Brown Tumor (Osteitis Fibrosa Cystica) in the Setting of Renal Osteodystrophy
Roberto Antonio Garcia
Mount Sinai Medical Center
New York, NY
Clinical history :
A 50-year-old male presented with a large mass in the right iliac wing. He recently underwent right
nephrectomy for renal cell carcinoma. A resection of the iliac mass was performed. The preoperative
diagnosis was metastatic renal cell carcinoma. The patient had a history of Alport's syndrome and
chronic renal insufficiency on hemodialysis.
BUN: 45 (10-30 MG/DL)
Creatinine: 5.7 (0.7-1.4 MG/DL)
Hemoglobin: 7.2 (13.9-16.3 G/DL)
Hematocrit: 22.5 (42.0-52.0 %)
Red blood cells: 2.78 (4.50-6.00 x10 6µL)
Calcium: 7.2 (8.5-11.0 MG/DL)
Phosphorus: 8.1 (2.4-4.7 MG/DL)
PTH Intact: 1491 (16-87 PG/ML)
Case 4 - Slide 1
Preoperative radiograph showing a large lytic lesion in the right iliac wing.
The resected tumor is well circumscribed with a fleshy, tan-pink to brown cut surface.
Low power view shows a nodular configuration with discernible giant cells.
Intermediate power showing fibrovascular stroma with numerous giant cells, abundant hemosiderin deposition and focal hemorrhage.
High power showing a proliferation of bland spindle cells with osteoclast-like giant cells aggregated around areas of hemorrhage.
Very high power view of the vascular spindle cell stroma with osteoclast-like giant cells and hemosiderin-laden macrophages.
Low power view of the trabecular bone adjacent to the tumor showing osteopenia and normocellular marrow.
Intermediate power showing tunneling resorption of trabecular bone with associated fibrosis (dissecting osteitis).
High power shows increased bone remodeling with marked osteoblastic and osteoclastic activity, irregular cement lines and peritrabecular fibrosis.
Very high power demonstrating tunneling resorption by osteoclasts (cutting cones) with fibrosis and increased osteoblastic activity.
Final Diagnosis :
Brown tumor (osteitis fibrosa cystica) in the setting of renal osteodystrophy.
Brown tumor, osteitis fibrosa cystica, hyperparathyroidism, renal osteodystrophy.
Alport's syndrome is an inherited progressive nephropathy, often associated with sensorineural
deafness and ocular lesions. It arises from mutations in the genes encoding for type IV collagen, which
is the primary structural component of all basement membranes. X-linked Alport's syndrome accounts for
~85% of the cases and arises from mutations in the COL4A5 gene. Autosomal recessive Alport's
syndrome accounts for ~15% of the cases and results from mutations of COL4A3 and COL4A4 genes. Rare
examples of autosomal dominant Alport's syndrome have been reported. The cardinal sign of renal disease
in Alport's syndrome is gross or microscopic hematuria, followed by proteinuria. The light microscopy
findings of Alport's syndrome are non-specific and include segmental glomerular sclerosis and
obsolescence, interstitial fibrosis, and infiltration by lymphocytes and plasma cells with clusters of
foam cells. Standard immunofluorescence studies are usually non-diagnostic. Electron microscopy
findings consist of variable thinning and thickening of the glomerular basement membrane combined with
multilamellation of the lamina densa. About 90% of males with X-linked Alport's syndrome progress to
end-stage renal disease before the age of 40 years compared to 12% of females.
Renal osteodystrophy is the term used to describe the complex skeletal disorders that occur in
patients with chronic renal disease. The widespread use of hemodialysis has increased survival of this
patient population at the expense of increased bone morbidity. Currently, renal osteodystrophy is
classified according to the state of bone turnover. High turnover bone disease (osteitis fibrosa)
represents the bone manifestations of secondary hyperparathyroidism. Low bone turnover syndromes are
represented by the increasingly prevalent adynamic bone or less frequently, osteomalacia.
The pathophysiology of high turnover renal osteodystrophy is explained mainly by the occurrence of
secondary hyperparathyroidism (parathyroid hyperplasia), as a consequence of:
1) Phosphorus retention due to a decreased excretory function of the failing kidney.
