Unusual radiographic progression of tumoral calcinosis along the anterior cruciate ligament in an adolescent male

Abstract

A 13-year-old boy was referred to orthopedic surgery for chronic intermittent pain and swelling of the left knee. Initial imaging was consistent with osteochondritis dissecans of the femoral condyle. Follow-up imaging demonstrated unexpected progression, with a mass extending into the notch, replacing the anterior cruciate ligament, and eroding the femoral and tibial condyles. Subsequent surgical biopsy and resection revealed tumoral calcinosis, with an ultimate diagnosis of autosomal recessive familial tumoral calcinosis. This case report highlights the radiographic appearance and progression of a rare disease in this unusual location and the differential diagnosis.

KEY POINTS

• Tumoral calcinosis (TC) is a rare disease that typically presents in the periarticular soft tissues along extensor surfaces of large joints in adolescents and young adults, with greater frequency in African-descent populations.^1,2

• TC may cause pain, swelling, and loss of range of motion of the nearby joint.¹

• On imaging, TC is typically superficial with calcified lobular masses, layering milk of calcium and/or hemorrhage in cysts on magnetic resonance imaging, and only septal enhancement. Atypical features include bone involvement, intra-articular/extrasynovial joint space involvement, and lack of cysts.^1,3–5

• Hyperphosphatemic TC, normophosphatemic TC, and secondary causes can usually be discerned with history and biochemical analysis (serum calcium, phosphorus, calcitriol, parathyroid hormone, and renal function tests). If the serum calcium and phosphorus are normal, connective tissue disease should be excluded with a negative antinuclear, anti-Smith, anti-centromere, and anti-scleroderma antibody profile.^1,6

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CASE SUMMARY

A 13-year-old male presented with a medical history of factor V Leiden, factor II deficiency, and 12q13.11 chromosome microdeletion, which explained his history of cleft palate, craniosynostosis, and retinal detachment. He was referred to orthopedic surgery for intermittent lateral left knee pain, swelling, and decreased range of motion over the last several years. There was no history of trauma or other affected joints.

Initial radiographs of the left knee demonstrated a subchondral lytic and sclerotic lesion of the lateral femoral condyle adjacent to the notch most consistent with osteochondritis dissecans (Figure 1a). Repeat radiographs 9 months later demonstrated interval increase in size and mineralization of the lesion, with extension into the notch, concerning for a more aggressive etiology (Figure 1b). Magnetic resonance imaging (MRI) of the left knee 3 months later demonstrated a heterogeneous hypointense mass arising from the lateral femoral condyle at the anterior cruciate ligament (ACL) origin, breaching the articular surface with an intra-articular component that replaced the substance of the ACL (Figure 2). There was no enhancing soft tissue and no cysts. At the origin and insertion of the ACL on the femur and tibia, there was osseous erosion and mild marrow edema. Chondroblastoma was suspected because of mineralization and osseous involvement. The patient was scheduled for biopsy and resection.

Figure 1.

(a) Initial radiograph of the left knee demonstrates a subchondral lytic and sclerotic lesion of the lateral femoral condyle adjacent to the notch (black arrows) most consistent with osteochondritis dissecans. (b) Repeat radiograph of the left knee 9 months after the first radiograph demonstrates interval increase in both size and degree of mineralization involving the left lateral femoral condyle lesion (arrows).

Figure 2.

(a) Coronal T1 MRI of the left knee 3 months after the second radiograph demonstrates a heterogeneous mass (M) arising from the lateral femoral condyle, breaching the articular surface, with a large intra-articular component, following and replacing the majority of the substance of the ACL. The mass extends distally to the articular cartilage of the proximal tibia with a component of cartilaginous invasion (arrows) into the lateral femoral condyle and proximal tibia. Markedly hypointense signal is related to calcification. (b) Axial T2 fat-saturated image demonstrates a mass (arrowheads) with markedly hypointense signal related to calcification and intervening heterogeneously increased signal intensity. It replaces the substance of the ACL. The posterior cruciate ligament (dashed arrows) is displaced by the mass. There is osseous invasion into the lateral femoral condyle with minimal edema (arrows).

