Tophaceous pseudogout (tumoral calcium pyrophosphate dihydrate crystal deposition disease)

Tophaceous Pseudogout (Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition Disease) TSUYOSHI ISHIDA, MD, HOWARD D, DORFMAN, MD, AND PETER G, BULLOUGH, MB, CHB Most cases of calcium deposition seen radiologically in soft tissues are caused by calcium hydroxyapatite and occur either as a complication of trauma with associated necrosis (eg, fat necrosis), generalized connective tissue diseases (eg, scleroderma), metabolic disturbances (eg, hyperparathyroidism, familial hyperphnsphatemia), sarcoidosis, myeloma, or metastases. Hydroxyapatite deposits are seen at many soft tissue sites, including joint capsules, ligaments, blood vessels, dermis, etc. On the other hand, deposits of calcium pyrophosphate are seen typically in the meniscus, articular cartilage, ligamentum flavum, and intervertebral disc. They usually are punctate or linear in distribution within the meniscus or parallel to the subchondral bone end plate. We report seven cases of massive focal calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (tophaceous pseudogout) that occurred in atypical locations for CPPD. The ages of the patients ranged from 31 to 86 years (average, 60.7 years). One patient was male and six were female. The temporomandibular joint was involved in three patients and the metatarsophalangeal joint of the great toe was involved in two patients. The hip joint and cervical spine were involved in one patient each. A mass or swelling with or without pain was a common symptom. None of the patients in our series had clinical or radiographic evidence of CPPD

Calcium pyrophosphate dihydrate (CPPD) crystals were first identified in 1962 in the synovial fluid of patients who had gout-like symptoms without sodium urate crystals; consequently, this entity was designated as pseudogout by McCarty et al. 1-3 The term "chondrocalcinosis" was independently applied by Zitnan and Sit'aj 4 for the condition radiographically characterized by multiple foci of calcification in hyaline and fibrocartilage both of the joints and of the intervertebral discs. Recently, the disease has been designated as CPPD crystal deposition disease, this being a more appropriate description of the condition. The term encompasses pseudogout, chondrocalcinosis, and pyrophosphate arthropathy. 5-7 Most cases of CPPD crystal deposition disease are asymptomatic. We report seven cases of a variant of CPPD crystal deposition disease, ie, tophaceous pseudogout. Deposition of CPPD commonly occurs in the articular and From the Section of Orthopedic Pathology, Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, and the Department of Pathology, The Hospital for Special Surgery, New York, NY. Dr Ishida is a Visiting Research Fellow at Montefiore Medical Center supported by Japan Society for the Promotion of Science, Postdoctoral Fellowships for Research Abroad, Tokyo, Japan. Accepted for publication August 10, 1994. Address correspondence and reprint requests to Howard D. Dorfman, MD, Section of Orthopedic Pathology, Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St, Bronx, NY 10467-2490. Copyright © 1995 by W.B. Saunders Company 0046-8177/95/2606-000155.00/0

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crystal deposition disease in any other joints. Roentgenograms showed calcified lesions with a granular or fluffy pattern. Histologically, the lesions showed small or large deposits of intensely basophilic calcified material containing needle shaped and rhomboid crystals with weakly positive birefringence characteristic of CPPD. Foreign body granulomatons reaction to the CPPD deposition was constantly found. Chondroid metaplasia around and in the areas of CPPD deposition was observed commonly. Some of the chondroid areas showed cellular atypia in chondrocytes suggestive of a malignant cartilage tumor. It is important to recognize this rare form of CPPD crystal deposition disease and to identify the CPPD crystals in the calcified deposits, thus avoiding the misdlagnosis of benign or malignant cartilaginous lesions. HLrM PATHOL 26:587--593. Copyright © 1995 by W.B. Saunders Company Key words: tophaceons pseudogont, tumoral calcimn pyrophosphate dihydrate crystal deposition disease, pseudotumor, chondrosarcoma. Abbreviations: CPPD, calcium pyrophosphate dihydrate; HE, hematoxylin-eosin; CT, computed tomography; MRI, magnetic resonance imaging; TMJ, temperomandibular joint.

para-articular tissuesa12; however, tophaceous pseudogout (tumoral or massive CPPD crystal deposition disease) in these tissues is rare. Because of its unusual location and histology, this condition may be misinterpreted both clinicoradiologically and pathologically as a benign or malignant cartilaginous lesion, especially chondrosarcoma.

