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Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
PATHOLOGY
Original Paper
RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp
Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition Disease A Clinicopathologic Analysis of Five Cases Koji Yamakawa1, Hiroshi Iwasaki1, Yuko Ohjimi1, Masahiro Kikuchi1, Akinori Iwashita2, Teruto Isayama3, and Masatoshi Naito3 The First Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan; 2 Department of Pathology, Chikushi Hospital, Fukuoka University, Fukuoka, Japan; 3 Department of Orthopaedic Surgery, Fukuoka University School of Medicine, Fukuoka, Japan 1
Summary We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm). Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCD including our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with Pathol. Res. Pract. 197: 499–506 (2001)
acute attack similar to tophaceous gout. Tumoral CPPDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors. Key words: Tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) – Chondrosarcoma – Gout – Calcinosis
Introduction Calcium pyrophosphate dihydrate (CPPD) crystals were first identified in 1962 in the synovial fluid of patients with gout-like symptoms without sodium urate crystals. Consequently, this entity was designated as pseudogout by McCarty et al. [17, 27, 28]. The term “chondrocalcinosis” was independently applied by Zitnan and Sit’aj [37] for the condition radiographically characterized by multiple foci of calcification in hyaline and fibrocartilage of the joints and intervertebral discs. Recently, the disease has been more appropriately designated as CPPD crystal deposition disease (CPPDCD). The term encompasses pseudogout, chondrocalcinosis, and pyrophosphyte arthropathy [25, 26, 31]. Address for correspondence: Koji Yamakawa, The First Department of Pathology, Fukuoka University School of Medicine, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. Phone: +81 (92) 801-1011, Fax: +81 (92) 861-7300. E-mail address: [email protected] 0344-0338/01/197/7-499 $15.00/0
500 · K. Yamakawa et al.
Although diffuse or nontumoral deposition of CPPD commonly occurs in articular and para-articular tissues [7, 8, 23, 24, 32], massive or tumoral deposits of CPPD in these tissues are very rare. At present, only 49 cases of tumoral CPPDCD have been reported in the literature. 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. In this report, we describe five cases of tumoral CPPDCD to further clarify the clinicopathologic features of this entity.
Material and Methods Histologic sections from five patients with tumoral CPPDCD were selected from the files of the bone and soft tissue tumors collected from 1989 to 2000 in the First Department of Pathology, Fukuoka University. Four cases of tumoral CPPDCD were retrieved from the consultation files of one of the authors (H.I.), and the remaining case came from the files of ordinary surgical specimens maintained at our institution. Formalinfixed and paraffin-embedded tissue samples were obtained from all five patients. Hematoxylin and eosin-stained slides were prepared for histopathologic review in each case. These slides were examined by compensated polarized light microscopy to identify the birefringence of the crystalline material. Roentgenographs were available for review in each case. Magnetic resonance images (MRI) were available in one case.
Results Clinical and roentgenographic features
The clinical features of patients with tumoral CPPDCD are summarized in Table 1. Four patients were males
and one was female, with a median age of 63 years (range, 49–70 years). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in each of one patient. Each case presented with a slowly growing periarticular swelling. The duration of this symptom ranged from 6 months to 4 years (median, 1 year). Although the wrist or hand swelling was painful in three patients, the condition was not clinically considered to be gouty tophus because of the lack of redness and local heat. Serum calcium and phosphate levels were within the normal range in each patient. Radiographically, in four lesions, a well-defined calcified mass was noted, which did not expand or erode the cortex (Fig. 1). One patient (Case 1) showed a well defined but irregularly dense calcified mass on the ulnar aspect of the right wrist (Fig. 2). This case had been diagnosed as chondrosarcoma before surgery. MRI was carried out on one patient (Case 3). The low-intensity signal of a mass seen on the T1-weighted coronal image (TR/TE, 550/38) was lower than that of the surrounding muscle (Fig. 3A). On T2-weighted axial image (TR/TE, 2100/38), the mass appeared as a mixture of high- and iso-intensity signals (Fig. 3B). Pathological features
Gross examination of each lesion showed a circumscribed whitish-gray mass with a more or less chalky appearance. The size of the lesion ranged from 1.0 to 6.2 cm (median, 2.5 cm, Table 1). Histopathologically, each lesion contained irregular massive deposits of CPPD crystals which were bordered by fibrous connective tissue presenting a lobulated or multinodular
Fig. 1. X-ray showing a well-defined calcified mass in the ulnar aspect of the left thumb (Case 3). Fig. 2. X-ray showing a well defined, but irregularly dense calcified mass on the ulnar aspect of the right wrist (Case 1). A provisional diagnosis of chondrosarcoma was made preoperatively.
