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From the Clinical Research Centers |
Division of Bone and Mineral Diseases (K.Z., M.P.W.) and Departments of Radiology (W.A.T.), Pathology (S.L.T.), and Surgery (M.D.), Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Dr. Michael P. Whyte, Division of Bone and Mineral Diseases, Barnes-Jewish Hospital, 216 South Kingshighway Boulevard, St. Louis, Missouri 63110.
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Abstract |
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A 45-yr-old black woman with neurofibromatosis, type I, and polyostotic PBD developed slowly-growing masses in the right posterior iliac and left upper parasacral regions. She had multiple cutaneous neurofibromas and café-au-lait spots. Serum alkaline phosphatase activity and urine hydroxyproline levels were elevated. Skeletal radiographs and bone scintigraphy showed changes of widespread PBD. Computerized tomography and magnetic resonance imaging (MRI) delineated masses in the right gluteal and the left lower lumbar paraspinal regions. Five additional smaller masses were found in the abdomen and in the pelvis. Biopsy of the right gluteal mass revealed a GCT. However, we found that this lesion had several histologic features distinct from those of giant cell reparative granulomas or GCT. In our patient’s tumor, the huge polykaryons, like osteoclasts, expressed abundant tartrate-resistant acid phosphatase activity, whereas those of GCRG lack this enzyme. Although the polykaryons in conventional GCTs and GCTs in PBD express tartrate-resistant acid phosphatase activity, the location of these tumors in bone differs from the extraskeletal masses encountered in our patient. Furthermore, the larger size of the polykaryons and the greater number of nuclei in our patient’s GCT differ from conventional GCTs, but not GCTs in PBD. Her extraskeletal osteoclastoma rapidly shrunk to one third its original size during 2 weeks of oral dexamethasone treatment. Significant clinical improvement lasted about 5 months before additional courses of dexamethasone therapy were necessary. Injections of synthetic salmon calcitonin alone did not affect the tumor’s size. Thus, PBD can be complicated by extraskeletal tumors that seem to contain osteoclasts and are responsive to dexamethasone treatment.
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Introduction |
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Recently, we investigated a Korean patient with familial PBD complicated by several extraskeletal osteoclastomas (9). His tumors contained huge, multinucleated giant cells that like osteoclasts (and unlike foreign body giant cells) expressed abundant tartrate-resistant acid phosphatase (TRAP) activity. The histologic features were distinct from either conventional GCT of bone or GCRG. Furthermore, these lesions occurred extraskeletally, and they responded rapidly to dexamethasone treatment (9).
Here, we describe a woman from St. Louis, Missouri, with widespread PBD and neurofibromatosis, type I, who developed palpable multicentric tumors containing TRAP-positive osteoclast-like cells. Findings in this patient support the concept that extraskeletal osteoclastomas can complicate PBD. Moreover, these tumors seem to be unique to the pagetic process and respond dramatically to dexamethasone treatment.
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Case Report |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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This 45-yr-old black woman was referred to us for PBD and a 4-yr history of progressive back discomfort and bilateral lower-limb pain. The symptoms kept her from walking more than 15 feet or sleeping soundly. The pain seemed to extend from her lumbar region to both thighs but not beyond her knees. It worsened with physical activity and was partly relieved by ibuprofen or acetaminophen therapy. In addition, she had noted two slowly-growing palpable masses, one in the right posterior iliac and one in the left parasacral regions, which had been present for about 31/2 yr.
At age 30, she was diagnosed with neurofibromatosis, type I, but had otherwise been in good health. Iron supplements had been taken intermittently for iron deficiency anemia. She had never smoked, abused alcohol, taken illegal drugs, or experienced fractures. She denied headache, tinnitus, or hearing loss. Family history was negative for PBD. Her daughters, 21 and 16 yr old, have café-au-lait spots but no other stigmata of neurofibromatosis.
Physical examination showed a well-nourished and well-developed
(height: 165 cm; weight: 52 kg) woman with multiple neurofibromas on
her extremities, trunk, face, and elsewhere (Fig. 1
). There were large, smooth-bordered
café-au-lait spots and a slightly bowed left lower extremity. A
soft systolic ejection murmur was heard along the lower left sternal
border. Firm, nonfluctuant masses were present in the right posterior
iliac (15 x 10 cm) and left lower parasacral (6 x 6 cm)
regions (Fig. 1).