MATERIALS AND METHODS Five cases of tophaceous p s e u d o g o u t 'tumoral CPPD crystal deposition disease) were retrieved f r o m the consultation files of one investigator (H.D.D.) and two cases were taken f r o m the consultation files of a n o t h e r investigator (P.G.B.). Hematoxylin-eosin ( H E ) - s t a i n e d slides were available for review in all cases. Histological slides f r o m all cases were studied by c o m p e n s a t e d polarized light microscopy to identify the birefringency of the crystalline material. Roentg e n o g r a p h s were available for review in six cases. C o m p u t e d tomography (CT) a n d / o r magnetic resonance imaging (MRI) scans also were available for review in three cases.

RESULTS

Clinical and Roentgenographic Features Clinical features of the patients with tophaceous pseudogout are summarized in Table 1. The ages of the patients ranged from 31 to 86 years (average, 60.7 years). One patient was male and six were female. The temporomandibular joint (TMJ) was involved in three patients and the metatarsophalangealjoint of the great

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TABLE 1. Summary of Clinical Data on Tophaceous Pseudogout Age at Patient Diagnosis No. (yr) Sex

Location

Symptoms

1

76

M

MTPJ, great toe Painful mass (2 yr)

2

47

F

TMJ

Mass (8 yr)

3

50

F

TMJ

Swelling (20 yr)

55

F

31

F

80

F

86

F

RadiographicAppearance

Treatment

Comment

Soft tissue calcification with degenerative changes of MTPJ Slightlycalcified lesion with pressure erosion of the mandibular condyle NA

Excision

Clinical diagnosis was tophaceous gout

Excision Excision

History of excision of TMJ tumor; re-excision of recurrent tumor 2 years later; initial diagnosis was chondroblastoma TMJ No symptoms Tumorous mass in the region Wide Preconsultation diagnosis was of infratemporal fossa; excision chondrosarcoma adjacent TMJ in MRI Hip Hip pain Soft tissue calcification Excision anterolateral to hip joint (1.5 V) C2-3vertebrae Progressive Tumor mass with spotty Excision Preoperative diagnosis was myelopathy calcification compressing chondroid chordoma spinal cord MTPJ,great toe Painful mass Calcified mass of the plantar Excision Clinical diagnosis was "calcified aspect of the MTPJ bursa"; preconsultation diagnosis was soft tissue chondroma

Abbreviations: MTPJ, metatarsophalangeal joint; NA, not available.

toe was involved in two patients. T h e hip j o i n t and cervical spine were involved in one patient each. Longstanding swelling of the affected area was n o t e d in two patients with TMJ involvement. Two patients had a painful mass of the great toe, which was clinically considered to be gouty tophus. O n e patient noticed increasing hip pain of 18 m o n t h s ' duration. Rapid progressive myelopathy at an u p p e r cervical level developed in a n o t h e r patient. T h e other patient was asymptomatic and the lesion was discovered incidentally in imaging studies d o n e for other reasons. T h e r e was no patient in w h o m a serum calcium or p h o s p h a t e abnormality was noted. N o n e of the patients in our series had radiographic evidence of chondrocalcinosis or clinical symptoms in any other joints. Radiographically, the lesion a p p e a r e d as a slightly or densely calcified mass; the pattern of calcification was granular or fluffy (Figs 1 to 4). Unlike myositis ossificans, peripheral density was not observed. T h e b o n e adjacent to the calcified mass showed pressure erosion in some cases. T h e calcification itself and its pattern were d e m o n s t r a t e d well in the available CT scans.

Pathological Features Grossly, the lesion was a circumscribed whitish-gray mass with a m o r e or less chalky appearance. T h e sizes of the lesions in o u r series ranged f r o m 2 to 4 cm (Fig 5). Histologically, the lesion consisted of cellular or less cellular tissues containing small to large islands of intensely basophilic calcified crystalline material (Fig 6). The crystals were r h o m b o i d or even needle shaped, similar to urate crystals. U n d e r c o m p e n s a t e d polarized light microscopy, the crystals exhibited the weak posi-

