Tumoral Calcinosis

Tumoral calcinosis is a lobulated periarticular deposit of calcium hydroxyapatite, and a frequently missed cause of a periarticular "tumour" in young patients. It is not a neoplasm. The deposition is almost always driven by one of two things: an inherited FGF23-axis defect, which is rare, familial and paediatric, or chronic renal failure with disordered mineral metabolism, which is common, adult and dialysis-dependent.

Why the diagnosis matters. Getting it right changes management completely. Surgery cures neither the familial form, in which recurrence is the rule, nor the uraemic form unless the metabolic state is corrected.

How common. The disease is rare, with an overall incidence estimated at roughly 1 in 100,000 to 1 in 1,000,000. Its forms occur in different populations:

• The familial (primary hyperphosphataemic) form is autosomal recessive and presents in the first or second decade, often in children of consanguineous parents. It has been described in clusters from the Middle East, North Africa and Turkey, and shows no strong sex predilection.
• The secondary (uraemic) form is the clinically dominant one and is rising in prevalence with the dialysis population. Its sex distribution tracks CKD demographics.
• High-frequency endemic clusters have been described in parts of sub-Saharan Africa and Papua New Guinea, often associated with low-calcium, high-phosphate dietary patterns.

Why surgeons see it. The typical referral pathway is biopsy or excision after the mass has been confused with a bone or soft-tissue tumour. Others present with mechanical symptoms, as large masses restrict joint motion, irritate a bursa or compress a nerve, or with functional limitation in sitting, walking and dressing, and some with skin breakdown. Recurrence after incomplete excision is the single most common reason for repeated referrals.

A deposition disorder, not a tumour. The mineral is calcium hydroxyapatite (calcium phosphate), not calcium oxalate or calcium pyrophosphate. It is laid down in lobulated sheets within periarticular soft tissue, often with a foreign-body giant cell reaction, and there is no cellular atypia.

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Where it forms. The deposits form at sites of microtrauma, repeated shear or bursal friction, which explains the predilection for the greater trochanteric, subdeltoid and olecranon bursae and the ischial region. Local tissue injury, an alkaline local pH and a high extracellular phosphate together favour hydroxyapatite rather than calcium oxalate precipitation.

The masses sit adjacent to the joint but not within it, and the mineral is rarely within the joint itself. They are lobulated and can exceed 20 cm.

The FGF23 axis. FGF23 is secreted by osteocytes and osteoblasts in response to phosphate load and active vitamin D. To be secreted in its intact, active form it needs O-linked glycosylation by GALNT3, and in the kidney it acts through its co-receptor KLOTHO to drive renal phosphate wasting and suppress 1-alpha-hydroxylase.

The familial defect. Biallelic loss-of-function of any of these three genes, GALNT3 most commonly, prevents FGF23 signalling, so both the phosphate wasting and the 1-alpha-hydroxylase suppression are abolished. The net result is phosphate retention and hyperphosphataemia, an inappropriately normal or elevated 1,25-(OH)2 vitamin D, normal calcium, normal or low PTH, and progressive periarticular hydroxyapatite deposition.

Secondary (uraemic) disease. CKD-mineral and bone disorder (CKD-MBD) is the umbrella term. As GFR falls below roughly 30 mL/min/1.73 m², phosphate excretion fails, FGF23 rises, active vitamin D falls and PTH rises in secondary hyperparathyroidism. The drivers of soft-tissue calcification in CKD include:

• hyperphosphataemia and a raised calcium-phosphate product
• calciphylaxis-spectrum small-vessel disease
• vitamin D analogue dosing
• calcium-based phosphate binders

In dialysis patients the lesions can reach enormous size at the hip, shoulder, elbow, hand or wrist, and frequently ulcerate.

Hyperostosis-hyperphosphataemia syndrome. Hyperphosphataemic familial tumoral calcinosis (HFTC) and hyperostosis-hyperphosphataemia syndrome (HHS) are two phenotypes of one disease. HHS is caused by the same biallelic GALNT3 (or FGF23) loss-of-function mutations and shows identical biochemistry: high phosphate, normal calcium, an inappropriately normal or elevated 1,25-(OH)2 vitamin D and increased tubular phosphate reabsorption.

Instead of, or as well as, periarticular calcific masses, HHS presents with painful diaphyseal hyperostosis: cortical thickening and periosteal new bone, classically of the long bones (the tibia and ulna are typical), with recurrent episodes of bone pain, local swelling and raised inflammatory markers. It is a recognised mimic of chronic recurrent multifocal osteomyelitis (CRMO), osteomyelitis or a bone tumour.