During surgery, a medial parapatellar approach provided exposure to the knee joint. Upon capsulotomy, the tumor intimately encompassed the entire ACL, including the tibial and femoral footprints. The tumor-encased ACL was excised in its entirety, beginning at the tibial footprint, continuing along the intact normal posterior cruciate ligament, and ending at the lateral wall of the intercondylar notch of the femur. The intraoperative gross appearance was consistent with chondroblastoma. The tibial and femoral footprints were curettaged and treated with argon beam, which has been shown to improve recurrence rates of benign aggressive bone tumors without the toxic effects of other adjuvants like phenol.⁷ ACL reconstruction was performed using an open iliotibial band autograft technique, previously described using arthroscopic portals.⁸

Histologically, the lesion consisted of a 3.3 × 3.0 × 1.8 cm pink-tan to yellow unencapsulated nodule along with a 3.5 cm aggregate of tissue fragments. The cut surfaces were chalky-yellow with tan-brown trabeculae. Hematoxylin and eosin sections demonstrated fibroconnective tissue with foci of amorphous dystrophic calcifications arranged in a multilobulated pattern separated by fibrous septa bordered by a histiocytic giant cell reaction with occasional nodules showing cystic change (Figure 3). The pathologic diagnosis was tumoral calcinosis (TC).

Figure 3.

(a) Hematoxylin and eosin section (5×) showing nodules of amorphous calcified material separated by bands of fibrous tissue. (b) The amorphous calcified material is surrounded by multinucleated, osteoclast-like giant cells (10×).

Because of differing treatment and prognosis for types of TC (Table 1), further diagnostic workup was pursued. Serum calcium, vitamin D, and parathyroid hormone were all within normal range. Phosphorus was elevated at 5.6 mg/dL (normal range 3.3–5.4), prompting genetics consultation and whole exome sequencing. The patient was compound heterozygous for a pathogenic variant and a likely pathogenic variant in the GALNT3 gene, which is consistent with a diagnosis of autosomal recessive hyperphosphatemic familial TC. A pathogenic variant of the GALNT3 gene was maternally inherited, and a likely pathogenic variant of the GALNT3 gene was paternally inherited, reflecting an autosomal recessive inheritance pattern, as expected. He is being followed by nephrology for medullary nephrocalcinosis. Over 3 years the patient has had no recurrence or new mass. He takes Sevelamer 800 mg twice daily as a phosphate binder.

Table 1.

Types of tumoral calcinosis

	Primary normophosphatemic	Primary hyperphosphatemic	Secondary
Synonyms	Idiopathic	Familial	Renal failure: uremic TC, pseudotumor calcinosis, nonfamilial TC, tumoral calcification, TC-like lesion1
Etiology/pathogenesis	Theories center around trauma ± bleeding and with dysfunctional or exaggerated reparative response1,9	Theories center around trauma ± bleeding and with dysfunctional or exaggerated reparative response1,9	Renal osteodystrophy, hyperparathyroidism, connective tissue disease1, malignancy, sarcoid, hypervitaminosis D, milk-alkali syndrome, massive osteolysis10
Presentation	Onset before second decade, tropical/subtropical, more often single mass10	Onset before second decade, strong familial pattern, African descent, more often multiple masses10	Onset before second decade, more common in Caucasians and females, familial occurrence10
Labs/metabolic studies	Normal serum calcium and phosphate; lower prevalence of elevated renal tubular resorption of phosphate and elevated serum calcitriol10	Normal serum calcium, elevated serum phosphate, renal tubular resorption of phosphate, and serum calcitriol; normal dynamic response to parathyroid hormone in proximal renal tubule10	Elevated serum phosphate, renal tubular resorption of phosphate, and serum calcitriol; calcium variable depending on underlying condition10
Genetics	None initially evident10; recently, familial cases (SAMD9)6	AD with variable expressivity or AR, GALNT3, FGF231, KLOTHO6	Depends on underlying condition; overall strong familial association
Treatment	Low recurrence with complete resection, high recurrence with partial resection unless using a low calcium/low phosphorus diet and oral aluminum hydroxide10/phosphate binders	High recurrence after partial or complete resection; limited benefit of low calcium/low phosphate diet or oral aluminum hydroxide10/phosphate binders	Poor response to complete or partial resection; low calcium/low phosphate diet and oral aluminum hydroxide/phosphate binders are beneficial; treating underlying condition may result in resolution of calcifications10

