Definition of tumoral calcinosis (TC)  

Tumoral calcinosis (TC) is an uncommon condition, both clinically and histologically, marked by the accumulation of calcium salts in the soft tissues surrounding the joints. This disorder typically appears during childhood or adolescence and presents as painless, firm, tumour-like growths near the joints. While these masses are often not painful, they can cause limitations in joint movement, especially when they are large. The most frequently affected areas include the soft tissues around the upper limbs (shoulder and elbow) and the hip. However, there have also been cases involving other regions such as the spine, temporomandibular joint, metacarpals/metatarsals, and the popliteal space.¹

Epidemiology  

Studies indicate that the condition is more prevalent among females and African-American populations. It typically begins in childhood or early adolescence.²

Pathophysiology 

• Unknown²
• Initial Trauma: Minor, repetitive injuries cause tissue haemorrhage and histiocytic response²
• Calcification Process: Elevated calcium-phosphorus levels, with hyperphosphatemia being key²
• Genetic mutations (e.g., FGF23, GALNT3, KLOTHO) and secondary factors like CRF lead to phosphate retention²

Etiology 

The exact cause of tumour calcinosis (TC) remains uncertain despite several proposed theories. In 1996, Smack et al. reviewed 122 cases and classified TC based on its pathogenesis into three main types. Primary normo-phosphatemic TC is characterised by normal calcium and phosphate levels, typically occurring before the second decade of life, with a higher prevalence in tropical and subtropical regions. It is usually associated with solitary calcifications, and although initially thought to have no familial pattern, recent studies suggest a genetic link involving mutations in the SAMD9 gene. Primary hyperphosphatemic TC is distinguished by normal calcium but elevated phosphate levels, often presenting in the first or second decades, with a higher incidence among people of African descent. Genetic predisposition plays a key role, with hyperphosphatemia resulting from mutations in GALNT3 and KLOTHO, leading to the inactivation of FGF23, a phosphaturic hormone. Lastly, secondary TC is most commonly linked to chronic renal failure (CRF), where impaired kidney function leads to phosphate retention and abnormal mineral metabolism, contributing to the development of calcific deposits.¹

Importance of understanding the anatomical sites involved 

The anatomical distribution also plays a vital role in treatment planning, especially surgical intervention. Tumour calcinosis near joints requires a careful surgical approach to avoid damage to surrounding structures, including nerves and blood vessels, and to preserve joint function. Additionally, TC tends to recur more often when located near joints due to mechanical stress, which may necessitate more extensive resection or follow-up care. Moreover, TC is often linked with underlying conditions, such as familial hyperphosphatemic tumoral calcinosis or chronic kidney disease, which can affect areas like muscle, connective tissue, and skin. Understanding these associations aids in comprehensive treatment strategies and helps clinicians monitor for systemic complications. In summary, the anatomical sites involved in tumour calcinosis are key to accurate diagnosis, effective treatment, and long-term management, including recurrence monitoring and addressing underlying conditions.^1,2,3

Characteristics of calcified masses

The calcified masses found in tumoral calcinosis (TC) exhibit several distinct characteristics that aid in their identification. These masses typically form around large joints, particularly the shoulders, elbows, hips, and knees, but can also be located in the hands, feet, and other peri-articular regions. Imaging studies commonly reveal that the calcifications appear amorphous, multilobulated, and cystic in shape, often exhibiting a well-defined, firm structure. Over time, the masses may increase in size, which can lead to joint discomfort, limited movement, or deformity if they impact the surrounding joint function.^1,4,5

In addition to their appearance, these calcified masses often show fluid layering on computed tomography (CT) scans, which is referred to as the "sedimentation sign." This sign indicates that the calcium deposits within the mass are layered, suggesting an ongoing process of calcification. The masses can contain cystic loculi, where the density of the calcium varies, further contributing to their distinctive radiographic appearance. Histologically, these masses are made up of compartmentalised areas filled with a chalky, gritty substance. These calcifications are generally surrounded by histiocytes, with occasional signs of mild inflammation.⁵ Ultimately, the unique features of these calcified masses, including their location, appearance, fluid layering, and lack of bony destruction, help in distinguishing TC from other calcifying soft tissue conditions.