Tumoral CPPDCD · 501 Table 1. Clinicopathological characteristics of five cses with tumoral CPPD Case Age Sex Site (yrs)
Size (cm)
1 2
65 70
M M
3 4
63 52
M M
5
49
F
Ulnar side of right wrist Palmar side of proximal phalanx of left middle finger Ulnar side of left thumb Dorsum of carpal bone of right hand Palm of left wrist
Symptoms
Duration of mass (yrs)
Rhomboid crystals
Needleshaped crystals
Chondro- Giant metacells plasia
6.2 × 3.7 Tumor, pain 2.5 × 1.0 Tumor
1 4
++ +
+ –
+++ ++
+++ ++
2.7 × 2.2 Tumor 1.0 × 1.0 Tumor, pain
1 0.5
++ ++
+ +
++ ++
+++ +
1.2 × 0.8 Tumor, pain
2
+++
+
+++
++
– no; + few; ++ moderate; +++ abundant
pattern (Fig. 4). Many crystals exhibited a rhomboid configuration characteristic of CPPD, but there were also some needle-shaped ones resembling urate crystals (Fig. 5). Under polarized light microscopy with a red compensator, the crystals showed weakly positively birefringence, indicative of CPPD (Fig. 6). The number of crystals varied from one lesion to another and in different areas of the same lesion. The crystals were often embedded in a background of an amorphous pale substance reminiscent of a chondroid matrix. In addition, CPPD crystals were often admixed with a basophilic granular substance, the feature being suggestive of coexistence of calcium hydroxyapatite. One of the lesions showed a large amount of intensely basophilic deposits, indicative of a high concentration
of hydroxyapatite in the matrix (Fig. 7A and B). In all cases, varying amounts of metaplastic cartilage (chondroid metaplasia) were found in and around the areas of CPPD deposition (Fig. 8A). The cartilaginous cells in most lesions showed no evident cellular atypia, whereas one lesion, which had been suspected clinically as chondrosarcoma (Case 1), exhibited proliferation of mildly atypical chondrocytes with swollen nuclei and sometimes prominent nucleoli (Fig. 8B). Foreign body granulomatous reaction was found in all cases. Aggregates of histiocytes and foreign body type giant cells, together with lymphoid cells and occasional neutrophils, were found around the CPPD deposits and in the fibrous stroma between the deposits (Fig. 9).
Fig. 3. (A) T1-weighed coronal image shows a mass of a slightly less intense signal than adjacent muscle (Case 3). (B) A mass with a mixture of high- and iso-intensity signals is shown by T2-weighted axial image (Case 3).
502 · K. Yamakawa et al.
Fig. 4. Low magnification of a tumoral calcium pyrophosphate dehydrate (CPPD) crystal deposition disease. The lesion shows irregular massive deposits of CPPD crystals bordered by a fibrous connective tissue presenting a lobulated or multinodular pattern (Hematoxylin and eosin, ×24).
Fig. 5. (A) A high magnification of one of the multinodular deposits, showing crystals embedded in a background of an amorphous pale substance surrounded by fibrous tissue (Hematoxylin and eosin, ×47). (B) Same area of specimen shown in (A), examined under polarized light, revealing one nodular deposit of numerous crystals (Hematoxylin and eosin, ×47). (C) Under high-power examination, many crystals exhibit a rhomboid configuration characteristic of CPPD, but note also the presence of some needle-shaped ones, resembling urate crystals under polarized light (Hematoxylin and eosin, ×490).
Tumoral CPPDCD · 503
Fig. 6. Polarizing light microscopy used with a red compensator to demonstrate the presence of weakly positively birefringent crystals. (A, B) hematoxylin and eosin stain, ×710. (C, D) hematoxylin and eosin stain, ×410.
Fig. 7. (A) The lesion shows massive deposition of intensely basophilic calcified deposits indicative of a high concentration of hydroxyapatite, arranged in multinodular configuration (Hematoxylin and eosin, ×15). (B) High magnification of some of the multinodular deposits, showing intensely basophilic calcified deposits indicative of a high concentration of hydroxyapatite, surrounded by fibrous tissue (Hematoxylin and eosin, ×34).
504 · K. Yamakawa et al.
Fig. 8. (A) Metaplastic cartilaginous cells are seen in this lesion. The cartilaginous cells show no atypical features (case 5, Hematoxylin and eosin, ×70). (B) Mildly atypical chondrocytes with swollen nuclei and sometimes prominent nucleoli can be seen in the metaplastic cartilage (case 1, Hematoxylin and eosin, ×70).
Fig. 9. Aggregates of histiocytes and foreign body type giant cells together with lymphoid cells are found around the CPPD deposits (Hematoxylin and eosin, ×670).