Recognising the hyperphosphataemic biochemistry and the family history prevents misdiagnosis and unnecessary biopsy or antibiotics. The two phenotypes can coexist in the same family or even the same patient, so a child with unexplained diaphyseal hyperostosis and hyperphosphataemia should be worked up for the FGF23-axis defect. The metabolic phosphate-lowering treatment is the same.

Classify by mechanism. Smack (1996) proposed classifying tumoral calcinosis by pathogenesis rather than by site, and pathogenesis matters because it dictates whether the disease is curable, controllable or simply manageable. The scheme has four groups:

• Primary (idiopathic) - hyperphosphataemic familial (GALNT3, FGF23, KLOTHO) and normophosphataemic sporadic. The familial form often begins in childhood or adolescence, and in it recurrence after surgery is the rule.
• Secondary - chronic renal failure with disordered mineral metabolism (the most common clinically), hyperparathyroidism (primary or secondary), vitamin D toxicity, milk-alkali syndrome, and connective tissue disease with dystrophic calcification.
• Dystrophic - calcification within damaged or devitalised tissue, post-traumatic, post-surgical or in areas of fat necrosis. Tumoral calcinosis-like lesions can form around the elbow or hip after local injury.
• Iatrogenic and miscellaneous - calcium-based binder excess, vitamin D analogue overdose, and tumoral calcinosis-like lesions in calcinosis cutis and CREST.

The four working types. Treatment decisions use four working types, which keep Smack's two primary forms, reserve "secondary" for uraemic (CKD and dialysis) disease, and group hyperparathyroidism, vitamin D toxicity and milk-alkali syndrome, which Smack lists as secondary, with local tissue damage as "dystrophic / other".

Site. The order of frequency is hip, then shoulder, then elbow, then wrist. Location is the most important surgical variable, because neurovascular proximity dictates resectability.

History. Years of slow, often painless growth is the rule. Pain usually comes late, when the mass irritates a bursa, compresses a nerve or ulcerates the skin, and an ulcerated mass may discharge chalky white "toothpaste". The rest of the history looks for the driver:

• Renal disease - dialysis vintage, transplant status, and medications (calcium-based binders, vitamin D analogues)
• Family history - sibling or parental cases, as inheritance is autosomal recessive
• Diet and drugs - high phosphate intake, vitamin D supplementation, calcium supplements

Examination. The mass is firm, lobulated and "stony-hard", non-tender, and often warm but not inflamed. It usually involves a single limb or a single joint, although familial disease can be multifocal and uraemic disease often involves multiple sites. It is usually fixed to the deep soft tissues but not to the skin until late, when tethering, erythema, ulceration and sinus tracts appear.

Joint range is often preserved unless the mass blocks it mechanically, and the lymph nodes are not enlarged, which is reassuring against malignancy. Document neurovascular function before any operation: the sciatic nerve at the hip, the axillary at the shoulder and the ulnar at the elbow.

Look beyond the joint. The familial form is a systemic phosphate-handling disorder, so deposition is not confined to the periarticular soft tissue, and the extra-skeletal features are powerful diagnostic and counselling clues:

• Teeth, near-characteristic - pulp stones, obliteration or narrowing of the pulp chambers, and short, bulbous ("thistle-shaped") roots, often visible incidentally on a panoramic dental radiograph and a useful confirmatory sign when the joint masses are atypical
• Eyes - conjunctival and eyelid calcific deposits, and angioid streaks
• Vessels - medial arterial calcification
• Testes - testicular microlithiasis has been reported

A child or young adult with periarticular calcific masses, the characteristic dental phenotype and hyperphosphataemia has hyperphosphataemic familial tumoral calcinosis until proven otherwise. These features support the diagnosis when imaging is equivocal, justify whole-patient surveillance, and inform genetic counselling for an autosomal recessive condition, which matters where consanguinity raises the sibling risk.

The differential. The two diagnoses that matter are parosteal osteosarcoma and myositis ossificans.

