Version May 2024
INTRODUCTION — The majority of benign soft tissue masses are nonneoplastic and of little clinical consequence. However, some locally aggressive fibromatoses (desmoid tumors), infiltrating lipomas, neurofibromas, and vertebral hemangiomas may cause significant morbidity and, in some cases, mortality.
Treatment for a variety of benign diseases affecting soft tissue and bone will be reviewed here. These include Gorham disease, desmoplastic fibroma of bone, symptomatic vertebral hemangioma, and tenosynovial giant cell tumor (pigmented villonodular synovitis). Treatment for other conditions affecting soft tissue, such as desmoid tumors, keloids, ganglia, and Dupuytren's contracture, is discussed separately. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy" and "Keloids and hypertrophic scars" and "Ganglion cysts of the wrist and hand" and "Dupuytren's contracture", section on 'Other interventions'.)
GORHAM DISEASE — Gorham disease (also known as Gorham-Stout disease, disappearing bone disease, or essential osteolysis) is a rare disorder characterized by relatively painless bone destruction with massive osteolysis due to progression of lymphangiomatous tissue [1]. There may also be significant osteoclast activation. Why this occurs is not clear, but increased levels of interleukin 6 may contribute to the osteolysis [2].
The pattern is that of lytic destruction of cortical bone and extension across joints to adjacent bone. There is usually little or no soft tissue mass.
Treatment — Treatment consists of resection when this is feasible from the standpoints of the medical condition of the patient, the technical aspects of the procedure, and the likelihood of retained function. There is observational evidence that radiation therapy also may be effective [3-5]:
●In one report, two patients with disease involving C1 and the occiput were managed with 45 to 50 Gy alone [4]. Both patients experienced cessation of progression and were otherwise well at follow-up exceeding 12 years. There was no remodeling of bone in either of these patients.
●Others have demonstrated benefit from radiation therapy in treating chylothorax related to chest wall involvement [6] and a lesion in the mandible [7].
●A patterns of care study from Germany with literature review concluded that radiation therapy (30 to 45 Gy) may prevent disease progression in 77 to 80 percent of cases [5].
The role of systemic therapy has not been systematically evaluated. There are reports of benefit from bisphosphonates alone [8] and with sunitinib plus low-dose metronomic paclitaxel in two patients, one with generalized lymphatic anomaly and one with lymphatic malformation in Gorham disease, both of whom had severe exacerbation during puberty [9]. The first child presented with florid pulmonary failure and pleural effusion; the other presented with severe pain due to bone destruction of the pelvis and inability to walk. Both patients experienced clinical and radiologic response without major toxicities.
DESMOPLASTIC FIBROMA OF BONE — Desmoplastic fibroma of bone, known as collagenous fibroma, is a benign tumor of bone that has a histologic appearance similar to that of a desmoid tumor. This is an uncommon tumor that represents fewer than 0.1 percent of bone tumors. These lesions appear in young adults, with approximately equal frequency in males and females. Affected patients typically present with a history of a painless, slowly growing mass, often of relatively long duration [10].
These lesions can also appear as soft tissue tumors; in these cases, the lesions are predominantly subcutaneous, but fascial involvement is common, and approximately one-quarter involve skeletal muscle [10]. When they arise in bone, the most frequently involved sites are the pelvic and other flat bones, the jawbones, and for the long bones, the diaphyseal regions. The tumors are often large, ranging in size from 1 to 20 cm. They are firm and pearl gray in color on gross examination. The lesional cells are bland stellate and spindle-shaped fibroblasts separated by a collagenous matrix; there is typically no mitotic activity [10]. A characteristic (2;11)(q31;q12) translocation has been reported in several affected patients [11]. The beta-catenin pathway does not seem to have the same essential role in the tumorigenesis of desmoplastic fibroma as it has in desmoid-type fibromatosis [12]. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy".)
Desmoplastic fibroma of bone is managed with surgical resection, with extremely few exceptions. One patient with a 7.6 cm lesion in the iliac crest responded well to a course of fractionated radiation therapy (60 Gy) [13], as did a patient with a mandibular lesion who refused surgery [14].
Recurrent disease appears to be rare. In one study, none of the 39 patients developed a recurrence at a median follow-up of 11 years [10].
SYMPTOMATIC VERTEBRAL HEMANGIOMA — Hemangiomas are benign neoplasms consisting of blood vessels. Autopsy series suggest a prevalence of 10 to 12 percent for vertebral body hemangiomas [15], but most remain asymptomatic [16-18].