Discussion The clinical manifestations of CPPDCD vary widely. Many cases are found incidentally and may be asymptomatic [31]. In symptomatic patients, the lesions may
be misdiagnosed as pseudorheumatoid arthritis, pseudoosteoarthritis or pseudoneuropathic joints [25, 26]. Tumoral CPPDCD is one of the rarest clinical forms of CPPDCD. Based on a review of the reported cases, including the present series, a total of 54 cases of tumoral CPPDCD have been described [1, 3–5, 9, 10,12–14, 16, 18, 19, 21, 22, 29, 30, 33–36, 38]. Many of these examples appeared as single case reports. Analysis of the data available in the reported cases of tumoral CPPDCD indicated that the condition occurs in patients with a median age of 60 years (range, 31–90 years), and mostly in females (male:female ratio = 1:1.7). The anatomical distribution of tumoral CPPDCD differs from that of the common forms of CPPDCD in which the knee and wrist are the most frequently affected sites [8, 32]. The most common anatomic location of tumoral CPPDCD was the temporomandibular joint, followed by the cervical spine and hand (Table 2). Other less common locations included the hip, toe, wrist, shoulder, elbow, and parotid gland (Table 2). Based on the anatomic location of these lesions, we can divide the lesions into two categories: the central (head and neck) type, and the distal (extremity) type (Table 2). The presence of these two different types of CPPDCD has not been clearly recognized in previous reports. There were 33 cases of the central type and 21 cases of distal type. These two groups of CPPDCD were not different with respect to age and sex distributions, but showed different clinical symptoms. In the central type, the most common symptom was the presence of a painful mass, which was described in 15 pa-
Tumoral CPPDCD · 505 Table 2. Anatomic locations of reported cases* of tumoral CPPDCD, including our series Anatomic Location
Number of Cases (%)
Central (head and neck) type Temporomandibular joint Cervical spine Parotid gland Distal (extremity) type Upper extremities Hand Wrist Elbow Shoulder Lower extremities Toe Hip
33 20 12 1 21 15 10 2 1 2 6 3 3
Total
54 (100)
(61) (37) (22) (2) (39) (28) (18) (4) (2) (4) (11) (5.5) (5.5)
*[1, 3–5, 9, 10, 12–14, 16, 18, 19, 21, 22, 29, 30, 33–36, 38]
tients (46%), followed by neurological disturbances in 11 patients (33%). In the distal type, the most common symptom was a painless mass or swelling in 12 patients (57%), but no neurological signs were described, although 8 patients (38%) had an acute attack similar to that occurring in tophaceous gout. Involvement of the adjacent bone was noted in 18 (38%) patients. The most common pattern of bony involvement of tumoral CPPDCD was pressure erosion [14]. There are some discrepancies in sex distribution of patients and location of lesions between our cases and Ishida’s report [14]. Since the number of the analyzed cases was limited, further studies collecting large numbers of tumoral CPPDCD are required to resolve the issue. Histopathologically, metaplastic cartilage is often found in and around areas of CPPD depositions; these areas are surrounded by fibrous tissue with histiocytes, giant cells, and mononuclear cells. It has been suggested that metaplastic cartilaginous cells play an important role in the initial precipitation of CPPD [1, 15]. In our series, the number of crystals varied from lesion to lesion and in different areas of the same lesion. The crystals were often embedded in a background of an amorphous pale substance reminiscent of a chondroid matrix. In addition, the CPPD crystals were often admixed with a basophilic granular substance, this feature being suggestive of a coexistence of calcium hydroxyapatite. One of the lesions showed intensely basophilic deposits, indicative of a high concentration of hydroxyapatite in the matrix (Fig. 7). Although a destructive tophaceous calcium hydroxyapatite tumor indicative of weakly birefringent crystals has been reported [11], we consider that the intensely basophilic deposits in our case were mixed with CPPD and calcium hyddroxyapatite.
