Primary synovial chondromatosis is a proliferation of cartilaginous bodies
within the synovial membrane, bursa, or tendon sheath. Historically, it has
been characterized as a rare, monoarticular, benign arthropathy of uncertain
etiology, typically involving a single large joint in a young adult. Males are
affected more commonly than
females1. The knee
is involved most frequently, followed by the hip, elbow, shoulder, ankle, and
wrist2-4;
however, smaller joint involvement, including that of the spine, foot, and
hand, has been
reported5-8,
as has involvement of the acromioclavicular, temporomandibular, and
sternoclavicular
joints9-12.
The Massachusetts General Hospital tumor database contains eighty-six recorded
cases of synovial chondromatosis; these cases include involvement of the knee
(thirty-three cases), the hip (sixteen cases), the shoulder (eight cases), the
ankle (seven cases), the foot (seven cases), the elbow (five cases), and
miscellaneous locations (ten cases).
Malignant degeneration of synovial chondromatosis into chondrosarcoma is a
described, but extremely rare, event. We describe a unique case of synovial
chondromatosis in the shoulder, which, following multiple recurrences with a
repeatedly benign histologic appearance but abnormal results on
deoxyribonucleic acid (DNA) flow cytometry, ultimately demonstrated histologic
evidence of malignant transformation. The aneuploid DNA of this specimen
distinguishes it from all other cases of synovial chondromatosis in the
Massachusetts General Hospital tumor database. Our patient was informed that
data concerning the case would be submitted for publication.
A forty-seven-year-old man presented in February of 1999 with a two-year
history of right shoulder pain and generalized shoulder discomfort that was
most frequently related to activity. In addition, the patient reported that
lying on the shoulder at night caused pain. The patient had not experienced
trauma or any other inciting event, nor did he have any motor or sensory
deficits or any additional masses on physical examination. He had no history
of fevers or other systemic symptoms. The medical history was notable for
hypertension, hypercholesterolemia, and a motor-vehicle accident at age four
years, in which the patient had sustained a brain injury and severe crush
injuries, the repair of which required multiple surgical procedures.
Specifically, he had not sustained any injuries to the right shoulder or right
upper extremity. Both his mother and his sister had a history of carcinoma of
the breast.
On physical examination, a 4 × 8-cm soft-tissue mass, nontender to
palpation and without evidence of associated skin changes, was identified
along the anterior aspect of the right shoulder. The range of motion was
recorded as lacking 10° to 15° of both flexion and abduction compared
with that of the contralateral shoulder. Discomfort was notable at the
extremes of motion. Pain was also produced with resisted active motion. The
motor and sensory examinations indicated no deficit, and pulses were recorded
as strong.
Plain radiographs demonstrated subtle and minute stippled heterotopic
calcification within the soft tissues, which was suggestive of a soft-tissue
mass. No obvious osseous invasion was seen. Magnetic resonance imaging
findings included a mass within the glenohumeral joint, which appeared
septated and bright on T2-weighted magnetic resonance imaging
(Fig. 1-A) and had rim
enhancement on T1-weighted magnetic resonance imaging with gadolinium contrast
(Fig. 1-B). A computed
tomography-guided biopsy was performed, which revealed benign cartilaginous
tissue. The diagnosis of synovial chondromatosis was made, and the patient
underwent excision of the mass through a standard deltopectoral approach.
Intraoperative frozen-section histopathologic analysis confirmed the diagnosis
of synovial chondromatosis (Figs. 2-A and
2-B). Postoperative cytogenetic testing revealed DNA aneuploidy
with a hyperdiploid peak: flow-cytometric DNA and cell-cycle analysis of
>10,000 cells demonstrated aneuploidy (DNA index, 1.84) with 32%
G0G1 and 0% S-phase. The postoperative course was
uneventful and the patient had relief of pain and improved shoulder motion
postoperatively.