Approximately one-half of vertebral body hemangiomas are associated with painful symptoms, and in a few cases, they cause neurologic emergencies such as acute spinal cord compression [16]. The diagnosis is usually confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) (image 1) [19].
Options for treatment include surgical procedures (such as decompressive laminectomy, vertebrectomy, or ligation of the segmental arteries) and conservative methods (such as embolization, vertebroplasty, and/or intralesional alcohol injection) [15]. Radiation therapy may be applied as a treatment for painful vertebral hemangiomas, both as a single modality and for postsurgical prevention of local relapse [20-22].
In one report, a total of 84 patients with 96 symptomatic lesions were irradiated for a symptomatic vertebral hemangioma (98 percent for pain; 29 percent had additional neurologic symptoms) [20]. Prior to undergoing radiation therapy, 31 patients had been treated with resection, embolization, or vertebroplasty. The median total dose was 34 Gy. At a median follow-up of 68 months, 62 percent had complete symptom relief, 29 percent had partial pain relief, and 10 percent had no pain relief. Total doses ≥34 Gy resulted in significantly greater symptom relief and a lower recurrence rate.
TENOSYNOVIAL GIANT CELL TUMOR — Tenosynovial giant cell tumor (TGCT), historically known as pigmented villonodular synovitis (PVNS), is a rare [23] but well-recognized proliferative lesion of synovial tissue. Due to the presence of a characteristic translocation TGCT is considered to be a clonal neoplastic lesion; it can recur locally and cause substantial morbidity, but metastases are rare.
Histopathology and presentation — TGCT is characterized by hypervascular proliferative synovium containing multinucleated giant cells, macrophages, and hemosiderin. The multinucleated cells express features of osteoclasts [24]. Progressive nodular disease near or in the joints limits function and may destroy adjacent bone.
TGCT occurs in two histopathologic forms:
●Localized form, which involves a discrete section of the synovium
●Diffuse form, which involves the entire synovium and accounts for the majority of cases
TGCT almost always involves a single joint; the knee and ankle synovial structures are most commonly affected (image 2), while involvement of the shoulder, elbow, wrist/hand (picture 1), and hip is less common [23,25-27]. TGCT can present with attacks of pain, swelling, arthritis, and spontaneous hemarthrosis. (See "Overview of hemarthrosis", section on 'Tenosynovial giant cell tumor/pigmented villonodular synovitis' and "Basic calcium phosphate (BCP) crystal arthritis, including Milwaukee shoulder syndrome", section on 'Differential diagnosis'.)
Initial imaging often consists of plain radiographs, which typically reveal well-circumscribed areas of bone erosion. Ultrasonography can also be used to identify hypervascular areas of tumor and optimally guide synovial biopsy [28].
However, magnetic resonance imaging (MRI) is key to establishing the correct diagnosis [29,30]. MRI shows a characteristic lack of signal on both T1 and T2 images, which has been attributed to the presence of large amounts of hemosiderin in the synovium (image 3). (See "Radiologic evaluation of knee tumors in adults", section on 'Tenosynovial giant cell tumor' and "Imaging evaluation of the painful hip in adults", section on 'Pigmented villonodular synovitis and synovial osteochondromatosis'.)
Treatment-naïve patients — In patients with treatment-naïve TGCT, the principal treatment modality is resection [31,32]. Although limited data support the efficacy of radiation therapy, we do not offer this approach due to the risks of long-term toxicity and the availability of alternative systemic therapies for unresected and/or relapsed disease.
Although marginal excision represents the optimal treatment for localized TGCT, diffuse TGCT is more difficult to eradicate and is optimally treated with total or near total synovectomy [33]. The approach is similar to that used for inflammatory arthritis. (See "Synovectomy for inflammatory arthritis of the knee".)
Patients with diffuse disease can have multiple recurrences and bulky disease, resulting in significant bone destruction. Although observational data suggest some local disease control with adjuvant or perioperative radiation therapy, no randomized trials have evaluated this approach [34-40], and it is not our standard practice.
Examples of relevant data include the following:
●In one meta-analysis of 35 observational studies containing over 600 patients with TGCT of the knee, perioperative radiation therapy was associated with a reduced rate of recurrence (odds ratio 0.31, 95% CI 0.14-0.70), although the evidence was of low quality [33].
●In the largest series of 50 patients, 49 of whom had microscopic or gross residual disease prior to radiation therapy, 47 maintained local control at an average follow-up of 94 months [40].
