Localized type tenosynovial giant cell tumor with metastases to lungs and pleura: a case report and literature review

Abstract

Background

Tenosynovial giant cell tumor is a rare soft tissue tumor of the synovium of joint, bursae, or tendon sheath. It is divided into localized or diffuse types on the basis of the growth pattern. Localized tenosynovial giant cell tumors are usually benign and treated successfully by excision. Diffuse tenosynovial giant cell tumors, in contrast to localized type, can destroy bone and cartilage and are associated with frequent local recurrences and distant metastasis. Localized type tenosynovial giant cell tumors rarely metastasize to distant organs. Here, we report a case of localized tenosynovial giant cell tumor presenting with lung metastases and systematically review literature.

Case presentation

A 55-year-old Asian male presented with a dry cough, right-sided chest pain and progressive dyspnea for 1 month. At 18 months before this presentation, he had undergone excision of a painless swelling on his right index finger. The swelling recurred within 3 months of excision, and a biopsy was then suggestive of a giant cell tumor. Given the suspicion of a giant cell tumor, a wide excision of the lesion was performed and the excisional biopsy was consistent with a diagnosis of tenosynovial giant cell tumor, localized type. At admission to our hospital, the patient had tachypnoea and absent breath sounds on the right side. A chest radiograph showed a right-sided pleural effusion with a homogenous opacity in the left mid-zone. A contrast-enhanced computed tomography of the chest and abdomen showed right massive pleural effusion and bilateral multiple lobulated heterogeneously enhancing pleural-based masses with areas of internal calcification. Pleural fluid analysis revealed an exudate with no malignant cells on cytology. A lung biopsy showed osteoclast-like giant cells and mononuclear spindle cells with areas of hemorrhage and necrosis, suggesting tenosynovial giant cell tumor metastasis. A final diagnosis of localized type tenosynovial giant cell tumor of the right index finger with metastases to the lungs and pleura was made. The patient passed away after receiving three cycles of denosumab injection owing to progressive disease.

Conclusion

Lung metastasis is extremely rare in patients with localized tenosynovial giant cell tumor. The survival is usually poor in patients with lung metastasis. A close follow-up of patients with localized type tenosynovial giant cell tumor is necessary for early detection of pleuropulmonary complications.

Background

Tenosynovial giant cell tumor (TGCT) is a type of giant cell tumor arising from the synovium of joint, bursae, or tendon sheath [1, 2]. Classically, TGCTs are considered benign lesions akin to other giant cell tumors. The World Health Organization has divided TGCT into localized types (formerly named giant cell tumor of tendon sheath/nodular tenosynovitis) and diffuse types (formerly called pigmented villonodular sclerosis/tenosynovitis/fibrous xanthoma of synovium) on the basis of their growth pattern [1,2,3,4]. Localized TGCT most commonly involves the digits and wrists, accounting for two-thirds of cases, while diffuse TGCT commonly affects major joints, such as the knee, hip, ankle, and elbow [1,2,3]. TGCTs are usually considered benign tumors with rare incidences of distant metastases seen with diffuse forms [2, 3]. Localized TGCT rarely manifests with distant metastasis. We found only one case of localized TGCT with lung metastasis [5]. Here, we report the second case of localized TGCT presenting with lung metastasis and pleural effusion. Further, we performed a systematic review and described the clinical characteristics of patients with TGCTs and lung metastasis.

Case presentation

A 55-year-old Asian male, a farmer and never smoker, presented with a dry cough, right-sided chest pain and progressive dyspnea for 1 month. He denied having any comorbidity or past respiratory symptoms. Notably, he reported the excision of a painless swelling of size 5 × 4 cm on his right index finger 18 months before at another hospital. The swelling recurred within 3 months (Fig. 1a, b). This time, a biopsy finding was consistent with a giant cell tumor. A wide excision of the tumor with amputation of the right index figure was performed, including disarticulation of the carpometacarpal joint and reconstruction of the interdigital space. The tumor was well-circumscribed, with a fibrous capsule and composed of mononuclear cells, foamy macrophages and multinucleated giant cells with few areas containing hemosiderin and occasional cleft-like spaces with zones of hyalinization and focal areas of hemorrhage suggestive of tenosynovial giant cell tumor, localized type. A chest radiograph done at the time of initial excision (15 months before this presentation) was normal (Fig. 1c).