Clinical presentation and symptoms

Common clinical symptoms of tumoral calcinosis include joint tenderness, restricted joint mobility, and skin ulcerations. However, some cases may be asymptomatic. For instance, a study reported that 14% of patients with secondary tumoral calcinosis (1 out of 7) experienced no symptoms. Inflammation and redness around the affected areas are possible (2,4). In certain cases, the overlying skin may ulcerate, leading to the exudation of a chalky fluid and increasing the risk of secondary infections.⁵

Common anatomical sites affected by tumoral calcinosis

• Hip (Most Common Site)

The hip is the most frequently affected location in tumoral calcinosis. Calcium deposits typically form in the gluteal and iliotrochanteric bursae, presenting as firm, painless masses. As these calcifications enlarge, they can compress surrounding muscles and nerves, leading to discomfort, restricted movement, and, in severe cases, difficulty walking. Large deposits may sometimes mimic soft tissue tumours and require surgical intervention for relief.^5,6

• Elbow

The elbow joint is another common site, especially in individuals who engage in repetitive arm movements. Calcifications usually occur in the olecranon bursa, which may result in joint stiffness and restricted extension. Unlike other locations, elbow TC lesions have a higher tendency to ulcerate through the skin, potentially leading to secondary infections and chronic drainage of a chalky, milk-like substance due to the liquefied calcium deposits. This location is frequently involved in both primary and secondary TC cases.^6,5

• Shoulder

The shoulder is frequently affected due to its wide range of motion and exposure to mechanical stress. Calcium deposits commonly develop in the subacromial or deltoid bursae, forming firm masses that are often painless. However, in some cases, these deposits can lead to restricted shoulder mobility as they enlarge. Unlike other sites, shoulder involvement is often bilateral and may be mistaken for calcific tendinitis.^5,6

• Foot (Metatarsals & Achilles Tendon Region)

The foot is a less commonly affected site, but when involved, it can cause significant discomfort, particularly if deposits develop near weight-bearing areas. The plantar soft tissues, metatarsals, and Achilles tendon sheath are the primary locations of TC-related calcifications in the foot. Patients often experience localised pain and difficulty walking due to mechanical irritation. Additionally, ulceration and secondary infections are more likely in this area due to constant pressure and friction.^5,6

• Wrist (Least Common Site Among Major Joints)

The wrist is rarely affected in tumoral calcinosis, but when involved, deposits typically form around the flexor and extensor tendons in the carpal region. Patients may present with stiffness, localised swelling, and mild pain if the calcifications interfere with tendon movement. Wrist TC can sometimes be misdiagnosed as gout or rheumatoid arthritis due to its similar clinical presentation.⁶

• Other Reported Sites of TC Involvement

Although less common, tumoral calcinosis has been reported in other soft tissue regions. Involvement of the spine can lead to nerve compression and back pain. Rarely, calcifications may form in the temporomandibular joint (TMJ), causing jaw stiffness and limited mouth opening. TC can also affect the posterior knee (popliteal fossa), resulting in discomfort and restricted movement. In some cases, deposits have been found in the small bones of the hands and feet (metacarpals and metatarsals.^6,5

• Summary

Tumoral calcinosis most commonly affects large periarticular bursae, with the hip, elbow, and shoulder being the most frequently involved sites. These calcium deposits can lead to joint stiffness, pain, and, in severe cases, ulceration and infection. Less frequently, TC may affect the spine, TMJ, and knee, causing localised symptoms that can mimic other conditions. Understanding the typical locations and their clinical implications is essential for accurate diagnosis and effective management.

Differential diagnosis

Hyperparathyroidism (most frequently in chronic renal failure), calcium pyrophosphate deposition disease (CPPD), myositis ossificans, calcinosis circumscripta, calcinosis universalis, milk-alkali syndrome, hypervitaminosis D, calcinosis of chronic renal failure, calcific tendinitis, synovial osteochondromatosis, synovial sarcoma, osteosarcoma, calcific myonecrosis, and tophaceous gout.⁵

Calcinosis in renal failure, specifically secondary tumoral calcinosis, occurs in about 1% of patients with periarticular masses and can develop independently of hyperparathyroidism. It shares no distinguishing radiological or histological differences from primary tumoral calcinosis, and its diagnosis involves evaluating vitamin D levels, glomerular filtration rate, hyperphosphatemia, and a history of chronic renal failure or long-term dialysis.

