28/01/2008Brown tumor is a rare clinical non-neoplastic reactive growth that is well described in human medicine in association with primary, secondary (Scholl and others 1999, Mafee and others 2003), or tertiary hyperparathyroidism (Sittampalma and Rosenberg 2001). This lesion is also considered a variant of osteitis fibrosa cystica (Mafee and others), a bone lesions also related with secondary hyperparathyroidism due to chronic renal dysfunction. Most lesions of brown tumor have been described in the ribs, clavicles, pelvic bones and, mandible (Younes and others 2004), but could arise from any bone (Scholl and others 1999, Takeshita and others 2004). Lesions are solitary or multiple (Blaschke 1994, Scholl and others 1999), slow growing and aggressive (Emin and others 2004). Persons with 30-40 years of age are more frequently affected, and there is an apparent female predominance (Blaschke 1994, Sittampalma and Rosenberg 2001, Emin and others 2004). Radiographically, there is demineralization of the medullary bones and marked loss of the lamina dura around the roots of teeth (Blaschke 1994, Scholl and others 1999). Histologically, these lesions are characterized by fibrous proliferation containing woven bone, plump fibroblasts, severe hemorrhage, hemosiderin-laden macrophages, and giant cells (Blaschke 1994, Sittampalma and Rosenberg 2001). Comparable oral lesions described in domestic animals and that must be included in the differential diagnosis include the central giant cell granuloma (Valentine and others 1988) and the peripheral giant cell granuloma (Schneck 1975, Valentine and Eckhaus 1986, Head 1990).
A recent Medline review did not locate a similar lesion described in domestic animals, so this article is unique and opportune as it presents the radiological, gross, and histological findings observed in a brown tumor-like lesion of a young dog. Differential diagnoses of other similar lesions and the pathogenesis associated with this neoplastic-like lesion are also discussed.
The case in question was a 14 month-old, female, English bulldog, with a long-standing clinical history of renal failure. In early January 2005, the owner reportedly noticed the unusual growth of soft tissue in the mouth. The animal was examined routinely at the clinic where mastication and swallowing were not affected, but sporadic vomiting was reported. Laboratory examinations revealed abnormal renal values (urea nitrogen 250 mg/dl; creatinine 6 mg/dl); similar laboratory values and occasional vomiting, progressive wasting, and auto-mutilation were observed during the rest of her life leading to chronic renal insufficiency, that cumulated in extreme values of severe renal dysfunction (urea nitrogen 309 mg/dl; creatinine 11 mg/dl) just before death. Three months later (March 2005) the animal returned to the clinic because of the increasing size of the oral masses that at this time made chewing and eating extremely difficult. At this time, there were several multiple nodular masses, partially recovered by erythematous and ulcerated mucosa, growing in the maxillary bone. These masses extended from the canine tooth to the molar area bilaterally. Teeth (mostly molars and premolars) were severely displaced, with severe expansion of oral and palatal cortical bone. Additionally, there was marked emaciation, extensive salivation, anorexia, auto-mutilation, generalized weakness, azotemia, and paleness of mucus membranes; the owner opted for sacrificed due to the extensive oral lesions and the terminal stage of the animal; necropsy was performed soon after death. Radiological evaluation of the head revealed bilateral destruction of the lamina dura around teeth resulting in a floating appearance to the demineralized bony structures within the maxilla and mandible, associated with marked mandibulary and maxillary osteopenia (Fig. 1). Selected tissues were fixed in 10% formalin solution and processed for routine histopathological evaluation; sections of the oral lesion were demineralized and processed for histopathology.
Marked gross lesions were restricted to the oral lesions and the kidneys. Several whitish-grey, different sized (1.5 x 3.5 x 5.5 cm), smooth-surfaced invasive masses were observed, being more prominent at the oral surface of the maxillary bone (Fig. 2). These tumor-like masses resulted in severe teeth displacement (Fig 3). The sectioned surface revealed the tooth embedded in a firm reddish-brown colored solid tissue. The kidneys were pale, firm, and shrunken with marked adhesion of the capsule to the adjacent cortex. The capsular surfaces of both kidneys were remarkably scarred, irregular with several whitish, finely stippled lines located principally at the cortex of the sectioned renal surface.