2) Lack of renal 1α-hydroxylase activity with subsequent decrease in active vitamin D (1,
3) Hypocalcemia resulting from lack of tubular resorption and intestinal absorption of calcium.
The pathogenesis of renal bone disease has centered on perturbations in the parathyroid
hormone-vitamin D axis. Excess parathyroid hormone can give rise to the high turnover state of osteitis
fibrosa, and conversely, relatively low levels are associated with the low bone turnover state of
High turnover bone disease (osteitis fibrosa) is characterized histologically by the presence of
peritrabecular fibrosis associated with increased bone resorption and formation. Osteitis fibrosa
cystica (brown tumor) encompasses the formation of cystic lytic lesions in bone characterized
histologically by fibrovascular stroma with osteoclast-like giant cells, hemorrhage and hemosiderin
pigment deposition. The lesion is reactive and not a neoplasm. About half of patients with chronic
renal failure may develop osteitis fibrosa cystica. Brown tumor was originally described in primary
hyperparathyroidism but it is now more commonly seen in chronic renal failure. Brown tumors may be mono
or polyostotic, commonly painless, and found incidentally. The majority of cases are reported in the
maxilla and mandible, followed by the clavicles, scapula, pelvis and ribs. The radiological features of
brown tumors are rather non-specific. They appear as well-circumscribed lytic lesions with thinned
cortical bone. Cystic change and pathological fractures may occur.
Low turnover bone disease or adynamic bone occurs frequently in diabetics and elderly patients. In
most cases, it is iatrogenic in nature, resulting from previous parathyroidectomy or excess calcium and
vitamin D therapy. There is an apparent increase in the incidence of this condition. The inhibitory
actions of vitamin D on PTH synthesis and secretion have provided the basis for its widespread use in the
management of secondary hyperparathyroidism of chronic renal failure. Long-term use of high intermittent
doses of vitamin D can lead to the development of adynamic bone in adults and growth retardation in
children. Adynamic renal osteodystrophy was originally described as a manifestation of bone aluminum
toxicity, which is rarely seen nowadays. Pathologically, adynamic bone is characterized by marked
depression of bone turnover with absence of osteoclastic and osteoblastic activity and decreased
Osteomalacia has also been associated to aluminum toxicity and to the very low levels of active
vitamin D that compromise bone mineralization. Histologically, osteomalacia is characterized by
prominent unmineralized osteoid seams on trabecular surfaces. It is currently very rare as the risk of
chronic massive exposure to aluminum has been practically eliminated and vitamin D is the mainstay of
treatment for renal osteodystrophy. Aluminum sources included dialysate solutions and phosphate binders
used in the past in the treatment of chronic renal failure. Aluminum adversely affects the
differentiation and proliferation of osteoblasts (adynamic bone). It also interferes with adequate
mineralization of osteoid (osteomalacia).
In recent times, there have been significant advances in our understanding of the complex biology of
bone with the demonstration that a multitude of local and circulating growth factors and cytokines play a
major role in bone cell biology. Abnormalities in several of these factors may be present during the
course of chronic renal failure, and therefore should be considered for their contribution to the
abnormalities of bone remodeling seen in uremia. The normal remodeling cycle requires that the processes
of bone resorption and bone formation take place in a coordinated fashion, which in turn depends on the
orderly development and activation of osteoclasts and osteoblast respectively. Osteoblasts are the cells
that posses surface receptors for PTH and vitamin D. They in turn govern the differentiation and
activation of osteoclasts.
The development of osteoclasts requires close interaction between osteoclast precursors and
osteoblastic stromal cells. The latter produce an osteoclast differentiating factor in response to a
variety of stimuli called RANKL (receptor activator of NF-κB ligand), which is essential for the
formation of mature osteoclasts. This membrane protein belonging to the TNF family is expressed on the
osteoblast stromal cell. Osteoclast progenitors express a surface receptor for RANKL that is known as
RANK. The interaction between RANKL and RANK is essential for the development of mature osteoclasts.
RANKL also plays a key role in stimulating osteoclast activity. This interaction takes place in the
presence of M-CSF (macrophage colony stimulating factor), which is necessary for osteoclastogenesis.