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tive birefringence characteristic of CPPD (Fig 7). T h e cellular tissues contained large n u m b e r s of histiocytes and foreign body type giant cells surrounding the calcified areas, representing a foreign body granulomatous reaction (Fig 8), whereas the less cellular tissues consisted of metaplastic c h o n d r o i d tissues (Fig 9). T h e c h o n d r o i d cells in three patients were atypical with variable nuclear size and shape mimicking a malignant cartilage t u m o r (Fig 10). T h e c h o n d r o i d cells were f o u n d b o t h in and a r o u n d the calcified areas. In three patients the histological sections were available for review f r o m b o t h decalcified and undecalcified material (Figs 6 t h r o u g h 8). T h e CPPD crystals were removed by decalcification and their basophilic features in HE stain were lost (Fig 11). A m o r p h o u s intercellular matrix, somewhat similar to the chondroid matrix, was left b e h i n d in the areas of CPPD deposition. T h e preconsultation diagnoses in our seven patients (Table 1) included two malignant tumors, chondrosarcoma, and c h o n d r o i d c h o r d o m a , as well as benign lesions, soft tissue c h o n d r o m a , and chondroblastoma.

DISCUSSION T h e clinical manifestations of CPPD crystal deposition disease vary widely. Many are f o u n d incidentally and may be asyrnptomafic. 7 In symptomatic patients the symptoms suggest pseudogout, p s e u d o r h e u m a t o i d arthrifts, pseudo-osteoarthritis with or without acute inflammatory episodes, and p s e u d o n e u r o p a t h i c joints 5'6 as well as the solitary tophaceous deposits described in this article. T o p h a c e o u s p s e u d o g o u t is one of the rarest clinical forms of CPPD crystal deposition disease. A total of 29 cases of tophaceous pseudogout (tu-

TOPHACEOUS PSEUDOGOUT (Ishida et ai)

tients. The most c o m m o n pattern of bony involvement of tophaceous pseudogout was pressure erosion. The most c o m m o n symptom was a painless mass or swelling f o u n d in 15 patients. A mass with pain was reported in nine patients with tophaceous pseudogout, six of whom had reported acute attacks similar to those occuring in tophaceous gout. In the case of tophaceous pseudogout involving the spine (as in our patient no. 6), neurological disturbances may develop as initial symptoms. Several examples of cervical radiculomyelopathy caused by CPPD deposition in the ligamentum

FIGURE 1. Dorsoplantar radiograph of the right foot showing soft tissue mass with calcification surrounding the first metatarsophalangeal joint of the great toe (patient no. 7).

moral or massive CPPD crystal deposition disease), including those in our series, have been reported, a~34 One example of tophaceous pseudogout occurring in a dog also was reported. 35 Almost all of these examples appeared as single case reports. Based on the data in the reported cases with tophaceous pseudogout, including those in our series, the following features were disclosed. Tophaceous pseudogout mainly affects middle aged and elderly patients (average age, 59.7 years). T h e r e is a female p r e d o m i n a n c e (the male to female ratio is 1 to 1.9). N o n e o f the patients had familial CPPD crystal deposition disease or other associated metabolic disorders. T h e most c o m m o n anatomic location was the TMJ joint (10 patients), followed by the finger (six patients) and toe (three patients). The wrist, hip, and cervical spine were involved twice each, and the shoulder, elbow, hand, and knee were involved in one patient each (Table 2). The skeletal distribution of tophaceous pseudogout differs from that of the c o m m o n forms of CPPD crystal deposition disease in which the knee and wrist are the most frequently affected joints. 1°'11 Radiographic evidence of other joint involvement by CPPD crystal deposition disease in the patients with tophaceous pseudogout was f o u n d in five of 24 patients for whom the information was available. 14 ' 18 '20 '23 '32 Involvem e n t of the adjacent bone was noted in 18 of 28 pa-

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FIGURE 2. (A) Anteroposterior radiograph of the right hip showing a calcified soft tissue mass (arrow) adjacent to the acetabular margin. (B) Calcified soft tissue mass (arrow) of the anterolateral aspect of the right hip joint in an axial CT scan (patient no. 5).