Radiographs first. AP and lateral views of the involved joint, plus a long-bone view. Pattern recognition is often diagnostic: lobulated, periarticular, 'cloud-like' calcification without cortical or medullary involvement in a young person is tumoral calcinosis until proven otherwise. Sensitivity is high at a typical site, and in familial or uraemic disease the film can be diagnostic. Look for:

• lobulated, dense periarticular calcification with a 'cloud-like' or 'chicken-wire' internal architecture
• a corticated or uncorticated margin
• no bony attachment and no periosteal reaction
• a preserved cortex, marrow and joint space, the point that separates it from a bone tumour or myositis ossificans

The sedimentation sign. Look specifically for horizontal fluid-calcium levels within the lesion, produced by hydroxyapatite crystals layering dependently inside cystic spaces. The sign was first described on plain radiographs, is seen readily on CT and MRI, and on ultrasound appears as echogenic debris settling in the dependent part of the cyst.

In this clinical context it is close to diagnostic, and it is the feature that most quickly separates tumoral calcinosis from the solid calcified matrix of a parosteal osteosarcoma or the zonal maturation of myositis ossificans.

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CT and MRI. In the typical case these are for surgical planning, not diagnosis. CT excludes bony attachment and confirms the lobulated architecture: there should be no continuity with the cortex, no marrow involvement and no soft-tissue mass with calcified matrix to suggest sarcoma, which separates it from parosteal osteosarcoma, myositis ossificans and synovial chondromatosis.

MRI is for an atypical site, atypical imaging or diagnostic doubt, when cancer is being considered. Expect homogeneous low T1 signal, variable T2 signal (often low because of the calcium), no marrow oedema and no enhancing soft-tissue mass, and avoid biopsy until the MRI and an orthopaedic oncology review are done.

The metabolic panel, always, and before any biopsy. The result may make the biopsy unnecessary. It separates primary hyperphosphataemic, primary normophosphataemic and secondary uraemic disease from hyperparathyroidism and vitamin D toxicity:

• Serum - calcium, phosphate, magnesium, alkaline phosphatase, 25-OH vitamin D, 1,25-(OH)2 vitamin D, PTH, creatinine, eGFR, urate
• Urine - 24-hour urinary phosphate (and calcium)
• Calculated - calcium-phosphate product, tubular reabsorption of phosphate (TRP), TmP/GFR

The FGF23 assay trap. If you send FGF23 in suspected hereditary disease, specify which assay, because the two give opposite-looking answers in GALNT3 disease. Failure of O-glycosylation means FGF23 is cleaved before secretion, so the intact (biologically active) FGF23 is low or inappropriately normal, which is what causes the hyperphosphataemia.

The C-terminal assay, which also detects the cleaved fragments, is markedly elevated, reported at roughly 40 times normal in one family and consistently high across the NIH cohort. A "raised FGF23" therefore does not exclude the diagnosis and may confirm it, and a normal intact FGF23 in a hyperphosphataemic patient is the expected finding, not a reassuring one.

Genetics. Test a child or young adult, sibling cases, consanguinity, recurrence after excision, and hyperphosphataemia with normal calcium and PTH. The genes are GALNT3, FGF23, KLOTHO, SLC34A3 (NaPi-IIc) and SLC9A3R1 (NHERF1), sought with a targeted panel or whole-exome sequencing, together with genetic counselling.

Biopsy. Reserve it for atypical imaging, a rapidly enlarging mass, suspected malignancy, or a first presentation in an older patient without metabolic risk factors. It is a core needle biopsy by the orthopaedic oncology service, placed in the planned resection tract. Histology shows lobulated basophilic calcium deposits with surrounding fibrosis, histiocytes and foreign-body giant cells, and no atypia.

Metabolic first, surgery for symptoms. The goal is to lower serum phosphate, correct the calcium-phosphate product and stop further deposition. This is the only durable therapy for familial disease and the only curative strategy for secondary uraemic disease. Never excise without a metabolic workup, and never operate without a metabolic plan. NSAIDs have no role in this metabolic process.