Osteoprotegerin is another TNF-related molecule, which is produced and secreted by the osteoblastic
stromal cell, which acts as a decoy receptor and blocks the interaction between RANKL and RANK,
inhibiting osteoclastogenesis and bone resorption. There is accumulating evidence to suggest that the
various cytokine systems involved in the regulation of different stages of the bone remodeling cycle may
be altered in patients with chronic renal failure and are likely to contribute to the pathogenesis of
renal osteodystrophy. Disturbances in the RANK/RANKL/OPG system may have a significant impact on renal
bone disease. Other cytokines like IL-1, IL-6, TNF-α and IGF-I may also play a role in this complex
Differential diagnosis :
Giant cell tumor of bone is characterized by a uniformly distributed population of multinucleated
giant cells in a background of polygonal mononuclear cells, which represent the actual neoplastic
population. The giant cells of giant cell tumor are usually larger and contain a higher number of nuclei
in comparison with other giant cell containing lesions. These tumors are more common in skeletally
mature individuals (peak incidence is in the 3rd decade of life). The metaphysis and
epiphysis of long bones of appendicular skeleton are among the most common locations. The sacrum and
pelvis are the most common flat bones involved by this lesion. Giant cell tumors are considered benign,
locally aggressive neoplasm with low metastatic potential.
- Giant cell tumor
- Giant cell reparative granuloma
- Solid ABC
Giant cell reparative granuloma and brown tumor of hyperparathyroidism are histologically
indistinguishable. They are benign, reactive granuloma-like proliferations of fibrovascular tissue with
multinucleated giant cells. The giant cells in both lesions are smaller, contain less number of nuclei
and tend to aggregate around areas of hemorrhage. Giant cell reparative granuloma was originally
described in the jaws as part of cherubism but currently most cases encountered in clinical practice
arise in the small bones of the hands and feet.
Solid ABC may also be histologically indistinguishable from giant cell reparative granuloma and brown
tumors. It may occur as a secondary component to other bone lesions. It is essentially a diagnosis of
Serum calcium, phosphorus, and PTH are normal in patients with giant cell tumor, giant cell reparative
granuloma and ABC, and are very important in the differential diagnosis of bone lytic lesions.
In summary, renal osteodystrophy is a multifactorial disorder of bone remodeling commonly manifested
in patients with chronic renal failure, which has been traditionally attributed to calciotropic hormone
metabolism. However, there is accumulating evidence to suggest that abnormalities of bone acting
cytokines and growth factors as well as the receptors and endogenous modulators are also present in
uremia, and should be considered as potential contributors to the pathogenesis or renal bone disease.
Brown tumors should be considered in the differential diagnosis of patients with chronic renal disease
and osseous masses.
- Fechner RE, Mills SE: Tumors of bones and joints. Atlas of tumor pathology. Fascicle 8, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1993.
- Flinter, F. Alport's syndrome. J Med Genet 1997;34:326-330.
- Dorfman HD, Czerniak B: Bone Tumors. St. Louis: Mosby, 1998.
- Gonzalez, EA. The role of cytokines in skeletal remodeling: possible consequences for renal osteodystrophy. Nephrol Dial Transplant 2000;15:945-950.
- Gonzalez EA, Martin, KJ. Renal Osteodystrophy. Rev Endocr Metab Disord. 2001 Apr;2(2):187-193.
- Kuizon BD, Salusky IB. Cell biology of renal osteodystrophy. Pediatr Nephrol 2002;17:777-789.
- Ferreira A. Development of renal bone disease. Eur J Clin Invest 2006;36 (Suppl. 2):2-12.
- Thorner PS. Alport Syndrome and Thin Basement Membrane Nephropathy. Nephron Clin Pract 2007;106:c82–c88.
- Vigorita VJ: Orthopaedic Pathology, 2nd ed. Philadelphia: Lippincott Williams and Wilkins, 2008.
- Campuzano-Zuluaga G, Velasco-Perez W, Marin-Zuluaga JI. A 60-year-old man with chronic renal failure and a costal mass: a case report and review of the literature. J Med Case Reports . 2009 Aug 4;3:7285.