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seen in chondrosarcoma. A foreign body type granulomatous reaction containing histiocytes and giant cells is a helpful finding to distinguish it from chondrosarcoma. More important, however, is the identification by polarized light microscopy of birefringent crystals characteristic of CPPD. The exact nature of these crystals can be determined by radiographic diffraction or electron probe analysis. Even in the decalcified sections empty outlines of crystals in the chondroid matrix can be seen, although birefringent crystals are not identified directly. Synovial chondromatosis and soft tissue chondromas are the other lesions that can be confused with tophaceous pseudogout, especially those in which heavily calcified cartilage matrix may obscure their cartilaginous n a t u r e Y However, the calcified areas of synovial FIGURE 3. Axial view of T2-weighted MRI scan demonstrates a tumorous mass (arrows) of the infratemporal fossa adjacent to the right temporomandibular joint (patient no. 4).

flavum have been reported, se~3s The crystal deposits in these patients, however, measured less than 1 cm in size. The critical location of a CPPD deposit plays an important role in the development of neurological symptoms in these patients. Tophaceous pseudogout may recur after complete or incomplete surgical excision. Six cases recurring 11 months to 6 years after surgery have been reported. 14' 17 .19. . 2431 . 33 Multiple recurrences (three times) were noted in one patient. 14 One of the patients in our series also developed recurrences on two occasions during a 20-year span. The clinical and radiographic features of the reported patients with tophaceous pseudogout initially led to the consideration of a malignant tumor in 14 patients (Table 3). Seven of these instances of tophaceous pseudogout were dia nosed as or suspected of being chondrosarcomas. 13 '20-~4 " '30 For some patients the preoperative misdiagnosis led to more radical surgery than was appropriate. To avoid unnecessary radical treatment, it is of the utmost importance to be aware that tophaceous pseudogout may present as a calcified soft tissue mass with or without b o n e erosion, suggesting a malignant soft tissue tumor. Histologically, c h o n d r o i d metaplasia in and a r o u n d the areas of CPPD deposition was found in 15 patients with tophaceous pseudogout. Metaplastic chondrocytes could play an important role in the initial precipitation of CPPD crystals, 39'4° and synovial chondrometaplasia was observed in five of 12 patients with pyrophosphate arthropathy. 41 The metaplastic chondrocytes found in our series of patients sometimes showed cytological atypia (three patients) analogous to that seen in some patients with synovial chondromatosis, which superficially resembled chondrosarcoma. Particularly in decalcified sections from which CPPD crystals are lost, atypical features in metaplastic chondrocytes may lead to the histological misdiagnosis of chondrosarcoma. 41'42 Grossly, tophaceous pseudogout is a calcified chalky mass unlike the calcification

590

FIGURE 4. (A) Axial CT scan at the C1-C2 junction demonstrating extradural calcific mass compressing the thecal sac (arrows). (B) Sagittal MRI scan shows a large anterior extradural mass at the cranioveffebral junction causing posterior displacement and kinking of the spinal cord at this level (arrowhead) (patient no. 6).

TOPHACEOUS PSEUDOGOUT (Ishida et ai)

FIGURE 5. Cut surface of the excised mass from patient no. 7 shows solid, whitish, chalky appearance.

FIGURE 6. Islands of basophilic calcified crystalline material in metaplastic chondroid tissue. (Hematoxylin-eosin stain; original magnification ×200.)

FIGURE 8. Foreign body granulomatous reaction around basophilic calcified deposits. (Hematoxylin-eosin stain; original magnification x200.)

FIGURE 9. An area of chondroid metaplasia with focal deposits of crystalline material. (Hematoxylin-eosin stain; original magnification ×200.)

FIGURE 10. Atypical chondrocytes can be seen in the metaplastic cartilage. (Hematoxylin-eosin stain; original magnification x400.)

FIGURE 7. Rhomboid and needle shaped crystals exhibiting positive birefringence under compensated polarized light microscopy (bar : 100 #m).

591

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Volume 26, No. 6 (June 1995) TABLE 3. Suggested Preoperative Diagnoses in Reported Cases of Tophaceous Pseudogout

FIGURE l l . Decalcified section shows Iobular arrangement of chondromyxoid matrix with atypical chondroid cells mimicking chondromyxoid fibroma or chondrosarcoma. Note the loss of basophilia at the site of crystalline material removed by decalcification (arrows). (Hematoxylin-eosin stain; original magnification × 100.)