Tumoral CPPDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors. In gout, urate crystals are water-soluble and are not preserved in conventionally fixed histological sections [20]. In alcohol-fixed material, they appear as needle-shaped crystals easily distinguished from rhomboid crystals of CPPD. Tumoral calcinosis is another entity characterized by massive calcified deposits in soft tissues, often around major joints such as the hip and shoulder. It is predominant in adolescents and young adults, and is more often multiple than solitary. The calcified material in tumoral calcinosis lacks crystalline structures and is composed mainly of hydroxyapatite [2, 6]. The clinical and radiographic features of reported patients with tumoral CPPDCD initially led to a provisional diagnosis of malignant tumors in 14 patients. Seven of these cases were diagnosed as – or suspected of being – chondrosarcomas [14]. In some patients, the preoperative misdiagnosis resulted in more radical surgery than was appropriate. The metaplastic chondrocytes described by Ishida et al. [14] occasionally showed cytological atypia (3 of 7 patients) analogous to that seen in synovial chondromatosis, which superficially resembled chondrosarcoma. Metaplastic chondrocytes with cytological atypia were found in one of our cases. A foreign body-type granulomatous reaction containing histiocytes and giant cells is a helpful finding to differentiate tumoral CPPDCD from chondrosarcoma. More important, however, is the identification of birefringent crystals characteristic of CPPD. Empty outlines of crystals in the cartilaginous matrix can be seen, even if birefringent crystals are not identified. It is important to recognize the characteristic clinicopathologic features of tumoral CPPDCD in order to establish the correct diagnosis, which should then allow for appropriate treatment. Acknowledgement. We are grateful to the staff of the First Department of Pathology, Fukuoka University, for technical assistance, and to the following physicians for providing case material for our study: Dr. Takahide Kohzuma, Munakata, Fukuoka, Japan; Dr. Kenji Shitama, Maebaru, Fukuoka, Japan; Dr. Norio Ohnishi, Iyo, Ehime, Japan; Dr. Masanobu Oyama, Fukuoka, Japan; and Dr. Noriko Uesugi, the Second Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan.
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506 · K. Yamakawa et al. 3. Chuong R, Piper MA (1995) Bilateral pseudogout of the temporomandibular joint: report of case and review of literature. J Oral Maxillofac Surg 53: 691–694 4. de Vos RA, Brants J, Kusen GJ, Becker AE (1981) Calcium pyrophosphate dihydrate arthropathy of the temporomandibular joint. Oral Surg Oral Med Oral Pathol 51: 497–502 5. Dijkgraaf LC, De Bont LG, Liem RS (1992) Calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint: report of a case. J Oral Maxillofac Surg 50: 1003–1009 6. Dryll A, Bardin T, Lansaman J, Tran Van P, Bard H, Ryckewaert A, Cywiner Golenzer C (1984) Tumoral calcinosis: light and electron microscopic study with electron diffraction and X-ray microanalysis of the mineral deposits. J Submicrosc Cytol 16: 577–583 7. Ellman MH, Krieger MI, Brown N (1975) Pseudogout mimicking synovial chondromatosis. J Bone Joint Surg Am 57: 863–865 8. Fam AG, Topp JR, Stein HB, Little AH (1981) Clinical and roentgenographic aspects of pseudogout: a study of 50 cases and a review. Can Med Assoc J 124: 545–551 9. Fye KH, Weinstein PR, Donald F (1999) Compressive cervical myelopathy due to calcium pyrophosphate dihydrate deposition disease: report of a case and review of the literature. Arch Intern Med 159: 189–193 10. Good AE, Upton LG (1982) Acute temporomandibular arthritis in a patient with bruxism and calcium pyrophosphate deposition disease. Arthritis Rheum 25: 353–355 11. Grant GA, Wener MH, Yaziji H, Futran N, Bronner MP, Mandel N, Mayberg MR (1999) Destructive tophaceous calcium hydroxyapatite tumor of the infratemporal fossa: case report and review of the literature. J Neurosurg 90: 148–152 12. Gross BD, Williams RB, DiCosima CJ, Williams SV (1987) Gout and pseudogout of the temporomandibular joint. Oral Surg Oral Med Oral Pathol 63: 551–554 13. Hutton CW, Doherty M, Dieppe PA (1987) Acute pseudogout of the temporomandibular joint: a report of three cases and review of the literature. Br J Rheumatol 26: 51–52 14. Ishida T, Dorfman HD, Bullough PG (1995) Tophaceous Pseudogout (tumoral calcium pyrophosphate dihydrate crystal deposition disease). Hum Pathol 26: 587–593 15. Ishikawa K, Masuda I, Ohira T, Yokoyama M (1989) A histological study of calcium pyrophosphate dihydrate crystaldeposition disease. J Bone Joint Surg Am 71: 875–886 16. Kamatani Y, Tagawa T, Hirano Y, Nomura J, Murata M (1987) Destructive calcium pyrophosphate dihydrate temporo-mandibular arthropathy (pseudogut). Int J Oral Maxillofac Surg 16: 749–752 17. Kohn NN, Hughes RE, McCarty DJ Jr, Faires JS (1962) 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 18. Kokubun S, Ozawa H, Sakurai M, Tanaka Y (1996) Tumoral calcinosis in the upper cervical spine: a case report. Spine 21: 249–252 19. Lambert RG, Becker EJ, Pritzker KP (1990) Case report 597: calcium pyrophosphate deposition disorder (CPPD) of the right temporomandibular joint. Skeletal Radiol 19: 139–141 20. Lichtenstein L, Scott HW, Levin MH (1956) Pathologic changes in gout: survey of 11 necropsied cases. Am J Pathol 32: 871–895 21. Luisiri P, Blair J, Ellman MH (1996) Calcium pyrophosphate dihydrate deposition disease presenting as tumoral calcinosis (periarticular pseudogout). J Rheumatol 23: 147–1650