Marked microscopic alterations were restricted to the masses removed from the oral cavity and the kidneys. The oral tumor-like lesion was characterized by marked osteolytic activity of the trabeculae of the alveolar bone associated with extensive proliferation of loose fibrous connective tissue that consisted principally of spindle-shaped cells and vascular channels; these channels were either demarcated by endothelial cells or multinucleated giant cells. The connective tissue was severely hemorrhagic with congested vessels and constituted of innumerous randomly distributed multinucleated giant cells, located within vascular channels or adjacent to alveolar bone (Fig. 4). Most giant cells were irregular, eosinophilic with extensive cytoplasm and randomly distributed nucleus (10 – 30); others were more regular in shape, smaller, with nucleus arranged around the periphery of the cellular margin. Mild irregularly distributed hemosiderosis was observed throughout the lesion. Additionally, there was marked focally extensive necrosis and chronic gingivitis of the revisiting squamous epithelium. Marked chronic renal dysfunction (Fig. 5) was characterized by severe focally extensive interstitial fibrosis, marked atrophy and deformation of renal tubules, severe multifocal membranoproliferative glomeruonephritis, glomerulosclerosis, obstruction glomerular, moderate, multifocal metastatic mineralization of tubular basement membranes and some vessels, and multifocal interstitial influx of mononuclear inflammatory cells.
A diagnosis of brow tumor was based on the radiological, gross, and histological findings observed in the mouth of this dog that are consistent with the non-neoplastic lesion described in human medicine (Scholl and others 1999, Okada and others 2000, Sittampalma and Rosenberg 2001, Takeshita and others 2004, Younes and others 2004); in this case the lesion was due to secondary hyperparathyroidism induced by chronic renal dysfunction.
Secondary hyperparathyroidism, as occurred in this case, is characterized by a marked increase in the secretion of the parathyroid hormone (PTH) to compensate for a chronically low concentration of serum calcium without any intrinsic parathyroid abnormality (Drüeke 1999, Mihai and Farndon 2000), due to chronic renal dysfunction. Super-production of PTH could be manifested pathologically by four disease syndromes: demineralization of the skeleton, osteitis fibrosa, brown tumors, and pathologic calcification (Blaschke 1994). Severe chronic renal dysfunction induces a series of sequential events such as the reduction of glomerular filtration, retention of phosphorus, hyperphosphatemia, hinders the production of the active metabolite of vitamin D, stimulates mobilization of skeletal calcium, causes subsequent fibrous osteodystrophy (Capen 1995), and marked activation of osteoclasts (Mafee and others 2003). This explains the predominantly fibrous relative to osseous nature and the marked destruction of alveolar bone in the neoplastic-like oral masses observed in this bitch. In chronic renal failure, as occurred in this case, there is a reduction in the hydroxylation of 25-dehyrodcholesterol to 1,25-dehyrodcholesterol in the kidneys resulting in hypocalcemia due to impaired calcium absorption and hyperphosphatemia (Blaschke 1994).
Additionally, in severe renal dysfunction soft tissue mineralization may occur (Blaschke 1994, Confer and Panceira 1995, Mihai and Farndon 2000). In this case, metastatic mineralization as part of the chronic renal insufficiency syndrome was only observed within the kidney; this has been related to crystallization due to an unusual increase in serum calcium phosphate (Mihai and Farndon 2000). Unfortunately, the serum levels of calcium phosphate, alkaline phosphatase, phosphorus, vitamin D, or PTH were not monitored in this case, since when these parameters are available, clinical characterization of hyperparathyroidism is facilitated (Blaschke 1994, Drüeke 2000, Scholl and others 1999, Mihai and Farndon 2000). Nevertheless, the extremely high serum levels of urea nitrogen and creatinine (chronic azotemia) maintained during the terminal stage of this animal’s life associated with the histological renal lesions described in this report are sufficient to diagnose chronic renal insufficiency (Confer and Panceira 1995), and consequently secondary hyperparathyroidism.
The radiologic alterations observed in this dog characterized principally by the loss of lamina dura around teeth with marked mandibulary and maxillary osteopenia are characteristic of secondary hyperparathyroidism (Myer 1998), and is fundamental to differentiate brow tumor from other similar oral lesions (Blaschke 1994, Scholl and others 1999, Murphey and others 2001, Sittampalma and Rosenberg 2001). The disappearance of the lamina dura around the teeth, as occurred in this case, normally results in a floating appearance to the remaining teeth within the demineralized maxilla and mandible (Myer 1998). In severe cases, where there is concomitant fibrous osteodystrophy, marked thickening of the maxilla and filling of the nasal cavity with soft tissue may occur (Myer 1998); this was not observed in this case. Additionally, the marked teeth displacement, as described in this animal, has already been related to secondary hyperparathyroidism in young dogs (Myer 1998). A clinical sign also observed in secondary hyperparathyroidism in young dogs is the impaired eruption of permanent teeth (Myer 1998); unfortunately, it was not possible to evaluate this manifestation during this case.
In secondary hyperparathyroidism the degree of cortical thinning and decreased bone opacity is directly related to the severity of the mineral imbalance, age of the affected animal, and the chronicity of the disease (Myer 1998). However, the age-related effect has been considered as more characteristic of skull alterations relative to those observed in long bones. Skull demineralization tends to predominate in secondary renal hyperparathyroidism, while cortical thinning of long bones is most severe in the secondary nutritional manifestation of the hyperparathyroidism (Myer 1998); this animal demonstrated marked reduction of bone opacity in the maxillary and mandibulary regions of the head.
