant of a common tumor.Hum Pathol Case Rep. 2018; 12: 56-59Crossref Scopus (1) Google Scholar L-TGCTs are well-circumscribed while D-TGCTs have an infiltrative growth pattern with more conspicuous cleft-like spaces.2de St Aubain Somerhausen N. van de Rijn M. Tenosynovial giant cell tumour.in: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC, Lyon2020: 133-136Google Scholar Several histological variants have been reported including TGCTs with extensive chondroid metaplasia11Nagase M. Araki A. Ishikawa N. et al.Tenosynovial giant cell tumor, localized type with extensive chondroid metaplasia: a case report with immunohistochemical and molecular genetic analysis.Int J Surg Pathol. 2020; 28: 447-453Crossref PubMed Scopus (3) Google Scholar and myxoid change.3Nagaputra J.C. Sittampalam K. Tenosynovial giant cell tumor with extensive myxoid change: a rare variant of a common tumor.Hum Pathol Case Rep. 2018; 12: 56-59Crossref Scopus (1) Google Scholar While the relative prognosis of these variants is unknown, their significance lies in distinguishing them from other histological mimics. Here, we report a case of a 49-year-old male with TGCT of the right calf showing extensive stromal hyalinisation and absence of giant cells, resulting in a diagnostic challenge, and discuss features which distinguish it from other differential diagnoses. A 49-year-old male with no notable past medical history, presented with a progressively enlarging lump on the right lower limb of 3 weeks' duration. Physical examination revealed a 3×3 cm soft tissue mass over the distal lateral aspect of the right calf with no surrounding skin changes. Given its superficial location and absence of worrisome features, no imaging was performed. The patient was counselled and opted for surgical excision. Intraoperatively, the mass measured 2×2 cm and was not adherent to the underlying muscle fascia. The entire mass was excised without gross residual disease. Macroscopic pathological examination showed a firm mass measuring 1.5×1.0 cm. Histological examination revealed a mass within the subcutaneous tissue with vaguely nodular architecture and composed of a moderately cellular population of neoplastic epithelioid cells, set within a hyalinised eosinophilic stroma (Fig. 1A). Interspersed areas of reactive changes including spindled fibroblastic proliferation, fibrosis, capillary proliferation and entrapped fat necrosis were present (Fig. 1B). The epithelioid cells showed abundant dense eosinophilic cytoplasm, enlarged eccentrically-placed nuclei and prominent nucleoli (Fig. 1C). Scattered small histiocytoid cells were seen within the stroma. Some areas of dense hyalinised stroma mimicked osteoid matrix (Fig. 1D). The classic ladybird cells were not identified. No significant cytological atypia or mitotic activity was seen. No multinucleated osteoclast-like giant cells, foamy histiocytes or haemosiderin deposition were present. Tumour was present at the resection margin. The neoplastic epithelioid cells were positive for clusterin and D2-40 (Fig. 2) and negative for CD163 immunohistochemical stains. CD163 immunostain highlighted dispersed histiocytoid cells. The neoplastic epithelioid cells were also negative for MNF116, desmin, SMA, caldesmon, S100, SOX10, CD31, ERG, SATB2, CD21, DOG1, MUC4 and H3K36M immunohistochemical stains (not shown). Nuclear staining for H3K27Me3 was retained. The final diagnosis was a hyalinised TGCT, favour localised type. This case was also reviewed by a pathologist with expertise in soft tissue tumours who agreed with the diagnosis (see acknowledgement below). At 12 days post-operation, the wound had healed and sutures were removed. The patient recovered well and remains on follow-up.Fig. 2(A) High magnification histological view of neoplastic epithelioid cells demonstrating dense eosinophilic cytoplasm, eccentrically-placed nuclei and prominent nucleoli (H&E) and positivity for (B) clusterin and (C) D2-40 immunohistochemical stains.View Large Image Figure ViewerDownload Hi-res image Download (PPT) TGCTs are known to have varying degrees of stromal collagen deposition, however, to our knowledge, this is the first case report of TGCT with extensive stromal hyalinisation. The diagnosis was clinched by first recognising the characteristic epithelioid cells on morphology, even though there were no osteoclast-type giant cells present and confirming their synoviocyte lineage through strong and diffuse expression of clusterin and D2-40 on immunohistochemistry. The presence of extensive stromal hyalinisation in TGCT may pose a diagnostic challenge as it may mimic other tumours with prominent fibrosis or osteoid deposition. Differential diagnoses include hyalinising deep fibrous histiocytoma, chondroblastoma, sclerosing epithelioid fibrosarcoma and osteosarcoma. Deep fibrous histiocytoma (DFH) is a dermatofibroma that arises in the subcutaneous and deep soft tissues of the extremities and head and neck. Histologically, DFH is composed of a storiform pattern of monomorphic spindle cells with vesicular nuclei and branching staghorn-like vessels surrounded by a fibrous pseudocapsule. Often, there is prominent stromal hyalinisation and occasionally foamy histiocytes and osteoclast-like giant cells. Compared with TGCT, DFH lacks the sheets of large epithelioid and histiocytoid cells. In addition, the neoplastic cells in DFH are positive for CD34 