Pigmented Villonodular Synovitis

Insidious symptom onset and unspecific complaints are the main cause of delays in PVNS diagnosis; limited awareness of the disease among health care givers further complicates that issue. Thus, it is not uncommon to see PVNS patients who have been diagnosed with another pathology and who have suffered for years from unresolved symptoms.

PVNS most frequently develops in young adults who then present with unilateral, diffuse hip or knee pain. Other commonly affected structures are ankle, temporomandibular joint and the distal joints of hands and feet. Arthralgia is often intermittent and patients may experience prolonged asymptomatic periods. However, PVNS may also trigger acute exacerbation of joint pain, possibly due to hemorrhage into the joint space. Motion ranges are generally diminished, but the severity of disability may vary during the course of the day. Rest alleviates symptoms.

A medical history of joint disorders is uncommon but may be expected in older patients [6]. Patients are generally unable to define a precise time of symptom onset. Complaints are not directly related to trauma but a significant share of patients may report previous traumatic injury of the affected joint.

Depending on disease progress, more or less severe swelling may be noted during physical examination. Joint effusion and a synovial mass may be palpable.

Although a biopsy needs to be performed in order to confirm suspected PVNS, the need for this procedure is not usually realized until plain radiography, magnetic resonance imaging and/or computed tomography scans have been carried out. These techniques will not yield pathognomonic findings but may help to rule out differential diagnoses that don't justify a biopsy. Of note, those strategies described for articular PVNS are also applicable to patients who present with bursal or tendon sheath pathologies, but sonography may be more helpful during workup [7].

Plain radiography may not reveal any anomalies, but soft tissue swelling and joint effusion may be visible. Narrowed joint spaces are not typical for PVNS but should neither be considered an exclusion criterion. Only during later stages of the disease become lesions of the underlying bone recognizable. Irregularities in bone density, subchondral cysts and osteophytes may be observed. Calcifications are rare. In case of localized PVNS, anomalies are only detected in a restricted area of the joint [8].

With regards to the knee, joint and bone lesions are best recognizable in the patellofemoral joint: The suprapatellar pouch may be distended, and lateral and medial epicondyles as well as patellofemoral articular surfaces may show an altered osseous structure. In case of hip PVNS, acetabulum and femoral head and neck are generally involved.

Magnetic resonance imaging is the most sensitive technique to detect PVNS-associated joint alterations; it may also be applied as a supplementary method to assess the extent of tissue damage before deciding on an a therapeutic approach. By means of magnetic resonance imaging, synovial proliferation may be depicted directly. Furthermore, hip joint effusion will hardly be visible in plain radiographic images but are identifiable with this technique. PVNS-related joint effusions may be rich in hemosiderin, a degradation product of hemoglobin, and hemosiderin deposits appear as hypointense areas in both T1- and T2-weighted images and [9]. In images obtained by means of computed tomography, such hemosiderin-rich fluids correspond to hyperdense areas.

In case of joint effusion, an arthrocentesis may be indicated. Recovery of reddish-colored synovial fluid is highly suspicious for PVNS.

Of note, important differential diagnoses of articular PVNS are rheumatoid arthritis, osteoarthritis / degenerative joint disease, synovial osteochondromatosis, and neoplasms. If laboratory analysis of blood samples are conducted, elevated inflammatory parameters may be detected in all kinds of synovitis and/or arthritis. However, serum concentrations of autoantibodies like the rheumatoid factor may be of great value to distinguish between those diseases [10]. Rheumatoid arthritis and advanced osteoarthritis are polyarticular disorders.

PVNS requires surgical treatment. Synovectomy, i.e., resection of the synovial membrane at sites of villonodular proliferation, is generally indicated as first-line therapy. Arthroscopic procedures may suffice if patients don't present extensive lesions and are preferred over open surgery. If lesions of the underlying bone have been identified, curettage may be required. In case of extensive osseous lesions, volume defects may need to be filled with bone grafts.

Unfortunately, the likelihood of recurrence is very high - a fact that argues for the hypothesis of synovial proliferation corresponding to a neoplasm. Consequently, standard approaches to cancer treatment have been considered in case of PVNS. Adjuvant radiotherapy has been reported to be effective after incomplete resection and in case of relapses [11]. Of note, complete removal of degenerated synovial membrane is still the gold standard of PVNS therapy [12].

Synovectomy and/or radiotherapy yield satisfying results in mild to moderate cases of PVNS. However, severe damage of intraarticular structures may not be reversible and patients may continue to suffer from pain and limited motion ranges. Here, arthrodesis or arthroplasty may be required to relieve symptoms.