Calcific tendinitis primarily affects the shoulder and other joints, presenting within tendons without calcium sedimentation, unlike tumoral calcinosis. Synovial osteochondromatosis arises within joints or tendon sheaths, characterised by "rings and arcs" on imaging, differentiating it from tumoral calcinosis. Myositis ossificans and heterotopic ossification evolve rapidly from faint calcification to organised cartilage and bone within weeks, with later lesions showing developed cortices and medullary cavities. Gout, often associated with hyperuricemia, is marked by focal erosions of the underlying bone.²

Laboratory findings 

The laboratory results revealed a significantly low serum calcium level of 7.5 mg/dL (normal range: 8.8–10.1 mg/dL), an elevated phosphate level of 4.8 mg/dL (normal range: 2.7–4.6 mg/dL), and markedly increased blood urea nitrogen (35 mg/dL; normal range: 8–20 mg/dL) and serum creatinine (6.9 mg/dL; normal range: 0.46–0.79 mg/dL), indicating renal dysfunction. Total protein was low at 5.5 g/dL (normal range: 6.6–8.1 g/dL), and albumin was reduced at 2.7 g/dL (normal range: 4.1–5.1 g/dL). Additionally, the intact parathyroid hormone level was elevated at 390 pg/mL (normal range: 10–60 pg/mL), which may suggest secondary hyperparathyroidism. The white blood cell count was normal, ruling out significant infection or inflammation. Radiographs of the chest and hips revealed cardiomegaly with pulmonary congestion, along with large, irregular calcified masses located adjacent to both shoulders, below the right lower ribs, on the left side of the lower lumbar spine, at the hip joints, and over both ischial tuberosities, consistent with calcinosis. These findings suggest a complex clinical picture, likely involving secondary tumoral calcinosis in the context of renal failure and associated metabolic disturbances.⁴

Diagnostic considerations

Diagnosing TC requires differentiating it from similar conditions and classifying it into one of its subtypes. Patients commonly present with multiple or solitary joint-related swellings, often accompanied by discomfort, pain, and restricted movement. The most frequently affected joints include the hip, elbow, shoulder, foot, and wrist. The growth of these lesions is typically slow and progressive over several years. In some cases, skin ulceration may occur, sometimes leading to secondary infections. Although rare, large bilateral cases of TC have been documented in the literature.

Imaging plays a crucial role in diagnosing TC. Plain X-rays typically reveal amorphous, multilobulated, and cystic calcifications in peri-articular locations. Computed tomography (CT) scans help determine lesion extent and assist in surgical planning by showing cystic loculi with fluid-fluid levels, known as the "sedimentation sign." In certain cases, lesions appear homogeneous, indicating a less active stage of the disease. Magnetic resonance imaging (MRI) often shows inhomogeneous high signal intensity on T2-weighted sequences and either a diffuse low-intensity pattern or a nodular pattern with alternating high and low signal areas.

On T1-weighted sequences, lesions appear inhomogeneous with low signal intensity. Additional imaging techniques, such as scintigraphy using technetium-99m methylene diphosphonate, can detect multiple or newly forming lesions, assess bone marrow involvement, and monitor disease progression. Ultrasonography may also be useful in identifying loculated fluid collections, which can provide insights into disease activity.^1,2

TC can be confused with several other conditions, including calcinosis universalis, calcific tendonitis, synovial osteochondromatosis, synovial sarcoma, osteosarcoma, myositis ossificans, tophaceous gout, and calcific myonecrosis. A combination of radiological features and serum biochemical tests, including calcium, phosphorus, renal function tests, parathormone, and vitamin D levels, is essential for distinguishing TC from these conditions.