in almost 40% of cases. Chondroblastoma is a primary bone tumour that most commonly occurs in the epiphysis of long bones such as the tibia, femur and humerus and rarely in the bones of the hands and feet. Microscopically, it is composed of sheets of polygonal chondroblasts with eosinophilic cytoplasm, central grooved nuclei and delicate pericellular chicken-wire calcification. The matrix can be eosinophilic or chondroid with areas of osteoclast-like giant cells and haemosiderin deposition. Neoplastic cells are positive for S100, DOG1 and SOX9 immunostains. Up to 95% of chondroblastomas demonstrate a K36M mutation in either the H3F3A or H3F3B gene which can be confirmed by immunohistochemical staining. This mutant protein is absent in TGCT. Sclerosing epithelioid fibrosarcoma (SEF) is a malignant neoplasm that arises most often in the deep soft tissues of the extremities, limb girdle, trunk and head and neck in adults. Histologically, lobules of monomorphic epithelioid cells with clear cytoplasm arranged in cords are present within a hyalinised sclerotic stroma. The margins typically infiltrate into adjacent muscle and adipose tissue. Immunohistochemically, SEFs show strong diffuse cytoplasmic positivity for MUC4 and are negative for cytokeratin. SEFs harbour multiple chromosomal rearrangements, most commonly the EWSR1::CREB3L1 fusion. In contrast, TGCTs are negative for MUC4 and show the COL6A3::CSF1 fusion. Osteosarcoma is a high grade sarcoma of bone that has a bimodal age distribution and most commonly arises in the intramedullary metaphyseal regions of long bones of the extremities such as the femur, tibia and humerus. Histologically, sheets of pleomorphic spindle cells in a background of malignant osteoid deposition lacking osteoblastic rimming, is characteristic. Stromal hyalinisation in a TGCT may mimic the osteoid deposition seen in osteosarcoma (as seen in our case), however, the lack of malignant features and absence of woven bone formation favour the former. The standard treatment for TGCTs is complete local excision. This is generally curative for L-TGCTs which exhibit a low recurrence rate of 0–15%.1Gouin F. Noailles T. Localized and diffuse forms of tenosynovial giant cell tumor (formerly giant cell tumor of the tendon sheath and pigmented villonodular synovitis).Orthop Traumatol Surg Res. 2017; 103: S91-S97Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar D-TGCTs are locally aggressive and have a higher recurrence rate ranging from 21 to 50%.1Gouin F. Noailles T. Localized and diffuse forms of tenosynovial giant cell tumor (formerly giant cell tumor of the tendon sheath and pigmented villonodular synovitis).Orthop Traumatol Surg Res. 2017; 103: S91-S97Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Factors that contribute to recurrence include incomplete resection, presence of satellite lesions, incomplete encapsulation and intraosseous involvement.3Nagaputra J.C. Sittampalam K. Tenosynovial giant cell tumor with extensive myxoid change: a rare variant of a common tumor.Hum Pathol Case Rep. 2018; 12: 56-59Crossref Scopus (1) Google Scholar Patients may require multiple surgical resections which can reduce their quality of life, increase morbidity and reduce function of the affected joint.12Monestime S. Lazaridis D. Pexidartinib (Turalio). The first FDA-indicated systemic treatment for tenosynovial giant cell tumor.Drugs R D. 2020; 20: 189-195Crossref PubMed Scopus (23) Google Scholar Adjuvant therapies are commonly incorporated in the management of TGCTs including radiotherapy and systemic therapy. Antagonists of the CSF1/CSF1R pathway including monoclonal antibodies such as emactuzumab and cabiralizumab and tyrosine kinase inhibitors (TKIs) such as imatinib and nilotinib have been disappointing.12Monestime S. Lazaridis D. Pexidartinib (Turalio). The first FDA-indicated systemic treatment for tenosynovial giant cell tumor.Drugs R D. 2020; 20: 189-195Crossref PubMed Scopus (23) Google Scholar However, in August 2019, the United States Food and Drug Administration (FDA) approved pexidartinib, an oral TKI with selective inhibition of CSF1R, for the treatment of symptomatic TGCT associated with severe morbidity or functional limitations not amenable to improvement with surgery.12Monestime S. Lazaridis D. Pexidartinib (Turalio). The first FDA-indicated systemic treatment for tenosynovial giant cell tumor.Drugs R D. 2020; 20: 189-195Crossref PubMed Scopus (23) Google Scholar In a randomised phase 3 trial (ENLIVEN), pexidartinib showed an overall response rate of 39% with a 14.8% complete and 24.6% partial response rate compared to the placebo.13Tap W.D. Gelderblom H. Palmerini E. et al.Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.Lancet. 2019; 394: 478-487Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar The prognosis of TGCT with extensive hyalinisation is not known. In our case, the tumour extended to the resection margin and therefore close clinical follow-up is recommended. This study was conducted in accordance with guidelines from the Centralised Institutional Review Board of SingHealth. Written consent was obtained from the patient for publication of this case report. The authors thank Prof Christopher D. Fletcher, Vice-Chair of Anatomic Pathology, Brigham and Women's Hospital for expert review of this case. The authors state that there are no conflicts of interest to disclose.