22. Magno WB, Lee SH, Schmidt J (1992) Chondrocalcinosis of the temporomandibular joint: an external ear canal pseudotumor. Oral Surg Oral Med Oral Pathol 73: 262–265 23. Martel W, Champion CK, Thompson GR, Carter TL (1970) A roentgenologically distinctive arthropathy in some patients with the pseudogout syndrome. Am J Roentgenol Radium Ther Nucl Med 109: 587–605 24. Martel W, McCarter DK, Solsky MA, Good AE, Hart WT, Braunstein EM, Brady TM (1981) Further observation on the arthropathy of calcium pyrophosphate crystal deposition disease. Radiology 141: 1–15 25. McCarty D (1983) Crystals, joints, and consternation. Ann Rheum Dis 42: 243–253 26. McCarty DJ (1976) Calcium pyrophosphate dihydrate crystal deposition disease-1975. Arthritis Rheum 19: 275–285 27. McCarty DJ, Hollander JL (1961) Identification of urate crystals in gouty synovial fluid. Ann Intern Med 54: 452–460 28. McCarty DJ, Kohn NN, Faires JS (1962) The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the “pseudogout syndrome.” I. Clinical aspects. Ann Intern Med 56: 711–737 29. Mogi G, Kuga M, Kawauchi H (1987) Chondrocalcinosis of the temporomandibular joint: calcium pyrophosphate dihydrate deposition disease. Arch Otolaryngol Head Neck Surg 113: 1117–1119 30. Pritzker KP, Phillips H, Luk SC, Koven IH, Kiss A, Houpt JB (1976) Pseudotumor of temporomandibular joint: destructive calcium pyrophosphate dihydrate arthropathy. J Rheumatol 3: 70–81 31. Resnick D, Niwayama G (1988) Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. In: Resnick D, Niwayama G (eds) Diagnosis of Bone and Joint Disorders. 2nd Ed, pp 1672–1732. Saunders, Philadelphia 32. Resnick D, Niwayama G, Goergen TG, Utsinger PD, Shapiro RF, Haselwood DH, Wiesner KB (1997) Clinical, radiographic and pathologic and abnormalities in calcium pyrophosphate dihydrate deposition disease (CPPD): Pseudogout. Radiology 122: 1–15 33. Rivera-Sanfeliz G, Resnick D, Haghighi P, Wong W, Lanier T (1996) Tophaceous pseudogout. Skeletal Radiol 25: 699–700 34. Vargas A, Teruel J, Trull J, López E, Pont J, Velayos A (1977) Calcium pyrophosphate dihydrate crystal deposition disease presenting as a pseudotumor of the temporomandibular joint. Eur Radiol 7: 1452–1453 35. Yu SL, Li RZ, Bian ZH (1992) Tumoral calcium pyrophosphate dihydrate deposition disease: report of a case with a review of the literature. Chin Med J Engl 105: 780–784 36. Zemplenyi J, Calcateterra TC (1985) Chondrocalcinosis of the temporomandibular joint: a parotid tumor. Arch Otolaryngol 111: 403–405 37. Zitnan D, Sit’aj S (1963) Chondrocalcinosis articularis. Section I. Clinical and radiological study. Ann Rheum Dis 22: 142–152 38. Zünkeler B, Schelper R, Menezes AH (1996) Periodontoid calcium pyrophosphate dihydrate deposition disease: “pseudo gout” mass lesions of the craniocervical junction. J Neurosurg 85: 803–809 Received: February 12, 2001 Accepted in revised version: March 21, 2001
Original Paper
RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp
Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition Disease A Clinicopathologic Analysis of Five Cases Koji Yamakawa1, Hiroshi Iwasaki1, Yuko Ohjimi1, Masahiro Kikuchi1, Akinori Iwashita2, Teruto Isayama3, and Masatoshi Naito3 The First Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan; 2 Department of Pathology, Chikushi Hospital, Fukuoka University, Fukuoka, Japan; 3 Department of Orthopaedic Surgery, Fukuoka University School of Medicine, Fukuoka, Japan 1
Summary We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm). Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCD including our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with Pathol. Res. Pract. 197: 499–506 (2001)
acute attack similar to tophaceous gout. Tumoral CPPDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors. Key words: Tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) – Chondrosarcoma – Gout – Calcinosis
Introduction Calcium pyrophosphate dihydrate (CPPD) crystals were first identified in 1962 in the synovial fluid of patients with gout-like symptoms without sodium urate crystals. Consequently, this entity was designated as pseudogout by McCarty et al. [17, 27, 28]. The term “chondrocalcinosis” was independently applied by Zitnan and Sit’aj [37] for the condition radiographically characterized by multiple foci of calcification in hyaline and fibrocartilage of the joints and intervertebral discs. Recently, the disease has been more appropriately designated as CPPD crystal deposition disease (CPPDCD). The term encompasses pseudogout, chondrocalcinosis, and pyrophosphyte arthropathy [25, 26, 31]. Address for correspondence: Koji Yamakawa, The First Department of Pathology, Fukuoka University School of Medicine, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. Phone: +81 (92) 801-1011, Fax: +81 (92) 861-7300. E-mail address: [email protected] 0344-0338/01/197/7-499 $15.00/0
500 · K. Yamakawa et al.