The medical protocol. It has five elements:

1. Diet. A strict low-phosphate diet, avoiding processed meats, cola drinks, excess dairy, nuts and beans, with a typical target of less than 800-1000 mg/day of dietary phosphate in adults. Dietician input is essential, ideally a renal dietician for CKD patients.
2. Phosphate binders, with meals. First-line are the non-calcium binders, sevelamer (hydrochloride or carbonate) and lanthanum carbonate, titrated to the pre-dialysis or fasting serum phosphate. Avoid calcium-based binders in patients with hyperphosphataemia and a high calcium-phosphate product, because they worsen soft-tissue calcification.
3. Acetazolamide, as an adjunct. A carbonic anhydrase inhibitor that increases renal phosphate excretion, given at 250-500 mg twice daily with monitoring of bicarbonate and potassium. Case series in familial disease show mass reduction and a fall in phosphate. It can worsen acidosis and hypokalaemia.
4. Sodium thiosulphate, case-specific. It forms soluble calcium thiosulphate complexes and is given topically for ulcerated lesions or intravenously in calciphylaxis-spectrum disease. The evidence is anecdotal and small case series, and it is not first-line.
5. Treat the underlying cause, always. Parathyroidectomy or calcimimetics (cinacalcet) for hyperparathyroidism; stop vitamin D analogues and calcium for vitamin D toxicity; stop intake and hydrate for milk-alkali syndrome; and for CKD-MBD a KDIGO-aligned bundle of diet, binders, dialysis adequacy, vitamin D analogues and calcimimetics.

When to operate. The aim of surgery is complete excision of the mass with relief of symptoms, protecting the neurovascular structures and minimising recurrence. In familial disease it is palliative: it relieves local symptoms but does not cure the metabolic defect.

• Definite indications - ulceration with discharge, infection, nerve compression, a mechanical block to the joint, diagnostic doubt after workup, and cosmesis after counselling
• Relative indications - a rapidly enlarging mass, pain limiting function
• Not indicated - a small, asymptomatic mass with well-controlled metabolic disease

Before the operation. CT or MRI maps the neurovascular structures at risk. Lower the phosphate beforehand if possible to reduce recurrence, below 1.5 mmol/L if it can be achieved. Consent covers recurrence, nerve injury, wound healing problems, and a skin closure that may need a flap.

The operation. Use a direct, extensile approach that follows the planned sarcoma biopsy tract if one exists. Extracapsular "shelling-out" is inadequate; the aim is complete removal of every lobule at the first operation, because debulking is rarely adequate.

Irrigate copiously and use intra-operative nerve stimulation at risk sites. Close primarily if the skin is intact, and with a local flap or VAC if it is ulcerated.

Afterwards. A drain is often required for 24-48 hours. Mobilise early but protect the limb for 2 weeks, restart binders and diet immediately, and review clinically and radiographically at 3, 6 and 12 months for recurrence.

Recurrent disease. In familial disease recurrence is often greater than 50%, sometimes approaching 100% after simple debulking. The goal is to avoid mutilating re-excision, treat the metabolic driver, and reserve surgery for genuinely symptomatic recurrence. It recurs because of:

• incomplete primary excision, the most common cause
• continuing metabolic drive, with phosphate still high and the FGF23 axis still defective
• a multilobulated architecture that leaves small residual lobules
• difficult anatomical sites (sciatic notch, subdeltoid) where complete resection is unsafe

Reducing it. Aggressive pre-operative metabolic control, complete primary excision and a combined medical-surgical pathway are the basis. In uraemic disease add renal transplantation if the mass is symptomatic and the patient is a candidate, and parathyroidectomy for secondary hyperparathyroidism. The adjuncts are sodium thiosulphate (topical or intravenous), bisphosphonates (limited evidence), and IL-1 antagonists where systemic inflammation dominates (NIH cohort).

Re-operation. The threshold for re-excision is a mass at least as large as it was pre-operatively on serial imaging, a symptomatic recurrence (pain, ulceration, nerve compression), metabolic control optimised beforehand, and a patient counselled that a second recurrence is common.

Emerging therapy. Burosumab (anti-FGF23) is licensed for X-linked hypophosphataemia and tumour-induced osteomalacia, where it raises serum phosphate, which is the wrong direction for this disease. In familial tumoral calcinosis the defect is too little functional FGF23, so FGF23-pathway agonism or replacement is the plausible but unproven direction. Cost and access are major barriers, and there are no randomised trial data yet.

Best and worst. The best prognosis belongs to sporadic normophosphataemic disease with complete primary excision, and to dystrophic disease whose underlying cause is treated. The worst belongs to familial hyperphosphataemic disease with multiple recurrences, and to uraemic disease on long-term dialysis with poor metabolic control.

Cure. Outside dystrophic disease, whose outcome follows control of its cause, cure is achievable in two settings only: complete excision of a solitary normophosphataemic mass, and successful renal transplantation in uraemic disease. The single biggest prognostic factor is whether the metabolic driver can be corrected, and in familial disease it usually cannot be cured, only controlled.