In human medicine, brown tumor is more frequently diagnosed in older persons principally women in menopausal age (Okada and others 2000, Sittampalma and Rosenberg 2001, Emin and others 2004); this lesion was observed in a relatively young bitch with chronic renal dysfunction. In this case, the history of an early onset of renal dysfunction that terminated in chronic bilateral renal fibrosis and azotemia are consistent with the clinical and pathological manifestations described in progressive juvenile nephropathy in some dog breeds (Confer and Panceira 1995). However, this syndrome has never been previously described in the English bulldog and the entire list of canine breeds included in this syndrome is unknown, therefore this disease entity should not be totally excluded as part of the etiopathogenia associated with chronic renal dysfunction and consequently secondary hyperparathyroidism in this case. Additionally, the brown tumor as described in humans is normally progressive and expansive, but slow growing lesion (Emin and others 2004), in this case the lesions reportedly reached marked noticeable attention within a period of approximately three to four months.
Brown tumor must be considered as a misnomer (Mafee and others 2003), since there are no neoplastic potential in this invasive growth. The name “brown tumor” is due to the brownish discoloration of the affected tissue seen grossly imparted by excessive hemorrhage and hemosiderosis (Blaschke 1994, Sittampalma and Rosenberg 2001, Emin and others 2004). In this case, hemosiderosis was not a predominant histological event, but the affected tissues were filled with hemorrhage and congested vessels. The randomly distributed multinucleated giant cells observed around the alveolar trabecular bone in this case are considered as osteoclasts by immunohistochemistry and electron microscopy (Okada and others 2000). In brown tumor, existing osteoclasts are activated and attracted to this lesion by matrix-dissolution products, marrow stromal cells, stimulated osteoblasts, and stem cell factor leading to an increase in the pool, differentiation and proliferation of osteoclasts (Mafee and others 2003). Osteoclasts are also considered as estrogen targeted cells (Oursler and others 1994, Roodman 1996), which may partially explain the predominance of brown tumor in adult menopausal females. Additionally, reactive osteoclasts are more predominant in cases of secondary hyperparathyroidism where there is an increased stimulation of osteoclastic bone destruction, hypercalcemia and consequent bone fibrosis (Roodman 1996), as occurred in this case.
To the authors’ knowledge, cases of brown tumor have not been previously described in the veterinary literature, so this lesion must be considered as extremely rare and therefore must be differentiated from other similar oral lesions of dogs. Other lesions described in the canine oral cavity include the central (Valentine and others 1988) and the peripheral giant cell granulomas (Valentine and Eckhaus 1986, Head 1990), the giant cell reparative granuloma (Trigo and others 1983), the giant cell epulis (Schneck 1975), and the giant cell tumor of bone (Head 1990).
The giant cell granulomas (previously described as lesion of giant cells, giant cell tumor, giant cell epulis, and giant cell reparative granuloma) is a collective name given to the occurrence of rare non-neoplastic reactive osseous proliferations described in the head, neck, maxilla, mandible, orbital, paraorbital, and nasopharyngeal regions of humans and animals (Valentine and Eckhaus 1986, Head 1990, Valentine and others 1988, Mafee and others 2003). There has been much confusion leading to the terminology used to describe these lesions previously. In fact, these granulomas are termed “central” when they are confined predominantly to intraosseous locations such as the maxilla and mandible, and “peripheral” when soft tissues (orbital, paraorbital, sinonasal, or oral) are the primary sites (Mafee and others 2003). Although the etiology of these lesions remains unclear, several theories have been postulated, including: 1) a reparative response to intra-osseous hemorrhage and inflammation, 2) a developmental anomaly (Stewart 2000), or hormone-stimulation (Mafee and others 2003). Histologically, these two granulomas are identical; being composed of a fibroblastic stroma with randomly distributed multinucleated giant cells that are found in hemorrhagic areas or in vascular spaces (Neville and others 1998, Stewart 2000, Mafee and others 2003). Additionally, both of these granulomas are considered histologically identical to the brown tumor of hyperparathyroidism (Murphy and others 2001, Mafee and others 2003), except that there are no alterations in the serum values of the PTH. Therefore, definite diagnosis requires serum evaluation of calcium phosphate, alkaline phosphatase, phosphorus, or PTH, if chronic renal insufficiency has not been diagnosed.
The “true” giant cell tumor of bone (previously known as osteoclastoma) is a rare tumor that has been described in domestic animals, principally dogs (Pool 1990). This is a primary tumor originating form the ends of long bones of the apendicular skeleton (Trigo and others 1983), but has also been described in the cranium, vertebral, costal, and metacarpal regions (Pool 1990). Histologically, this tumor is highly vascular and there are various multinucleated giant cells irregularly disturbed throughout the lesion (Trigo and others 1983, Pool 1990). These cells are formed by the fusion of spindle-shaped neoplastic cells and may not originate from osteoclasts (Pool 1990).