Although diffuse or nontumoral deposition of CPPD commonly occurs in articular and para-articular tissues [7, 8, 23, 24, 32], massive or tumoral deposits of CPPD in these tissues are very rare. At present, only 49 cases of tumoral CPPDCD have been reported in the literature. 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. In this report, we describe five cases of tumoral CPPDCD to further clarify the clinicopathologic features of this entity.
Material and Methods Histologic sections from five patients with tumoral CPPDCD were selected from the files of the bone and soft tissue tumors collected from 1989 to 2000 in the First Department of Pathology, Fukuoka University. Four cases of tumoral CPPDCD were retrieved from the consultation files of one of the authors (H.I.), and the remaining case came from the files of ordinary surgical specimens maintained at our institution. Formalinfixed and paraffin-embedded tissue samples were obtained from all five patients. Hematoxylin and eosin-stained slides were prepared for histopathologic review in each case. These slides were examined by compensated polarized light microscopy to identify the birefringence of the crystalline material. Roentgenographs were available for review in each case. Magnetic resonance images (MRI) were available in one case.
Results Clinical and roentgenographic features
The clinical features of patients with tumoral CPPDCD are summarized in Table 1. Four patients were males
and one was female, with a median age of 63 years (range, 49–70 years). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in each of one patient. Each case presented with a slowly growing periarticular swelling. The duration of this symptom ranged from 6 months to 4 years (median, 1 year). Although the wrist or hand swelling was painful in three patients, the condition was not clinically considered to be gouty tophus because of the lack of redness and local heat. Serum calcium and phosphate levels were within the normal range in each patient. Radiographically, in four lesions, a well-defined calcified mass was noted, which did not expand or erode the cortex (Fig. 1). One patient (Case 1) showed a well defined but irregularly dense calcified mass on the ulnar aspect of the right wrist (Fig. 2). This case had been diagnosed as chondrosarcoma before surgery. MRI was carried out on one patient (Case 3). The low-intensity signal of a mass seen on the T1-weighted coronal image (TR/TE, 550/38) was lower than that of the surrounding muscle (Fig. 3A). On T2-weighted axial image (TR/TE, 2100/38), the mass appeared as a mixture of high- and iso-intensity signals (Fig. 3B). Pathological features
Gross examination of each lesion showed a circumscribed whitish-gray mass with a more or less chalky appearance. The size of the lesion ranged from 1.0 to 6.2 cm (median, 2.5 cm, Table 1). Histopathologically, each lesion contained irregular massive deposits of CPPD crystals which were bordered by fibrous connective tissue presenting a lobulated or multinodular
Fig. 1. X-ray showing a well-defined calcified mass in the ulnar aspect of the left thumb (Case 3). Fig. 2. X-ray showing a well defined, but irregularly dense calcified mass on the ulnar aspect of the right wrist (Case 1). A provisional diagnosis of chondrosarcoma was made preoperatively.