Fig. 1

Radiograph of right hand anteroposterior (a) and oblique view (b) show soft tissue opacity and swelling in proximal to the mid phalanx of the index finger along radial and palmar aspects with no bony erosions and no interphalangeal joint extension marked by white arrows. Chest radiograph posteroanterior view (c) done at first recurrence (15 months before this presentation) was normal

At presentation to our hospital, the patient had tachypnea with a respiratory rate of 22 breaths/minute and absent breath sounds on the right side. A chest radiograph showed a right-sided massive pleural effusion with a homogeneous opacity in the left mid zone (Fig. 2a). A contrast-enhanced computed tomography (CT) of the chest and abdomen showed right massive pleural effusion and bilateral multiple lobulated heterogeneously enhancing pleural-based masses with areas of internal calcification (Fig. 2b and c). Pleural fluid was hemorrhagic in appearance, an exudate biochemically and had no malignant cells on cytology. CT-guided biopsy from the right upper lobe mass showed osteoclast-like giant cells and mononuclear spindle cells with areas of hemorrhage and necrosis suggestive of metastasis from TGCT (Fig. 3a, b). Bone scan showed no osteoblastic activity in the skeleton. A final diagnosis of localized type TGCT of the right index finger with metastases to the lungs and pleura was made. The patient passed away after receiving three cycles of denosumab injection (120 mg once every 3 weeks) owing to progressive disease.

Fig. 2

Chest radiograph (a) at this presentation shows evidence of right pleural effusion with a mass lesion in the left mid zone (white arrow). Axial computed tomography scan of the chest (b, c) shows significant pleural effusion causing compressive collapse of the right lower lobe. Multiple nodular enhancing pleural deposits were seen in bilateral pleural cavities, predominantly on the right side, with calcification in pleural deposits at places (white arrow)

Fig. 3

a and b Low power microscopy images with hematoxylin and eosin stain showed infarct type necrosis (arrow) with few viable areas with osteoclast-like giant cells (arrow) and mononuclear spindle cells with areas of hemorrhage

Discussion

We searched the PubMed and Embase databases until January 2024, using the following search terms: “tenosynovial giant cell tumor” OR “tenosynovial giant cell tumour” OR “tenosynovial giant cell tumors” OR “tenosynovial giant cell tumours” OR tenosynovial GCT OR “pigmented villonodular synovitis” OR “pigmented villonodular tenosynovitis” OR “giant cell tumor of tendon sheath” OR “giant cell tumour of tendon sheath” AND “metastasis” OR “metastases” OR “metastasising” OR “metastasizing” AND “pulmonary” OR “lungs” OR “lung” OR “lung metastasis,” The citations retrieved were imported to the reference manager software (EndNote 20), and duplicate citations were removed. Initially, the titles and abstracts were screened, including the full texts whenever necessary. We excluded animal studies, conference abstracts, non-English publications, and review articles. Further, articles not relevant to the review were excluded after full-text screening. Any disagreement between the authors was resolved by consensus. We captured the following data from the eligible studies in a standard data extraction form: age, sex, location of the tumor, type of the tumor, the subtype of the tumor, time to local recurrences from the initial diagnosis, time to lung metastasis from the initial diagnosis, treatment received, follow-up period and outcome as reported in the studies.

Our search strategy retrieved 137 articles, of which 12 were duplicate citations. Initial screening excluded 96 studies for not fulfilling eligibility. The remaining 29 studies reported either localized or diffuse or malignant type TGCT and were selected for full-text review. We found five additional studies on full-text reading. An in-depth reading of these 34 articles led to the exclusion of 12 studies for various reasons. We excluded two studies reporting cases of lung metastasis owing to a lack of individual patient data [3, 4]. Finally, 22 studies [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] reporting 34 cases (excluding the index case) of TGCT with lung metastasis were included for analysis (Fig. 4). We could not access the full text of two studies [7, 8], and the relevant data from these studies were extracted as reported in a previously published study [9]. The clinical characteristics of the previously published 34 cases of TGCTs with lung metastasis and the index case are summarized in Table 1.