Prognosis depends on the extent of the disease at the time of diagnosis. Unfortunately, several years may pass until PVNS is recognized and by the time the correct diagnosis is made, irreversible damage to articular structures and underlying osseous tissues has already occurred. Furthermore, extensive lesions complicate therapy and increase the risk of recurrence. Thus, PVNS is likely to cause permanent pain and moderate disability. Favorable prognostic parameters are early diagnosis of localized PVNS and complete resection of synovial proliferations.

Malignant degeneration is associated with a poor prognosis but is extremely rare.

The etiology of PVNS is poorly understood. There are two major hypotheses regarding the development of PVNS-like lesions: They are assumed to either result from an inflammatory process triggered by as of yet unknown factors, or villonodular projections of the synovial membrane are essentially a type of neoplasm. Furthermore, metabolic disorders may contribute to PVNS.

Those theories are based on histological analyses of tissue samples obtained from PVNS patients. Here, proliferation of synovial cells, infiltration with giant cells and local accumulation of xanthomatous cells can be observed. It is currently unclear which pathophysiological events precede which other ones.

The vast majority of PVNS cases follows a benign course, but malignant degeneration has been reported. In isolated cases, PVNS has been described to metastasize [2]. Consequently, neoplastic growth seems to be at least partially responsible for PVNS.

According to those observations, it may be suspected that any trigger - a traumatic lesion, for instance - provokes an inflammatory response that favors uncontrolled proliferation of synovial cells. A genetic predisposition cannot be ruled out at this time and in fact, overexpression of colony-stimulating factor 1 has been related to PVNS [3].

The annual incidence of PVNS has been estimated to range between 1 and 2 per 1,000,000 inhabitants.

In some studies, male predilection have been reported, but in sum, both genders seem to be equally affected.

Symptom onset usually occurs during the second to fifth decade of life, but PVNS has been diagnosed in pediatric patients and the elderly.

Diffused PVNS is much more common than localized PVNS and accounts for about 90% of all cases [4]. Three out of four patients present with unilateral knee lesions.

PVNS is characterized by local invasive growth of the synovial membrane, a pathomechanism that suggests a neoplastic process. Due to a local mass effect, synovial growth causes functional impairment of the affected joint, bursa or tendon sheath. Generally, this leads to decreased motion ranges and stiffness. In isolated cases, compression of adjacent structures may cause more severe symptoms: Elbow PVNS, for instance, has been related with radial, median and ulnar nerve palsies [5].

Although it is not clear whether an inflammatory response is induced by proliferating synovial cells or vice versa, inflammation does significantly contributes to PVNS pathogenesis. Effusion, swelling and pain are mainly ascribed to inflammatory mechanisms.

Because the etiology of PVNS is poorly understood, no specific measures can be recommended to prevent that disease. However, rising the awareness among health care givers may shorten the time between symptom onset and diagnosis of PVNS, and may thus allow for an early initiation of treatment - which is associated with a better prognosis.

Pigmented villonodular synovitis (PVNS) is an uncommon inflammatory disease that may affect single or multiple anatomical structures lined by synovial membranes. It has first been described by the US-American pathologist Henry Lewis Jaffe who referred to it as "pigmented villonodular synovitis, bursitis, and tenosynovitis" [1]. This descriptive designation emphasizes the disease's clinical and pathological features: Patients affected by PVNS may claim symptoms related to the inflammation of joints, bursae or tendon sheaths, and pathological examination of an affected part of the locomotor system reveals heterogenous discoloration as well as villous or nodular projections of the synovial membrane.

The direct cause of PVNS is an uncontrolled, locally invasive growth of the synovial lining of joints, bursae or tendon sheaths. The trigger of this aggressive proliferation has not yet been identified and further research is needed to confirm the hypotheses hitherto suggested. In the long term, synovial proliferation may affect the underlying bone, a process that can be visualized by means of diagnostic imaging.

In most cases, PVNS affects a single joint, most likely large joints like the hip or knee. Symptom onset typically occurs in early adulthood, but the disease has also been diagnosed in pediatric and elderly patients. In fact, children are more likely to develop polyarticular PVNS. The disease follows a slowly progressive course; effusion, swelling, pain and functional impairment aggravate over time.

As has been indicated above, imaging techniques are very helpful in diagnosing PVNS. Besides bone erosions, frequent findings comprise synovial proliferation, effusion, distension of the joint capsule, bursa or tendon sheath, and swelling of the adjacent soft tissue. To this end, magnetic resonance imaging is superior to plain radiography. A tentative diagnosis of PVNS needs to be confirmed by histopathological analysis of a tissue sample. Synovectomy is the treatment of choice.