In January of 2000, approximately eleven months later, the patient
presented again because of mild shoulder pain and recent swelling. Plain
radiographs revealed calcific densities within the superior portion of the
glenohumeral joint and a small amount of superior glenoid involvement. A
subsequent magnetic resonance imaging scan confirmed recurrence. The patient
underwent re-excision in March of 2000 without complications. Flow cytometric
DNA and cell-cycle analysis again revealed aneuploidy (DNA index, 1.86) with
39% G0G1, 1% S-phase, and 4% G2M. In
addition, five of seventeen metaphase cells demonstrated a balanced
translocation between chromosomes 12 and 16.
In August 2000, a second recurrence was confirmed on magnetic resonance
imaging, and three months later the patient underwent tumor excision and
shoulder hemiarthroplasty. Histologic analysis of removed tissue again
demonstrated findings that were compatible with synovial chondromatosis, with
flow cytometry characteristics similar to those found in previous specimens
and revealing aneuploidy (DNA index, 1.89; 36% G0G1, 0%
S-phase, and 4% G2M). However, cytogenetic testing at this time
found no cytogenetic aberrations in the twenty metaphase cells that were
analyzed. Two subsequent cytogenetic tests of specimens obtained years later
had too few viable cells to be studied. In light of the multiple recurrences
and the substantially shorter time to recurrence, the patient was treated with
postoperative administration of radiation therapy, consisting of 56 Gy in
twenty-eight fractions with a shrinking-field technique over a six-week
period. Physical therapy was prescribed, and gradual improvement in range of
motion ensued.
In August 2003, the patient returned with a small mass in the region of the
coracoid process. Radiographs were suggestive of recurrence. Over the
following year, the mass remained stable in size but shoulder motion
progressively declined and, by April 2004, the patient had appreciable
limitations of motion in all planes. Imaging studies demonstrated a large mass
(11.4 × 10 × 7.2 cm) involving the suprascapular notch, the spinal
glenoid notch, and the quadrilateral space. In May 2004, the patient underwent
revision of the right shoulder hemiarthroplasty and re-excision of the
shoulder mass. A histologic analysis again showed that the removed tissue was
benign. However, the symptoms quickly recurred, along with a clinically and
radiographically obvious mass within eight months. By this time, the patient
had lost nearly all active motion of the right shoulder.
In June 2005, in addition to multiple foci of recurrence about the
shoulder, the tumor showed evidence of erosion into bone
(Fig. 3). In addition, although
previous preoperative chest radiographs and two post-recurrence computed
tomography scans of the chest were negative for metastatic involvement, a lung
nodule was demonstrated on a computed tomography scan at this time. The
patient then underwent re-excision of the soft-tissue masses and a partial
scapulectomy. Histologic analysis of the removed tissue revealed a grade-2
chondrosarcoma of a conventional hyaline type
(Figs. 4-A and 4-B). Soon
thereafter, the patient underwent flexible bronchoscopy, a right thoracotomy,
and wedge resection of a 7-mm lung nodule that was found to be metastatic
chondrosarcoma, similar to the tumor that was previously excised from the
shoulder (Fig. 5).
Four months later, the patient returned with yet another recurrent
nontender mass over the anterior aspect of the right shoulder. Fine-needle
aspiration demonstrated malignant cells, and, in January 2006, nearly seven
years following the initial presentation, the patient underwent a forequarter
amputation of the right upper extremity.
Synovial chondromatosis is widely recognized as a metaplasia of the
synovial
membrane13,14,
the etiology of which remains unclear. The most common theory suggests that
pluripotent mesenchymal cells located within the subintimal layer at the
juncture of the synovium and the articular cartilage undergo a transformation
to chondrocytes, resulting in nests of cartilage embedded within the synovial
membrane, which become pedunculated and eventually extrude into the joint as
loose bodies. Over a course of time, these bodies become calcified or even
ossified, allowing for their identification on plain radiographs.
While various staging systems exist, there is some thought that the staging
of synovial chondromatosis is a matter of timing and that the process is in
fact self-limiting, as the cartilage nodules resorb over the course of years,
leaving many cases undiagnosed. Nevertheless, surgical removal combined with
partial synovectomy has demonstrated decreased recurrence rates and remains
the current standard of
care15,16.