Tumoral CPPDCD · 501 Table 1. Clinicopathological characteristics of five cses with tumoral CPPD Case Age Sex Site (yrs)
Size (cm)
1 2
65 70
M M
3 4
63 52
M M
5
49
F
Ulnar side of right wrist Palmar side of proximal phalanx of left middle finger Ulnar side of left thumb Dorsum of carpal bone of right hand Palm of left wrist
Symptoms
Duration of mass (yrs)
Rhomboid crystals
Needleshaped crystals
Chondro- Giant metacells plasia
6.2 × 3.7 Tumor, pain 2.5 × 1.0 Tumor
1 4
++ +
+ –
+++ ++
+++ ++
2.7 × 2.2 Tumor 1.0 × 1.0 Tumor, pain
1 0.5
++ ++
+ +
++ ++
+++ +
1.2 × 0.8 Tumor, pain
2
+++
+
+++
++
– no; + few; ++ moderate; +++ abundant
pattern (Fig. 4). Many crystals exhibited a rhomboid configuration characteristic of CPPD, but there were also some needle-shaped ones resembling urate crystals (Fig. 5). Under polarized light microscopy with a red compensator, the crystals showed weakly positively birefringence, indicative of CPPD (Fig. 6). The number of crystals varied from one lesion to another and in different areas of the same lesion. The crystals were often embedded in a background of an amorphous pale substance reminiscent of a chondroid matrix. In addition, CPPD crystals were often admixed with a basophilic granular substance, the feature being suggestive of coexistence of calcium hydroxyapatite. One of the lesions showed a large amount of intensely basophilic deposits, indicative of a high concentration
of hydroxyapatite in the matrix (Fig. 7A and B). In all cases, varying amounts of metaplastic cartilage (chondroid metaplasia) were found in and around the areas of CPPD deposition (Fig. 8A). The cartilaginous cells in most lesions showed no evident cellular atypia, whereas one lesion, which had been suspected clinically as chondrosarcoma (Case 1), exhibited proliferation of mildly atypical chondrocytes with swollen nuclei and sometimes prominent nucleoli (Fig. 8B). Foreign body granulomatous reaction was found in all cases. Aggregates of histiocytes and foreign body type giant cells, together with lymphoid cells and occasional neutrophils, were found around the CPPD deposits and in the fibrous stroma between the deposits (Fig. 9).
Fig. 3. (A) T1-weighed coronal image shows a mass of a slightly less intense signal than adjacent muscle (Case 3). (B) A mass with a mixture of high- and iso-intensity signals is shown by T2-weighted axial image (Case 3).
502 · K. Yamakawa et al.
Fig. 4. Low magnification of a tumoral calcium pyrophosphate dehydrate (CPPD) crystal deposition disease. The lesion shows irregular massive deposits of CPPD crystals bordered by a fibrous connective tissue presenting a lobulated or multinodular pattern (Hematoxylin and eosin, ×24).
Fig. 5. (A) A high magnification of one of the multinodular deposits, showing crystals embedded in a background of an amorphous pale substance surrounded by fibrous tissue (Hematoxylin and eosin, ×47). (B) Same area of specimen shown in (A), examined under polarized light, revealing one nodular deposit of numerous crystals (Hematoxylin and eosin, ×47). (C) Under high-power examination, many crystals exhibit a rhomboid configuration characteristic of CPPD, but note also the presence of some needle-shaped ones, resembling urate crystals under polarized light (Hematoxylin and eosin, ×490).
Tumoral CPPDCD · 503
Fig. 6. Polarizing light microscopy used with a red compensator to demonstrate the presence of weakly positively birefringent crystals. (A, B) hematoxylin and eosin stain, ×710. (C, D) hematoxylin and eosin stain, ×410.
Fig. 7. (A) The lesion shows massive deposition of intensely basophilic calcified deposits indicative of a high concentration of hydroxyapatite, arranged in multinodular configuration (Hematoxylin and eosin, ×15). (B) High magnification of some of the multinodular deposits, showing intensely basophilic calcified deposits indicative of a high concentration of hydroxyapatite, surrounded by fibrous tissue (Hematoxylin and eosin, ×34).
504 · K. Yamakawa et al.
Fig. 8. (A) Metaplastic cartilaginous cells are seen in this lesion. The cartilaginous cells show no atypical features (case 5, Hematoxylin and eosin, ×70). (B) Mildly atypical chondrocytes with swollen nuclei and sometimes prominent nucleoli can be seen in the metaplastic cartilage (case 1, Hematoxylin and eosin, ×70).
Fig. 9. Aggregates of histiocytes and foreign body type giant cells together with lymphoid cells are found around the CPPD deposits (Hematoxylin and eosin, ×670).