chondromatosis do not contain the rhomboid crystals characteristic of CPPD deposition. Indeed, radiographic diffraction studies in both synovial chondromatosis and soft tissue chondroma show that the mineral deposits represent hydroxyapatite. A peculiar case of soft tissue chondroma of the finger with deposition of CPPD crystals in a 67-year-old woman has been reported. 44 The patient had a strong family history of osteoarthritis, and the patient herself also suffered from osteoarthritis of multiple joints, including the lumbar spine, shoulder, elbow, wrist, hand, and knee, considered to be CPPD arthropathy. This single case report emphasizes the rarity of the two lesions coexisting. That a number of the reported cases have involved the TMJ (Table 2) has raised the question of synovial chondromatosis in the differential diagnosis because that entity is known to involve this site as well. Identification of the characteristic positively birefringent rhomboid and needle-like crystals that are not found in synovial chondromatosis will exclude that possibility. Tophaceous gout and tophaceous pseudogout may share some clinical manifestations; however, radiographic calcification in gouty tophi is a relatively uncommon finding. 45Identification of the specific positive

TABLE 2.

Anatomic Locations of Reported Cases of Tophaceous Pseudogout

Anatomic Location Temporomandibularjoint Finger Toe Cervical spine Wrist Hip Shoulder Elbow Hand Knee

Number of Cases (%) 10 6 3 2 2 2 1 1 1 1

(34.5) (20.7) (10.3) (6.9) (6.9) (6.9) (3.4) (3.4) (3.4) (3.4)

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Diagnosis

No. of Cases

Malignant tumor Chondrosarcoma Parosteal osteosarcoma Chordoma Malignant tumor, NOS Benign tumor Osteochondroma Chondroma Chondroblastoma Tumor, NOS Tumoral calcinosis Tophaceous gout Synovial chondromatosis Calcified bursa

13 (8) (3) (2) (4) 5 (2) (2) (1) 3 4 2 1 1

Abbreviation: NOS, not otherwise specified.

b i r e f r i n g e n c e o f c a l c i u m p y r o p h o s p h a t e crystals is the key to the differential diagnosis b e t w e e n these two entities. T u m o r a l calcinosis is a n o t h e r entity c a u s i n g differential diagnostic p r o b l e m s . U n l i k e t o p h a c e o u s pseud o g o u t , t u m o r a l calcinosis m a i n l y affects y o u n g , black individuals a n d o f t e n is associated with a family history o f t u m o r a l calcinosis a n d with h y p e r p h o s p h a t e m i a . 46 T h e calcified m a t e r i a l i n t u m o r a l calcinosis shows a n a m o r p h o u s , g r a n u l a r a p p e a r a n c e , lacks crystalline structure, a n d is c o m p o s e d m a i n l y o f hydroxyapatite. 47As

Acknowledgment. We thank the following individuals for referring cases: R.N. Fredreicks, MD, R. Lattes, MD, A.R. von Hochstetter, MD, M.P. Bronner, MD, and D. Watkins, MD. We also thank D. Crawley for typing the manuscript. REFERENCES 1. McCarty DJ, Hollander JL: Identification of urate crystals in gouty synovialfluid. Ann Intern Med 54:452460, 1961 2. McCarty DJ, Kohn NN, FairesJS: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: The "pseudogout syndrome." I. Clinical aspects. Ann Intern Med 56:711737, 1962 3. Kohn NN, Hughes RE, McCarty DJ, et al: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: The "pseudogout syndrome." II. Identification of crystals. Ann Intern Med 56:738-745, 1962 4. Zitnan D, Sit'aj S: Chondroealcinosis articularis. Section I. Clinical and radiological study. Ann Rheum Dis 22:142-152, 1963 5. McCartyDJ: Calcium pyrophosphate dihydrate crystal deposition disease--1975. Arthritis Rheum 19:275-285, 1976 6. McCarty D: Crystals,joints, and consternation. Ann Rheum Dis 42:243-253, 1983 7. Resnick D, Niwayama G: Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, in Resnick D, NiwayamaG (eds): Diagnosis of Bone and Joint Disorders (ed 2). Philadelphia, PA, Saunders, 1988, pp 1672-1732 8. Martel W, Champion CK, Thompson GR, et al: A roentgenologicallydistinctive arthropathy in some patients with the pseudogout syndrome. Am J Roentgenol 109:587-605, 1970 9. Ellman MH, Krieger MI, Brown N: Pseudogout mimicking synovial chondromatosis. J Bone Joint Surg [Am] 57:863-865, 1975 10. Resnick D, Niwayama G, Goergen TG, et al: Clinical, radiographic and pathologic abnormalities in calcium pyrophosphate dihy-

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