CLINICAL QUESTIONS

1. A 12-year-old boy of African descent with no past medical history complains of right hip and buttock pain with no known trauma. Palpation demonstrates a hard mass. Radiographs demonstrate periarticualar lobular calcification centered over the greater trochanter. MRI shows no enhancing soft tissue mass. There is a hypointense calcified mass in the subcutaneous fat with intervening cystic spaces and no osseous involvement. What is the next best step in the workup?

   1. Biopsy

   2. Surgical resection

   3. Serum calcium, phosphorus, calcitriol, renal function tests, parathyroid hormone

   4. Serum calcium, urine calcium, parathyroid hormone

2. TC is commonly located

   1. In the synovial space

   2. Near joints but not within joints

   3. In and around the spine

   4. In malignant tumors

Answers are provided at the end of the article.

DISCUSSION

TC is a rare disease that occurs in adolescents or young adults, more often in the African-descent population.^1,2 It is a systemic disorder that presents as slow-growing, firm, mobile, massive periarticular calcinosis due to phosphate dysregulation.³ It typically occurs in periarticular soft tissues of large joints including the hip, elbow, shoulder, foot, and wrist, where it can cause pain if impinging on a nerve, cause swelling, and interfere with range of motion of the nearby joint.¹ It is rarely seen at the knee and has not previously been described along the ACL. It tends to be superficial and multifocal, but rarely involves the bone or joint space.^1,4,9 Inclan first coined the term TC and differentiated it from dystrophic and metabolic calcification.² Hyperphosphatemic TC, normophosphatemic TC, and secondary causes¹⁰ can usually be discerned with history and biochemical analysis (serum calcium, phosphorus, calcitriol, parathyroid hormone, and renal function tests)⁶ (Table 1). If serum calcium and phosphorus are normal, connective tissue disease can be excluded with a negative antinuclear, anti-Smith, anti-centromere, and anti-scleroderma antibody profile.⁶

Our patient was diagnosed with autosomal recessive hyperphosphatemic familial TC. In this case we document imaging progression of this lesion into an aggressive, intracapsular, extrasynovial calcified mass with osseous involvement. In the early stage it mimicked osteochondritis dissecans, which is a common cause of pediatric knee pain. Later it mimicked an aggressive chondroid lesion. Unique clinical and imaging features of this case include monoarticular knee involvement, intra-articular and extrasynovial location with extension along the ACL, lack of cysts on MRI, and osseous involvement. The only other known case report of intra-articular TC of the knee was located in Hoffa’s fat pad, which is intracapsular but extrasynovial and was treated with resection with no known recurrence over 8 months.⁴ Slavin suggested that lack of cysts corresponds with a histologically quiescent lesion that may respond more favorably to resection.⁹ Despite lack of cysts, our case was invasive and progressive. Some authors state that lack of osseous involvement is a hallmark,¹ whereas others mention erosion is rare but possible.^3,5,11

This case demonstrates that TC is a rare cause of a calcified intra-articular, extrasynovial soft tissue mass associated with the ACL. Primary differential considerations for a calcified periarticular soft tissue mass on a pediatric knee radiograph include chondroblastoma, osteochondroma, calcific tendinitis, synovial chondromatosis, synovial sarcoma, osteosarcoma, myositis ossificans, and TC. To attempt differentiation, computed tomography (and perhaps radiographs) can be used to classify the calcification, and MRI can be used to define the anatomical location, involved structures, and whether a mass is present. A strategy for differentiation is outlined in Table 2.

Table 2.