●Similarly, in multiple observational cohort studies of patients with diffuse TGCT and in a national patterns of care study, the addition of radiation therapy to a dose of 35 to 50 Gy was associated with decreased local recurrence rates [34-40].
Despite these results, radiation therapy may cause long-term toxicities and subsequent morbidity, especially in young patients with TGCT, a nonlethal tumor. Examples of such toxicities include joint stiffness due to radiation fibrosis, skin changes, tissue necrosis, and radiation-associated secondary malignancies, including transformation into malignant sarcoma [27]. (See "Radiation-associated sarcomas" and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)
In addition, available data suggest that both systemic therapies and radiation therapy may be used effectively in the setting of relapse, making the incorporation of radiation therapy into the treatment strategy for treatment-naïve disease less appealing [33,40]. As such, it is our practice to reserve radiation therapy for patients with recurrent or relapsed disease who are nonsurgical candidates and who either fail or choose to avoid the use of systemic therapy due to potential toxicities. (See 'Recurrent and/or relapsed disease' below.)
Postoperative intra-articular administration of radioactive isotopes has been advocated in the past for patients thought to be at high risk for recurrence [37,41,42], but this approach has fallen out of favor.
Recurrent and/or relapsed disease — The local recurrence rate among patients with localized TGCT is low (approximately 10 percent in one large series), and it is higher with diffuse disease (between 19 and 44 percent) [23,43].
Although TGCT is a nonlethal disease with a low risk of systemic metastases, patients with locoregional recurrences may experience severe long-term morbidity and poor quality of life, including postoperative complications, compromised joint function, secondary arthritis, effusions, joint replacement, and possible amputation (image 2) [44].
Approach to therapy — Treatment options are individualized based on patient characteristics, symptoms, extent of progression, expected postoperative morbidity, and availability of systemic therapies. Patients with recurrent and/or relapsed disease may undergo observation or receive further surgical interventions, such as subtotal resection, joint replacement, or amputation. A decision regarding surgery versus systemic therapy should be made in a multidisciplinary setting. In patients where further surgery would result in significant morbidity or functional impairment, we suggest the colony stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib. Radiation therapy and/or enrollment in clinical trials may be reserved for those who are not surgical candidates and fail approved systemic therapies or who prefer to avoid the potential toxicities of systemic treatment [28,40]. (See 'Pexidartinib (CSF1R inhibitor)' below.)
Pexidartinib (CSF1R inhibitor) — In TGCT, a translocation in CSF1-COL6A3, t(1;2)(p13;q35-37), leads to overexpression of colony stimulating factor 1 (CSF1), with subsequent recruitment of the colony stimulating factor 1 receptor (CSF1R)-expressing macrophages that constitute the tumor mass [45,46]. Thus, in patients with unresectable relapsed and/or recurrent TGCT, agents that inhibit CSF1R, such as the oral agent pexidartinib [44,47-52], represent a logical therapeutic approach. Pexidartinib is approved by the US Food and Drug Administration (FDA) for patients with TGCT associated with severe morbidity or functional limitations and not amenable to surgery [53].
However, pexidartinib carries a black box warning for potentially fatal hepatotoxicity [54]; therefore, clinicians who offer pexidartinib to patients with TGCT, a nonlethal disease, should also provide a risk-benefit discussion regarding this particular toxicity. For patients who opt against pexidartinib, radiation therapy is a reasonable alternative. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Pexidartinib'.)
In addition, the following prescribing guidelines are recommended in discussions regarding pexidartinib [53]:
●Pexidartinib can only be prescribed through a Risk Evaluation and Mitigation Strategy (REMS) program (TURALIO REMS), a registration and monitoring program for the safe use of pexidartinib.
●Pexidartinib is administered at 250 mg orally twice a day with a low-fat meal (no more than approximately 11 to 14 grams of total fat). Patients should avoid taking pexidartinib with higher-fat meals (55 to 65 grams of total fat), which result in higher drug concentrations and increased risk of hepatoxicity. Patients may be referred to a dietician, if necessary.
●Given the risk of hepatoxicity, liver biochemical tests should be monitored prior to and during therapy with pexidartinib. Further details on the frequency of monitoring and other issues related to hepatoxicity with pexidartinib are discussed separately. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Pexidartinib'.)