Recurrences are known to occur on an infrequent basis and are believed to be
due to inadequate resection of loose bodies or diseased synovium at the time
of surgery. Recurrences have been described as occurring in 0% to 15% of
patients17,18.
Synovial chondromatosis occurs in the hip, knee, or elbow in at least 80% to
95% of patients, so most recurrences also occur in these
joints19. In fact,
in their review of the world literature, Small and Jaffe identified only
twenty-five cases of synovial chondromatosis involving the
shoulder20. To our
knowledge, prior to the case of our patient, there have been no described
cases of recurrence of synovial chondromatosis in the shoulder.
Synovial chondrosarcoma is an extremely rare diagnosis. The condition is
thought to arise either de novo or in the setting of synovial chondromatosis.
This distinction has remained controversial, as has the concept of malignant
degeneration. We performed a search of the literature spanning a century and
found only thirty-three cases of malignant transformation in the setting of
histologically confirmed synovial
chondromatosis21-42.
An important commonality among these cases is recurrence of benign disease
prior to a diagnosis of malignant disease. In a review of fifty-three patients
with primary synovial chondromatosis, Davis et al. identified nine patients
(17%) in whom recurrences developed and found that the tumors in three of
those nine patients had undergone malignant transformation. Two of the three
patients had multiple recurrences in the knee, and ankylosis of the knee
developed in the third patient just six months after
resection43. Our
patient had four recurrences over a period of five years. Although DNA
aneuploidy was present and one sample had an abnormal karyotype, each
specimen, even in retrospect, had been consistently interpreted pathologically
as synovial chondromatosis prior to its eventual transformation. In addition
to the risk factor of having a prolonged clinical course, the propensity of
some tumors to recur rapidly and frequently seems to portend a greater chance
for malignant transformation (Appendix).
Synovial chondromatosis is most commonly described as a non-neoplastic
process13,44,45.
Recent studies have attempted to support the claim of a metaplastic process by
demonstrating the absence of mitotic figures and the lack of staining with
Ki-67, a monoclonal antibody used as an indicator of proliferating
cells14,46.
At the same time, the cartilage in synovial chondromatosis is often very
cellular and contains pleomorphic and binucleate cells, making it difficult to
distinguish that cartilage from the cartilage seen in a low-grade
chondrosarcoma. These characteristics, in conjunction with the ability of
synovial chondromatosis to recur or, rarely, transform, suggest that the
disease process may not be solely metaplastic, but, in some cases, neoplastic.
Recent studies have suggested that the presence of clonal chromosomal changes
in synovial chondromatosis provides further evidence of a neoplastic
origin47,48.
Tallini et al. also described a positive correlation between histologic grade
of chondrosarcoma and the degree of karyotypic
complexity49. One
of two complete cytogenetic analyses of specimens taken from our patient
indicated a chromosome-12 translocation, which is a finding that has been
associated with some cases of synovial
chondromatosis49.
Therefore, the diagnosis of the condition in our patient remained synovial
chondromatosis on the basis of consistent histopathologic characteristics. The
final specimen from our patient, which was diagnosed as chondrosarcoma, did
not have enough viable cells for the cytogenetic analysis to be performed
successfully.
Flow cytometry has been of value as a method to characterize DNA ploidy in
a variety of tumors. These characteristics have been suggested to correlate
with the stage and grade of the disease as well as to distinguish benign
processes from those that are
malignant50-52.
In a review of 847 cases, Mankin et al. found that only 6% of benign bone
tumors demonstrated aneuploid DNA in comparison with 59% of malignant bone
tumors50.
Similarly, only 4% of benign soft-tissue tumors demonstrated aneuploid DNA in
comparison with 61% of malignant soft-tissue
tumors53. Of the
tumors recorded in our database, only 5% of benign cartilage tumors
demonstrated aneuploid DNA, with no tumor progressing to malignant disease, in
comparison with 48% of malignant cartilage tumors with aneuploid DNA.