Differential diagnosis for pediatric periarticular mineralization

Diagnosis	Mineralization	Location	Bone involvement	Tips
Tumoral calcinosis	Lobulated mineralization with fluid levels	Soft tissue near joints, often bursal distribution and extensor surfaces	Rarely erosions	Look for fluid levels, lack of enhancing mass
Myositis ossificans	Amorphous with lucent center, becoming ossific over week-months3	Location of trauma or peri-articular in those with neurologic deficits3	Rarely adherent to bone3	Usually in muscle, parallel to bone; observe radiographically over weeks since edema on MRI can be confusing3
Calcific tendonitis	Hydroxyapatite deposition3	Along tendons, sometimes soft tissue, bursae, joint capsule involved3	Rare and appears very aggressive on MRI when present3	Rare in children; correlate MRI with CT for tendon distribution3
Chondroblastoma	Chondroid; ring and arc	Epiphyses and equivalents; knee is common	Yes, marrow soft tissue mass and edema	Epiphyseal location, chondroid calcification, edema, effusion common
Osteochondroma	Chondroid at tip is variably seen	Usually metaphyses; rarely epiphyses and equivalents	Yes, arises from bone	When metaphyseal it is contiguous with the marrow cavity and cortex; when epiphyseal the chondroid calcification is encased in or protrudes from the epiphyseal cartilage
Osteosarcoma	Osteoid; cloud-like	Usually in bone, occasionally surface, rarely extraskeletal	Yes, if in bone or surface, variable for extraskeletal	Soft tissue mass present
Synovial chondromatosis	Chondroid; ring and arc or peripheral mineralization of small nodules3	Within synovial space of joint, tendon sheath, or bursa3	Variable; may peripherally erode the bone3	Rare in children
Synovial sarcoma	Punctate or lobular1	Soft tissue near but not within the joint space	Variable; none, erosion, periosteal reaction, invasion1	Soft tissue mass present

Resection is the treatment of choice, particularly if the mass is symptomatic and impedes range of motion or limits joint functionality. Variable recurrence after surgical resection depends on the type of TC (Table 1). Reducing serum phosphate with diet and phosphate binders has variable success alone and is most successful in conjunction with resection.^6,10

Imaging is often performed for symptoms prior to TC diagnosis or labs. The radiologist should look for typical and atypical findings to move TC up on the differential. Multifocality and cysts with calcium and/or hemorrhage make TC more likely³ but were not present in this case. TC is typically near but not in joints^1,3,6,11; the ACL is intra-articular but still extrasynovial and TC could therefore be included in the differential diagnosis.⁴ Lack of noncalcified enhancing soft tissue elements helps distinguish TC from synovial sarcoma, extraskeletal osteosarcoma, and chondrosarcoma.³ Osseous erosion is quite rare but can occur.^3,5,11 Once suspected, appropriate labs and history can discriminate between the types and guide treatment.

ANSWERS TO CLINICAL QUESTIONS

Question 1, c. The history, physical exam, and imaging findings are typical of TC. There is no medical history of renal failure, connective tissue disease, or malignancy. Since the findings are typical of TC, serum calcium, phosphorus, and calcitriol will help confirm the diagnosis and differentiate between the hyperphosphatemic form and the normophosphatemic form. Normal renal function tests and parathyroid hormone exclude many secondary causes. If calcium and phosphorus are normal, consider laboratory tests for connective tissue disease. Biopsy is acceptable if the diagnosis is still unclear after noninvasive evaluation. Surgical resection is warranted for symptomatic calcifications, especially if they are not responsive to medical and dietary management.⁶

Question 2, b. TC has not been reported in the synovial space. It is most commonly near joints on the extensor surfaces. Only this report and one other describes an intra-articular/extrasynovial location. Spinal TC is rare. Cacification in a maligancy is secondary to the malignancy rather than primary TC.¹

Disclosure statement/Funding

The planners and faculty for this activity have no relevant financial relationships to disclose. The authors report no funding. The patient and the patient’s father consented to publication of this case report.