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Routine laboratory work-up included normal leukocyte count/differential, serum electrolyte levels, and renal and thyroid function studies. Her hematocrit was 28.7% (nl: 36–44), hemoglobin 9.5 g/dl (nl: 12–15), and mean corpuscular volume (MCV) 75.4 fl (nl: 80–100), consistent with mild iron deficiency anemia. A multiphasic serum profile included normal levels of blood urea nitrogen, creatinine, calcium, inorganic phosphate, bilirubin, protein, alanine and aspartate aminotransferase, and lactate dehydrogenase. However, her serum alkaline phosphatase activity (443 IU/L; nl: 38–126) and her 24-h urinary hydroxyproline level (521 mg; nl: 15–45) were elevated. The erythrocyte sedimentation rate also was increased (55 mm/h; nl: 0–20).
Radiologic studies.
Scintigraphy showed markedly increased
radionuclide uptake throughout her skeleton, with relative sparing of
the distal tibias, the proximal two thirds of the right femur, and the
left scapula (Fig. 2). There was no
visualization of the kidneys, bladder, or soft tissues
(i.e., a superscan). The left tibia was bowed.
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).
In addition, the cortex of the right iliac wing, which was juxtaposed
to heterotopic calcification, was indistinct. The proximal one-half of
the right tibia demonstrated cortical thickening and a
well-circumscribed, sharply demarcated, advancing lytic wedge (blade of
grass sign) (Fig. 4). A similar two-front
lytic wedge on each side of the bone also was noted in the left
proximal femur (Fig. 5). Taken together,
the bone scan and radiologic findings were most consistent with
polyostotic PBD. Neoplastic degeneration of the pagetic bone of the
right iliac crest was considered. Bone (Fig. 6A) and soft tissue (Fig. 6B)
computerized tomography of the abdomen and pelvis showed a large
multilobulated right gluteal soft tissue mass, measuring 13 cm in the
greatest axial diameter, surrounding the iliac wing, involving the
iliopsoas muscle, and extending anterior to the right pubic body and
acetabulum and deep to the gluteal muscles. The ilium seemed sclerotic,
with thickened cortex, consistent with PBD. There was no evidence of
bone destruction of the ilium by the gluteal mass (Fig. 6A). A
saturated-out fat plane showed that the right gluteal mass was
separated from the underlying bone (Fig. 6). A second mass, measuring 4
cm in its greatest axial diameter, was located in the left paraspinal
area above the level of the iliac crest (not shown). Five additional,
but smaller, tumors were scattered throughout the abdomen and the
pelvis. MRI obtained with tissue-specific fat saturation techniques
matched the computerized tomography images (Fig. 7A). Diffuse marrow signal abnormalities
and loss of sharpness (involving numerous bones of the pelvis) also
were present, consistent with pagetic changes of the bones. Both of the
above masses showed enhancement after iv gadolinium, more evident
peripherally than centrally. The masses were homogeneous on T2 weighted
images, and there was no evidence of internal necrosis or hemorrhage.
Computerized tomography of the chest, in investigation for possible
metastatic disease, revealed a solitary uncalcified 1.2-cm nodule in
the right lower lobe adjacent to the major fissure and the pleura (not
shown).
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Sections from an open biopsy of the right
gluteal mass contained a cellular tumor comprised of numerous huge,
evenly distributed, multinucleated giant cells (Fig. 8). Mitotic figures were not evident. Of
significance, the lesion contained no bone, and the stromal component
was sparse. Furthermore, like osteoclasts (and unlike foreign body
giant cells), these cells had abundant TRAP activity
(10).
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After 90 mg Aredia
(pamidronate) iv (30 mg/day over 4 h in normal saline x
3 days) for her PBD, the patient received 8 mg/day dexamethasone orally
for 1 week, which was then gradually tapered off during the following
week. After 1 week of therapy, both the left paraspinal and right
gluteal tumors began to rapidly shrink and were no longer apparent by
physical examination when she returned 1 month later. A repeat MRI, 2
weeks after the first dose of dexamethasone, showed a dramatic decrease
in the size of both the right gluteal (Fig. 7B
) and the left paraspinal
tumors. Three months later, she remained free of bone pain and was able
to walk outdoors without discomfort. However, 5 months after
dexamethasone treatment, the patient noted reappearance of the right
gluteal swelling and pain and weakness of the lower limbs, which again
limited her activities. A second 2-week course of dexamethasone
treatment (8 mg/day for 7 days, then tapered off), but without Aredia,
led to almost complete but transient disappearance of the tumor. A
3-month course of synthetic salmon calcitonin injections (50 IU daily)
did not affect the tumor size. Currently, she is receiving
alternate-day dexamethasone treatment (2 mg/dose). The right gluteal
mass was deemed nonresectable by consulting surgeons.