Prior to this report, the Massachusetts General Hospital database did not
have a case of nondiploid primary synovial chondromatosis, which was
consistent with the data from previous
reports52,53.
However, since the time of those reports, the cytogenetic characteristics
reported in the literature have been variable. Davis et al. reported that the
histograms for eight of twenty synovial chondromatosis specimens were
nondiploid, and both that group of authors and Robinson et al., in
proliferative studies that made use of proliferating cell nuclear antigen,
Ki-67 staining, and DNA image cytometry, described synovial chondromatosis as
occupying an intermediate position between the activities of an enchondroma
and a
chondrosarcoma46,54.
Likewise, Davis et al. and Coughlan et al. showed that even though synovial
chondromatosis does not show intensive proliferative activity and is not
reactive for p-53, it does express c-erb
B-246,52,55.
The c-erb B-2 antigen is commonly expressed in chondrosarcomas but not in
other benign cartilage lesions or normal
cartilage55. It is
this intermediary nature that makes the differentiation of synovial
chondromatosis from chondrosarcoma even more difficult.
In a series that included fifty-three-patients, Davis et al. described
three malignant transformations of synovial chondromatosis to chondrosarcoma
and reported that the histograms of all three tumors demonstrated aneuploidy
by flow
cytometry43;
however, it was not reported whether these three tumors had aneuploid DNA
prior to transformation. In another report by Davis et al., none of the eight
cases of aneuploid primary synovial chondromatosis were described to have
subsequently undergone malignant
transformation46.
Therefore, an uncertain fraction of synovial chondromatoses appears to have
aneuploid DNA. Furthermore, it is unclear if aneuploidy is an indication of
inevitable malignant transformation. To the best of our knowledge, the case of
our patient represents the only case of synovial chondromatosis with aneuploid
DNA that has been followed to transformation into chondrosarcoma.
Whether DNA analysis can reliably serve as a prognostic indicator in
synovial chondromatosis requires further investigation. A DNA index of >1
has also been suggested to carry prognostic
value50. In that
study, by Mankin et al., the mean DNA index was also significantly different
between benign (1.03) and malignant (1.24) soft-tissue tumors and benign
(1.06) and malignant (1.19) bone tumors (p < 0.0001). While a DNA index of
>1 may be associated with malignant disease, approximately 14% of benign
lesions can also have an index
>151. The DNA
index for our patient averaged 1.88 during the course of the disease and may,
in retrospect, have been an indication of a malignant process. However, even
with knowledge of the ultimate diagnosis, a retrospective review of the data
indicates that the histopathologic and radiographic characteristics of the
specimens from our patient were most consistent with synovial chondromatosis.
While suggestive, the elevated DNA index was not deemed sufficient to
establish a diagnosis of malignant disease. In addition, while it is possible
that radiation contributed to the malignant transformation of this tumor, we
believe that it is not strictly a radiation-induced malignant neoplasm because
of the similar histologic characteristics of the specimens before and after
radiation treatment and because of the rarity of radiation-induced
chondrosarcoma. It remains unknown if or to what extent radiation induces or
accelerates the transformation of synovial chondromatosis to
chondrosarcoma.
In conclusion, synovial chondromatosis rarely involves the shoulder. In
general, recurrences are infrequent in the shoulder but have been well
described in sites other than the shoulder. For this reason, it is difficult
to know if a recurrence in the shoulder is in itself a risk for malignant
transformation. A review of the literature suggests that an extended clinical
course along with rapid and frequent recurrences may carry a risk for
transformation. This case report reinforces the importance of quick
recognition of unusual clinical characteristics of synovial chondromatosis,
which should raise the suspicion of malignant transformation even when
repeated prior pathologic testing indicates a benign process. Lastly, more
studies investigating the relationships of DNA ploidy and mean DNA index to
prognosis will need to be performed before we can determine whether
relationship testing is useful in distinguishing between benign and malignant
processes.
A table showing previously reported cases of malignant transformation of
synovial chondromatosis in the literature is available with the electronic
versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?