Of note, two types of PVNS are distinguished. In general, proliferation comprises the whole synovial membrane lining the affected anatomical structure. This type of PVNS is also known as diffuse PVNS. In rare cases, synovial lesions are restricted to isolated parts of the membrane, i.e., synovitis is localized. Interestingly, localized PVNS also differs from diffuse PVNS with regards to distribution patterns: While diffuse PVNS typically affects single, large joints, localized PVNS is more likely to be detected in small joints of the distal limbs, bursae and tendon sheaths. Localized proliferation of the synovial membrane of tendon sheaths gives rise to a particular type of PVNS also referred to as tenosynovial giant cell tumor.

Pigmented villonodular synovitis (PVNS) is an inflammatory disease characterized by local invasive growth of the synovial layer lining joints, tendons and bursae.

Causes

It is not yet clear which factors contribute to development of PVNS. An inflammatory response evoked by an acute trigger, benign neoplastic growth, disorders of lipid metabolism and genetic predisposition have all been proposed as possible causes of PVNS. Most likely, more than one of them does provoke symptom onset and affects the severity of the disease.

Symptoms

PVNS usually affects a single large joint, most commonly the hip or knee. Joint pain, swelling, stiffness and reduced motion ranges are characteristic yet unspecific symptoms of PVNS. The disease follows a progessive course, yet exacerbation of symptoms occurs very slowly. Patients may not even be able to define a precise time of symptom onset.

Severity of complaints varies during the course of a day and year: During periods of intense joint pain, patients may only find relief when resting. On the other hand, they may experience prolonged asymptomatic periods.

Diagnosis

Diagnostic imaging will be applied in patients who present with the above described symptoms. Plain radiography and magnetic resonance imaging allow for a precise evaluation of intra- and extraarticular structures and the underlying bone. By means of diagnostic imaging, certain differential diagnoses can be ruled out. However, in order to confirm a tentative diagnosis of PVNS, a biopsy needs to be obtained and analyzed.

Treatment

PVNS requires surgical treatment, proliferated synovial membranes need to be removed. If adjacent bones have been compromised by the joint disease, curettage and possibly bone grafts are indicated to reconstruct them.

Patients may benefit from adjuvant radiotherapy if a complete resection is not feasible or if relapses occur.

In case of severe PVNS or repeated recurrence, it may be necessary to replace the affected joint.

1. Jaffe HL, Lichtenstein L, Sutro CJ. Pigmented villonodular synovitis, bursitis, and tenosynovitis. Arch Pathol. 1941;31:731–65.
2. Sistla R, J VSV, Afroz T. Malignant Pigmented Villonodular Synovitis-A Rare Entity. J Orthop Case Rep. 2014; 4(4):9-11.
3. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007; 31(6):970-976.
4. Ottaviani S, Ayral X, Dougados M, et al. Pigmented villonodular synovitis: a retrospective single-center study of 122 cases and review of the literature. Semin Arthritis Rheum. 2011; 40(6):539-546.
5. Lu H, Chen Q, Shen H. Pigmented villonodular synovitis of the elbow with rdial, median and ulnar nerve compression. Int J Clin Exp Pathol. 2015; 8(11):14045-14049.
6. Zhao X, Ji W, Qian X, et al. Pigmented villonodular synovitis developing in a patient with rheumatoid arthritis. J Clin Rheumatol. 2014; 20(5):283-286.
7. Madruga Dias J, Costa MM, Duarte A, et al. Localized Pigmented Villonodular Synovitis of the shoulder: a rare presentation of an uncommon pathology. Acta Med Port. 2013; 26(4):459-462.
8. Carvalho Godoy FA, Faustino CA, et al. Localized Pigmented Villonodular Synovitis: Case Report. Rev Bras Ortop. 2015; 46(4):468-471.
9. Murphey MD, Rhee JH, Lewis RB, et al. Pigmented villonodular synovitis: radiologic-pathologic correlation. Radiographics. 2008; 28(5):1493-1518.
10. Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. Qjm. 2010; 103(3):139-146.
11. Heyd R, Micke O, Berger B, et al. Radiation therapy for treatment of pigmented villonodular synovitis: results of a national patterns of care study. Int J Radiat Oncol Biol Phys. 2010; 78(1):199-204.
12. Akinci O, Akalin Y, Incesu M, et al. Long-term results of surgical treatment of pigmented villonodular synovitis of the knee. Acta Orthop Traumatol Turc. 2011; 45(3):149-155.