Fig. 4

Preferred reporting of items for systemic review and meta-analysis flow diagram

Table 1 Clinical characteristics of reported cases of tenosynovial giant cell tumor and lung metastasis

We classified the tumor into three types, diffuse, localized, and malignant, on the basis of the location, clinical behavior, local recurrence characteristics, metastatic potentials, and morphological appearance. TGCTs were considered diffuse when displaying at least focally infiltrative borders with a lack of circumscription. Additionally, these tumors were categorized as extra-articular when presenting predominantly as a soft tissue mass with or without the involvement of the adjacent joint. Tumors predominantly confined to joint space were classified as intraarticular. Localized type TGCT presented as a single nodule in the hand/finger and were well-circumscribed lesions with a fibrous capsule. Tumors showing morphological features of sarcoma were classified as malignant TGCT. For this review, tumors that were benign diffuse-type at initial diagnosis and later demonstrated sarcomatous component are classified as malignant TGCT. Malignant TGCTs were further divided into primary if benign TGCT coexisted with the sarcomatous component, whereas sarcoma detected in recurrence of the previously diagnosed benign tumour was classified as secondary [1]. The histological features that favored a diagnosis of malignant tumor included features of sarcoma, such as diffuse pleomorphism, prominent nucleoli, high cytoplasmic to nuclear ratios, high mitotic rate per 10 high power fields, necrosis, discohesion of tumor cells, paucity of giant cells, and a diffuse growth pattern [10, 13, 18].

The study periods ranged from 1968 to 2022. The median age of patients, including our case, was 52 [interquartile range (IQR) 41–58] years. Out of 35 (including the index case) patients, 23 were male. Most tumors were classified as malignant 25 (71%), followed by diffuse type in eight (23%) patients, and only one case of localized TGCT with lung metastasis was reported [5]. We believe our case is the second case of localized TGCT presenting with lung metastasis. Malignant TGCTs were classified as primary in 10 patients and secondary in 11 patients, and subtype data was unavailable for 4 patients. Among the eight diffuse-type tumors, four were extra-articular, two were intra-articular, and data was unavailable for two patients. The median time to first local recurrence and lung metastasis was 24 (IQR 4.75–48) and 29 (IQR 6–106) months, respectively. In total, seven patients had no local recurrence, and no information on local recurrence was available for five patients. Similarly, the time to lung metastasis from the initial diagnosis was unavailable for six patients. Follow-up data was available for 33 patients. Most patients received surgery, chemotherapy, and radiotherapy in combination. Patients were followed up for a median period of 26 (IQR 17.5–93.5) months and 27 (77%) patients died during the follow-up period.

Tenosynovial GCT was first described by Jaffe et al. in 1941 [12]. TGCT is rare, with a prevalence of 1:800,000 population [5]. The TGCT, classified as a benign tumor has been further divided into two categories: localized and diffuse types [2, 5, 12]. The distinction is based on its pattern of spread and histopathology. TGCT rarely has a malignant counterpart named malignant TGCT or malignant pigmented villonodular synovitis. Owing to its aggressive nature, malignant TGCT is usually described as distinct from the localized and diffuse TGCTs [9, 10, 12, 13].

The clinical presentations in benign types of TGCT, that is, localized and diffuse types, also differ. Localized forms are seen in middle-aged individuals between 40–50 years of age, whereas diffuse forms are common below 40 years, with a female preponderance [2, 5]. Localized TGCTs predominantly involve the digits and wrist, as in our case, whereas diffuse forms affect the large joints of the body, such as knee, hip, ankle, and elbow. Localized TGCTs are usually benign, whereas diffuse forms are destructive and rarely malignant [2, 5, 12]. The localized forms are usually painless, with minor clinical manifestations [5]. On the contrary, the diffuse type is painful and progresses over months to years. The diffuse type tumors can be intra-articular and extra-articular in location [12, 13].