Additionally, connective tissue diseases, such as systemic sclerosis or lupus, should be ruled out, especially when calcium and phosphorus levels are normal. This can be achieved through negative results for antinuclear, anti-Smith, anti-centromere, and anti-scleroderma antibodies. Although biopsy is generally avoided due to the risk of infection, it may be necessary in difficult cases to confirm the diagnosis. Histopathological examination of TC lesions reveals characteristic morphological features, including compartmentalised calcifications containing liquid chalky material. This compartmentalised structure is often preserved even in the quiescent stage, further distinguishing TC from other calcifying conditions.¹

Treatment

The treatment of tumoral calcinosis (TC) should be customised based on the lesion type, stage of pathology, lesion characteristics (such as site, size, and relation to surrounding structures), and the patient’s symptoms. For primary TC, early surgical excision is the main treatment, although the high recurrence rate often necessitates repeated excisions. Surgical removal typically reveals cystic lesions with chalky material composed of calcium hydroxyapatite, calcium carbonate, and calcium phosphate. Angiographic findings of hypervascular regions outside the calcified mass suggest that a wider surgical margin could potentially reduce recurrence, though this theory requires further confirmation.

Immobilisation following surgery has been suggested to reduce the formation of new lesions. Large lesions may need extensive excision and reconstruction, with significant challenges posed by proximity to vital neurovascular structures, often resulting in partial excisions and rapid recurrence. Partial excision can provide substantial pain relief, particularly for large symptomatic lesions. Indications for surgical excision include recurrent infection, ulceration, and functional impairment.^1,2,4

However, surgery can be complicated by issues such as prolonged drainage, delayed wound healing, sinus tract formation, and secondary infections. Recurrence is common after incomplete excisions, often with accelerated growth. Medical treatment, such as phosphate depletion through dietary restrictions or phosphate-binding agents like oral aluminium hydroxide, has shown variable success in both normophosphatemic and hyperphosphatemic cases. Combining phosphate binders with acetazolamide, which induces phosphaturia, may provide a synergistic effect in reducing hyperphosphatemia. Given the high recurrence rate after surgical excision, medical treatment could be considered as an initial approach, particularly in hyperphosphatemic cases^1,2,4

In the active stage of TC, medical treatment may be more effective due to the high recurrence rate after surgery. Surgery might be more beneficial during the quiescent stage, when encapsulation impedes the ion exchange process, hindering phosphate depletion. Some experts advocate for a combined approach of surgery and medical treatment for resistant cases. Although alternative treatments like steroids, diphosphonates, calcitonin, and radiation therapy have been explored, they have not been proven to be effective.¹

For secondary TC, often associated with end-stage renal disease or hemodialysis, medical treatment is preferred, as surgery may lead to significant complications, including infections and fistula formation. Medical management includes calcium and phosphorus-restricted diets, dialysates, and phosphate binders (excluding aluminium-containing ones). Other treatments such as Vinpocetine, sodium thiosulfate, and intravenous pamidronate have been used with varying success rates. In cases of failed medical management, subtotal or total parathyroidectomy may be considered due to the underlying secondary or tertiary hyperparathyroidism, showing promising results. Kidney transplantation is another option for these patients.¹

Summary

• Summary of Common Affected Sites: Tumoral calcinosis (TC) most commonly affects the larger joints, especially the hip, elbow, and shoulder. Other areas like the foot, wrist, spine, and jaw can also be affected, though less often. The symptoms typically include joint pain, limited movement, and, in some cases, skin ulceration that can lead to infections. Recognising these areas helps doctors diagnose and manage the condition more effectively
• Importance of Early Diagnosis and Treatment: Catching TC early is crucial for avoiding complications like infections or severe pain and immobility. Since TC can resemble other conditions, distinguishing it is key to getting the right treatment. Starting treatment early, especially when the disease is still active, can make a big difference in outcomes, prevent further damage, and lower the chances of the condition coming back after surgery
• What Needs to be Researched More: To better treat TC, researchers need to understand the causes behind it, particularly in cases related to kidney failure and other underlying health conditions. There’s also a need for better treatments, such as more effective medications and new surgical approaches that reduce the chances of TC coming back. More studies should also look at the role of kidney transplants and parathyroid surgery, especially for patients with secondary TC linked to kidney disease. We also need more research into alternatives like steroids and other therapies that might help