Soon after our initial evaluation, the patient underwent resection of the lower lobe of the right lung, which contained an isolated poorly differentiated (Grade III) primary adenocarcinoma, stage T1,M0,N0, which was believed to be an incidental neoplasm.
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Discussion |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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GCT of bone (osteoclastoma) occurs infrequently in PBD (1, 2, 3, 4, 5, 6). In pagetic patients, these lesions commonly involve the skull and facial bones (1, 4, 5) and, less frequently, appear in the spine (11), pelvis (4), clavicle (12), or tubular bones (13). GCTs arise in areas of pagetic involvement (1), are usually associated with longstanding polyostotic PBD (3), and tend to occur in older pagetic patients (compared with conventional GCTs) (4). Histologically, conventional GCTs of bone contain large numbers of polykaryons, generally containing 15–20 nuclei distributed throughout a well-vascularized, relatively hypocellular stroma containing spindle-shaped or ovoid mononuclear cells (14).
Whether GCRG and GCT of bone are distinct entities in PBD is controversial (8). The term "giant cell reparative granuloma" was introduced in 1953 by Jaffe (15) to characterize benign osteolytic jaw lesions in nonpagetic patients, which he believed were not a neoplasm but represented a local reparative reaction of the bone tissue to intraosseous hemorrhage. Subsequently, cases of GCRG were reported in sites other than the jaw (14), and even outside the skull (16). GCRG also has been reported in pagetic patients (7, 8).
Compared with classical GCTs, GCRGs in general may possess fewer and smaller giant cells with less numerous nuclei, often clustered around areas of hemorrhage, and show greater collagen production. They also contain hemosiderin granules and inflammatory cells and frequently demonstrate foci of osteoid and new bone formation (8, 14, 17, 18). Upchurch and co-workers (8) first reported the association of GCRG with PBD in 1983. They concluded, by reviewing archival histological preparations of specimens reported as GCTs, that some GCTs were actually GCRGs in PBD (3, 8).
Extraskeletal osteoclastomas
The histopathological appearance of our patient’s gluteal tumor distinguishes it from GCRG. It contained sheets of giant cells evenly distributed in a relatively sparse stroma; an unusual finding for GCRG. Absence of areas of collagen (fibrosis), hemorrhage, foci of osteoid, or new bone formation are features of her tumor not in keeping with GCRG (14). In addition, the huge size of the polykaryons and the large number of their nuclei further distinguishes her tumor from GCRGs, which contain smaller giant cells with fewer nuclei.
Although her gluteal tumor exhibited some of the features of conventional GCTs of bone, the huge size of the giant cells and the especially numerous nuclei distinguish it from conventional GCTs of bone.
Histologically, our patient’s gluteal tumor was indistinguishable from GCT in PBD. However, these masses occurred extraskeletally in our patient. Perhaps the most interesting histological finding was the observation that the extraskeletal polykaryons in her tumor were rich in TRAP activity. In vivo, TRAP activity is unique in members of the monocyte/macrophage family to osteoclasts and their committed precursors (10). Foreign body giant cells are TRAP negative. Accordingly, we believe that our patient’s tumor(s) can be thought of as an extraskeletal osteoclastoma. Furthermore, as we describe in a preliminary report, though our patient’s gluteal tumor did not show the ruffled borders or the viral inclusion bodies on electron-microscopy consistent with PBD osteoclasts, PCR studies showed evidence of three calcitonin receptor isoforms characteristic of these bone-resorbing cells (19).
Our observations are provocative, because they suggest that osteoclast formation can occur extraskeletally in the setting of PBD (a condition in which osteoclasts are rapidly recruited and pathogenetic). Although extraskeletal osteoclastomas are clearly rare in PBD, we recently encountered a Korean man with longstanding, familial, polyostotic PBD and multiple, slowly growing, soft tissue masses (9). His tumors also contained numerous TRAP-expressing multinucleated giant cells that were histologically identical to our patient’s lesions and responded to dexamethasone treatment (see below).