The radiographic appearance of TGCT is non‑specific, ranging from soft tissue swelling to soft tissue mass, joint effusion, and bony involvement. Magnetic resonance imaging (MRI) is a sensitive tool to characterize the size, type, synovial involvement, hemosiderin deposition, and local extension of such tumor [2]. TGCT lesions generally have hemosiderin deposits appearing as dark, low‑signal regions on T1 and T2 weighted images [13, 18]. The localized type produces isointense or low signal intensity in T1-T2 weighted images [2, 5]. Furthermore, certain features in MRI indicate malignant TGCT, such as frequent lobulation, infiltrative lesions with poorly defined margins and proximity to tenosynovial structures and/or joint spaces [13, 18]. The definitive diagnosis of TGCT requires biopsy confirmation. TGCTs on microscopy are characterized by synovial hypertrophy and hyperplasia with hemosiderin deposition. These tumors frequently have osteoclast-like giant cells, mononuclear cells and foamy macrophages, which may be positive for RANKL expression, desmin, clusterin, and D2-40 [12, 24]. In the pathogenesis of giant cell tumors, RANKL plays an important role as it stimulates the recruitment and differentiation of osteoclast precursor cells into multinucleated osteoclast-like giant cells [24].

The treatment of choice for localized TGCT is excision [2, 5]. Local recurrence may occur owing to the involvement of surrounding structures like tendons and joint capsules. However, local recurrence is less commonly seen in localized type tumors than diffuse TGCTs [2, 5]. On the contrary, the standard of care for diffuse-type TGCT is not defined. Most patients undergo surgery, either arthroscopic or open resection, or a combination of both, to limit the progressive joint destruction, improve limb function and decrease the risk of local recurrence. However, diffuse-type TGCT is generally associated with a higher risk of recurrence and complications following resection [2, 27]. In the largest cohort of patients with diffuse TGCT, which included 1192 patients, 966 (81%) were surgically treated, of which 425 (44%) developed recurrence over a median follow-up of 54 months. Postoperative complications were reported in 105 (12%) of 906 patients for whom complete data on surgical complications were available [27]. Therefore, surgical resection alone is not the optimal treatment modality for diffuse-type tumors. Given the high recurrence and postoperative complication rates in diffuse type TGCTs, adjuvant Yttrium-90 radiotherapy or external beam radiotherapy are administered in patients with symptomatic residual disease, recurrent disease or when limb sparing is not feasible [2, 19, 27].

Additionally, in 30–60% of patients with TGCT, colony-stimulating factor 1 receptor (CSF1R) overexpression with CSF1 gene fusion to the collagen type VI a3 (COL6A3) promoter is found [3]. Therefore, systemic therapies targeting the CSF1/CSF1R signalling pathways have been a promising option in the recent past. Targeted therapy with imatinib that acts via blockade of the tyrosine kinase activity of CSF-1R or a monoclonal antibody targeting CSF1-R, that is, pexidartinib, has been tried in treating diffuse TGCT with variable success rates [2, 3, 25]. To date, pexidartinib, an oral selective inhibitor of CSF1R, is the only US Food and Drug Administration-approved drug for adult patients with symptomatic TGCT associated with severe morbidity or functional limitation that was not amenable to improvement with surgery. A randomized phase III trial comparing pexidartinib versus placebo showed a 39% overall response rate at week 25 in the treatment arm compared with 0% in the placebo group [2]. Similarly, in a retrospective series of advanced TGCT, imatinib showed about 30% overall response rate and symptomatic improvement. The median progression-free survival was 18 months over a median follow-up of 52 months [2]. Other selective agents targeting CSF1R, such as Nilotinib, Vimseltinib, Emactuzumab, and Cabiralizumab, are in various phases of clinical trials and results are awaited [2]. The optimal duration of CSF1R inhibitor therapy is unknown and should be based on patient tolerance and preferences. In summary, the prospect of managing TGCTs seems promising, given a better understanding of tumor biology, identification of fusion genes, and targeted chemotherapy.

The strength of our case lies in the detailed documentation of past clinical data and a chest radiograph showing normal lung parenchyma. Further, this is the second case, to the best of our knowledge, to report lung metastasis in a localized type tenosynovial giant cell tumor. Additionally, we performed a systematic review and presented the clinical characteristics of all cases of TGCTs with lung metastasis reported to date. The limitation of our case is that the patient did not report for follow-up after three cycles of chemotherapy and later passed away. Therefore, we could not include the patient’s perspective.

Conclusion

Localized TGCT is usually benign. Distance metastasis, including metastasis to lungs and pleura, is extremely uncommon in localized type tumor. Wide local excision is the treatment of choice in localized type TGCT. Recurrences at the excision site occur but are uncommon compared with the diffuse type of tumor. Survival is poor in patients with lung metastasis.