1. Blaschke DD: Systemic diseases manifested in the jaws. In: Goaz PW, White SC (eds) Oral pathology: principles and interpretation. 3 ed. Louis: Mosby, 1994. pp. 536-559.
2. Capen CC: Endocrine system. Carlton WW, McGavin MD (eds) Thomson’s special veterinary pathology. 2 ed. St. Louis: Mosby, 1995. pp. 247-284.
3. Confer WA, Panciera RJ: The urinary system. In: Carlton WW, McGavin MD (eds) Thomson’s special veterinary pathology. 2 ed St. Louis: Mosby, 1995. pp. 209-246.
4. Drüeke TB: Cell biology of parathyroid gland hyperplasia in chronic renal failure. Journal of the American Society of Nephrology 11: 1141-1152, 2000.
5. Emin AH, Süoğlu Y, Demir D, Karatay MC: Normocalecemic hyperparathyroidism presented with mandibular brown tumor: report of a case. Auris Nasus Larynx 31: 299-304, 2004.
6. Head WK: Tumors of the alimentary tract. In: Moulton JE (Ed) Tumors in domestic animals. Los Angeles: University of California Press, 1990. pp. 347-435.
7. Mafee MF, Yang G, Tseng A, Keiler L, Andrus K: Fibro-osseous and giant cell lesions, including brown tumor of the mandible, maxilla, and other craniofacial bones. Neuroimaging Clinics of North America 13: 525-540, 2003.
8. Mihai R, Farndon JR: Parathyroid disease and calcium metabolism. British Journal of Anesthesia 85: 29-43, 2000.
9. Murphey MD, Nomikos GC, Flemming DJ, Gannon FH, Temple HT, Kransdorf MJ: Imaging of giant cell tumor and giant cell reparative granuloma of bone: radiologic-pathologic correlation. RadioGrapics 21: 1283-1309, 2001.
10. Myer W: Cranial vault an associated structures. In: Thrall DE (Ed). Textbook of veterinary radiology. 3 ed. Philadelphia: WB Saunders, 1998. p. 47-xx.
11. Neville BW, Damm DD, Allen CM, Bouquot JE. Patologia oral e maxilofacial. Rio de Janeiro: Guanabara-Koogan, 1998. pp.331-341.
12. Okada H, Davies JE, Yamamoto H: Brow tumor of the maxilla in a patient with secondary hyperparathyroidism: a case study involving immunocitochemistry and electron microscopy. Journal of Oral Maxillaafacial Surgery 58: 233-238, 2000.
13. Oursler MR, Pederson L, Fitzpatrick L, Riggs BL, Spelsberg T: Human giant cell tumors of the bone (osteoclastomas) are estrogen targeted cells. Proceedings of the National Academy of Science 91: S227-S231, 1994.
14. Pool RP: Tumors of the bone. In: Moulton JE (Ed) Tumors in domestic animals. Los Angeles: University of California Press, 1990. pp. 157-230.
15. Roodman GD: Advances in bone biology: the osteoclasts. Endocrine Reviews 17: 308-332, 1996.
16. Schneck GW: A case of giant cell epulis (osetoclastoma) in a cat. Veterinary Record 97: 181-182, 1975.
17. Scholl RJ, Kellet HM, Neumann DP, Lurie AG: Cysts and cystic lesions of the mandible: clinical and radiologic-histopathological review. RadioGraphics 19: 1107-1124, 1999.
18. Sittampalma K, Rosenberg AE: Metabolic and reactive lesions simulating neoplasms. Pathology Case Reviews 6: 14-21, 2001.
19. Stewart JCB: Tumores benignos não-odontogênicos. In: Regezi JA, Sciubba JJ (Eds). Patologia bucal. 3 ed. Rio de Janeiro: Guanabara-Koogan, 2000, pp.331-341.
20. Takeshita T, Tanaka H, Harasawa A, Kaminaga T, Imamura T, Furui S: Brown tumor of the sphenoid sinus in a patient with secondary hyperparathyroidism: CT and MR imaging findings. Radiation Medicine 22: 265-268, 2004.
21. Valentine BA, Eckhaus MA: Peripheral giant cell granuloma (giant cell epulis) in two dogs. Veterinary Pathology 23: 340-341, 1986.
22. Valentine BA, Flanders JA, Corapi WV, Rendano VT: Central giant cell granuloma in the mandible of a dog. Journal of the American Veterinary Medical Association 192: 657-658, 1988.
23. Younes N, Mahafza WS, Agabi SS: Brown tumor of the femur associated with double parathyroid adenomas. Saudi Med J 25: 447-450, 2004.