The mechanism by which pagetic osteoclasts or their precursors could reach extraskeletal sites and evolve into an extraskeletal osteoclastoma, however, is unclear. Active bone marrow can exist outside intramedullary spaces, and this finding has been reported in pagetic patients with seemingly normal peripheral blood counts (20). Accordingly, it is possible that the diseased cortex of pagetic bone can leak marrow (including pagetic osteoclasts) into soft tissues (21). However, our radiologic studies showed no disruption of bone integrity at the site of our patient’s gluteal tumor. Alternatively, the osteoclastogenic stimulus in patients with PBD and extraskeletal osteoclastomas may be so powerful that there is de-novo differentiation of monocytes into polykaryons with osteoclastic phenotype within nonosseous tissues. This hypothesis is consistent with the many apparent sites of extraskeletal osteoclastomas in our patient. It has been shown that human osteoclast precursors circulate in the peripheral blood in the monocytic fraction, exhibiting initially a monocyte phenotype and acquiring phenotypic features of osteoclasts during differentiation conditioned by various factors (e.g., M-CSF, 1,25(OH)2D3) (22).
Like normal bone marrow, marrow derived from pagetic patients, and then maintained in culture, generates multinucleated osteoclast-like cells (23). Similar to authentic pagetic osteoclasts, osteoclast-like cells formed from PBD marrow, from both involved and noninvolved skeletal sites, are much larger and contain more nuclei than normal osteoclasts (23, 24). This finding suggests that either the bone marrow of PBD patients contains increased numbers of osteoclast precursors or that these precursors are abnormally predisposed to fusion (23, 25). Interleukin-6, which is produced in abundance by pagetic osteoclasts and/or osteoblasts, may be a major (though not the only) mediator responsible for this increase (26). This cytokine, through induction of interleukin-1, can preferentially stimulate the formation of osteoclast-like cells when added to human marrow cultures (27). Similar observations have been made with pagetic bone marrow cultures (26). This process could explain some of the differences observed between the osteoclasts of PBD/(extraskeletal osteoclastomas) and those of GCT not associated with PBD.
Dexamethasone treatment
To our knowledge, only two reports describe dexamethasone treatment for GCT of bone in pagetic individuals. In 1979, Jacobs et al. (3) described two patients with PBD and GCT who responded dramatically after short-term, high-dose dexamethasone treatment, only to have the tumors return shortly after abrupt discontinuation of the treatment. In 1991, Potter et al. (28) also reported two patients with polyostotic PBD and GCT that shrank significantly after dexamethasone therapy. Discontinuation of the steroid treatment led to regrowth of the tumors. Although glucocorticoids also have been reported to cause biochemical and symptomatic improvement in some patients with garden variety PBD (29, 30), there had been no other evidence that GCT or GCRG (with or without PBD) respond to this steroid.
Like Jacobs and co-workers and Potter and colleagues, we noted a rapid
and dramatic decrease in the size of our patient’s tumors during
dexamethasone therapy (Fig. 6B). Injections of synthetic salmon
calcitonin seemed to have no beneficial effect. Similar remarkable
response to dexamethasone treatment was observed in the aforementioned
Korean man with extraskeletal osteoclastomas (9). Unfortunately, after
discontinuation of the steroid therapy, his neoplasms also recurred
(Dr. Ghi Su Kim, personal communication). Hence, control of these
tumors may require a maintenance dose of glucocorticoid therapy if they
cannot be removed surgically. It is apparent that these extraskeletal
tumors must be distinguished from other GCTs of bone, because the
latter lesions may require excision and radiation treatment (31, 32).
Summary
A middle-aged black woman with neurofibromatosis, type I, and nearly panostotic PBD, developed multicentric symptomatic masses that we propose to call extraskeletal osteoclastomas, because of their unique histopathologic appearance (including huge, TRAP-positive staining, multinucleated polykaryons). These tumors are remarkably sensitive to dexamethasone treatment.
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Acknowledgments |
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Footnotes |
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Received March 3, 1997.
Revised June 24, 1997.
Revised July 22, 1997.
Accepted July 28, 1997.
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References |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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