Bone & Soft Tissue Pathology

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.

Labs:
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
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Figure 1
Preoperative radiograph showing a large lytic lesion in the right iliac wing.
Figure 2
The resected tumor is well circumscribed with a fleshy, tan-pink to brown cut surface.
Figure 3
Low power view shows a nodular configuration with discernible giant cells.
Figure 4
Intermediate power showing fibrovascular stroma with numerous giant cells, abundant hemosiderin deposition and focal hemorrhage.

Figure 5
High power showing a proliferation of bland spindle cells with osteoclast-like giant cells aggregated around areas of hemorrhage.
Figure 6
Very high power view of the vascular spindle cell stroma with osteoclast-like giant cells and hemosiderin-laden macrophages.
Figure 7
Low power view of the trabecular bone adjacent to the tumor showing osteopenia and normocellular marrow.
Figure 8
Intermediate power showing tunneling resorption of trabecular bone with associated fibrosis (dissecting osteitis).

Figure 9
High power shows increased bone remodeling with marked osteoblastic and osteoclastic activity, irregular cement lines and peritrabecular fibrosis.
Figure 10
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.

Key words:
Brown tumor, osteitis fibrosa cystica, hyperparathyroidism, renal osteodystrophy.

Discussion:
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, 25-dihydroxycholecalciferol).

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 adynamic bone.

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 unmineralized osteoid.

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 disease.

Differential diagnosis :
  • Giant cell tumor

  • Giant cell reparative granuloma

  • Solid ABC
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 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 exclusion.

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.

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