●In a randomized, placebo-controlled, double-blinded phase III trial (ENLIVEN) of 120 patients with unresectable TGCT, pexidartinib improved objective response rates at week 25 (39 versus 0 percent in the placebo group) [44]. At a median follow-up of six months, no responders had progressed. Pexidartinib also improved functional outcomes in the affected joint at a follow-up of 25 weeks, including increased mean range of motion (15.1 versus 6.2 percent), improved physical function, and decreased stiffness. In addition, although not statistically significant, a numerically greater proportion of patients had at least a ≥30 percent decrease in their pain score (on a scale from 1 to 10) without an increase in narcotics (31 versus 15 percent). Depigmentation of the hair was the most common adverse event (67 versus 3 percent with placebo). Grade ≥3 adverse events included hepatotoxicity, cholestasis, periorbital edema, and hypertension. Eight patients discontinued therapy, mostly for hepatotoxicity. (See "Ocular side effects of systemically administered chemotherapy", section on 'Periorbital edema'.)
For patients who do not tolerate pexidartinib or who choose to avoid it due to the risk of toxicity, radiation therapy is a reasonable alternative, with limited data suggesting low recurrence rates and good functional outcomes. As examples, in one meta-analysis including approximately 130 patients with recurrence after synovectomy, radiation therapy reduced recurrence by 70 percent, although the evidence was of low quality [33]. In another study evaluating radiation therapy in 50 patients, including two-thirds with relapsed disease treated with at least two previous surgeries, long-term local control and good joint function were achieved in 94 and 82 percent of patients, respectively [40]. However, radiation therapy may also cause specific long-term toxicities, such as joint stiffness due to radiation fibrosis, skin changes, tissue necrosis, and radiation-associated secondary malignancies [27].
Investigational agents
●Nilotinib – Nilotinib and other multitargeted tyrosine kinase inhibitors (such as sunitinib, sorafenib, and imatinib) inhibit CSF1R (which functions as a receptor tyrosine kinase) [55-57]. For example, a phase II study of 56 patients with progressive disease not amenable to conservative surgical treatment demonstrated disease stabilization in a large proportion of patients with nilotinib (12-week progression-free rate 93 percent) [49].
●Imatinib – Imatinib has also demonstrated activity in observational data [55,57]. For example, at least one report documents a brief complete response with imatinib in a patient with relapsed TGCT [55].
●Emactuzumab – The monoclonal antibody emactuzumab (RG7155), which inhibits CSF1R activation, remains an investigational agent in TGCT [50,58]. In a phase I trial of 68 patients with locally advanced TGCT of the soft tissues, emactuzumab demonstrated durable responses, with an objective response rate of 64 percent at two years, and was associated with improvements in quality of life [58].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma" and "Society guideline links: Bone sarcomas".)
SUMMARY AND RECOMMENDATIONS
●Benign neoplasms affecting soft tissue and bone – The majority of nonmalignant proliferative soft tissue and bone lesions are of modest clinical consequence. However, some locally aggressive proliferative lesions, despite their nonmalignant nature, can cause significant morbidity and, in some cases, mortality. These include the following:
•Desmoid tumors (aggressive fibromatosis) (see "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy" and "Desmoid tumors: Systemic therapy")
•Desmoplastic fibroma of bone (see 'Desmoplastic fibroma of bone' above)
•Vertebral hemangioma (see 'Symptomatic vertebral hemangioma' above)
•Tenosynovial giant cell tumor (pigmented villonodular synovitis) (see 'Tenosynovial giant cell tumor' above)
●Tenosynovial giant cell tumor – For patients with treatment-naïve tenosynovial giant cell tumor (TGCT) and those with recurrent/relapsed disease in whom surgical resection is feasible, we suggest surgery with either total or near total synovectomy rather than radiation or systemic therapy (Grade 2C). (See 'Treatment-naïve patients' above and 'Recurrent and/or relapsed disease' above.)
•For patients in whom further surgery would result in significant morbidity or functional impairment, options include pexidartinib or radiation therapy. Pexidartinib carries a black box warning for potentially fatal hepatotoxicity; therefore, clinicians who offer pexidartinib to patients with TGCT, a nonlethal disease, should also provide a risk-benefit discussion regarding this particular toxicity. For those who prefer to avoid the potential toxicities associated with pexidartinib, we offer radiation therapy. (See 'Pexidartinib (CSF1R inhibitor)' above.)
•For patients who fail systemic therapies such as pexidartinib, we offer radiation therapy or clinical trials. A decision between these options should be made in a multidisciplinary setting and should factor in patient characteristics, symptoms, and extent of progression. (See 'Investigational agents' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.
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