Discussion The clinical manifestations of CPPDCD vary widely. Many cases are found incidentally and may be asymptomatic [31]. In symptomatic patients, the lesions may
be misdiagnosed as pseudorheumatoid arthritis, pseudoosteoarthritis or pseudoneuropathic joints [25, 26]. Tumoral CPPDCD is one of the rarest clinical forms of CPPDCD. Based on a review of the reported cases, including the present series, a total of 54 cases of tumoral CPPDCD have been described [1, 3–5, 9, 10,12–14, 16, 18, 19, 21, 22, 29, 30, 33–36, 38]. Many of these examples appeared as single case reports. Analysis of the data available in the reported cases of tumoral CPPDCD indicated that the condition occurs in patients with a median age of 60 years (range, 31–90 years), and mostly in females (male:female ratio = 1:1.7). The anatomical distribution of tumoral CPPDCD differs from that of the common forms of CPPDCD in which the knee and wrist are the most frequently affected sites [8, 32]. The most common anatomic location of tumoral CPPDCD was the temporomandibular joint, followed by the cervical spine and hand (Table 2). Other less common locations included the hip, toe, wrist, shoulder, elbow, and parotid gland (Table 2). Based on the anatomic location of these lesions, we can divide the lesions into two categories: the central (head and neck) type, and the distal (extremity) type (Table 2). The presence of these two different types of CPPDCD has not been clearly recognized in previous reports. There were 33 cases of the central type and 21 cases of distal type. These two groups of CPPDCD were not different with respect to age and sex distributions, but showed different clinical symptoms. In the central type, the most common symptom was the presence of a painful mass, which was described in 15 pa-
Tumoral CPPDCD · 505 Table 2. Anatomic locations of reported cases* of tumoral CPPDCD, including our series Anatomic Location
Number of Cases (%)
Central (head and neck) type Temporomandibular joint Cervical spine Parotid gland Distal (extremity) type Upper extremities Hand Wrist Elbow Shoulder Lower extremities Toe Hip
33 20 12 1 21 15 10 2 1 2 6 3 3
Total
54 (100)
(61) (37) (22) (2) (39) (28) (18) (4) (2) (4) (11) (5.5) (5.5)
*[1, 3–5, 9, 10, 12–14, 16, 18, 19, 21, 22, 29, 30, 33–36, 38]
tients (46%), followed by neurological disturbances in 11 patients (33%). In the distal type, the most common symptom was a painless mass or swelling in 12 patients (57%), but no neurological signs were described, although 8 patients (38%) had an acute attack similar to that occurring in tophaceous gout. Involvement of the adjacent bone was noted in 18 (38%) patients. The most common pattern of bony involvement of tumoral CPPDCD was pressure erosion [14]. There are some discrepancies in sex distribution of patients and location of lesions between our cases and Ishida’s report [14]. Since the number of the analyzed cases was limited, further studies collecting large numbers of tumoral CPPDCD are required to resolve the issue. Histopathologically, metaplastic cartilage is often found in and around areas of CPPD depositions; these areas are surrounded by fibrous tissue with histiocytes, giant cells, and mononuclear cells. It has been suggested that metaplastic cartilaginous cells play an important role in the initial precipitation of CPPD [1, 15]. In our series, the number of crystals varied from lesion to lesion and in different areas of the same lesion. The crystals were often embedded in a background of an amorphous pale substance reminiscent of a chondroid matrix. In addition, the CPPD crystals were often admixed with a basophilic granular substance, this feature being suggestive of a coexistence of calcium hydroxyapatite. One of the lesions showed intensely basophilic deposits, indicative of a high concentration of hydroxyapatite in the matrix (Fig. 7). Although a destructive tophaceous calcium hydroxyapatite tumor indicative of weakly birefringent crystals has been reported [11], we consider that the intensely basophilic deposits in our case were mixed with CPPD and calcium hyddroxyapatite.
Tumoral CPPDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors. In gout, urate crystals are water-soluble and are not preserved in conventionally fixed histological sections [20]. In alcohol-fixed material, they appear as needle-shaped crystals easily distinguished from rhomboid crystals of CPPD. Tumoral calcinosis is another entity characterized by massive calcified deposits in soft tissues, often around major joints such as the hip and shoulder. It is predominant in adolescents and young adults, and is more often multiple than solitary. The calcified material in tumoral calcinosis lacks crystalline structures and is composed mainly of hydroxyapatite [2, 6]. The clinical and radiographic features of reported patients with tumoral CPPDCD initially led to a provisional diagnosis of malignant tumors in 14 patients. Seven of these cases were diagnosed as – or suspected of being – chondrosarcomas [14]. In some patients, the preoperative misdiagnosis resulted in more radical surgery than was appropriate. The metaplastic chondrocytes described by Ishida et al. [14] occasionally showed cytological atypia (3 of 7 patients) analogous to that seen in synovial chondromatosis, which superficially resembled chondrosarcoma. Metaplastic chondrocytes with cytological atypia were found in one of our cases. A foreign body-type granulomatous reaction containing histiocytes and giant cells is a helpful finding to differentiate tumoral CPPDCD from chondrosarcoma. More important, however, is the identification of birefringent crystals characteristic of CPPD. Empty outlines of crystals in the cartilaginous matrix can be seen, even if birefringent crystals are not identified. It is important to recognize the characteristic clinicopathologic features of tumoral CPPDCD in order to establish the correct diagnosis, which should then allow for appropriate treatment. Acknowledgement. We are grateful to the staff of the First Department of Pathology, Fukuoka University, for technical assistance, and to the following physicians for providing case material for our study: Dr. Takahide Kohzuma, Munakata, Fukuoka, Japan; Dr. Kenji Shitama, Maebaru, Fukuoka, Japan; Dr. Norio Ohnishi, Iyo, Ehime, Japan; Dr. Masanobu Oyama, Fukuoka, Japan; and Dr. Noriko Uesugi, the Second Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan.
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