DISEASES OF BONE

SECTION I

PSEUDO‑DISEASES

BONE MARROW DEFECT (Also: osteoporotic bone marrow defect,

hematopoietic bone marrow defect.)

The osteoporotic bone marrow defect occurs as a radiolucent area in the jaws. It is a variant of normal, but is often mistakenly diagnosed as abnormal. There are usually no clinical signs nor symptoms.

Radiographic Features

The bone marrow defect appears as a radiolucent area in bone. Although they occur in all areas of the jaws, the most common location is the molar and premolar region of the mandible. One study reports that 23% of marrow defects occur in old extraction sites. Women are more often affected than men and the median age is 41 years.

Slides #1, #2, #3 and #4 illustrate this condition. The size is ordinarily a few millimeters in diameter and seldom exceeds 1.5 cm. The perimeter may be sharply defined, but segments of the perimeter may gradually fade over a narrow zone into surrounding normal bone. This is especially true of the inferior border.

Histologic Features

Tissue curetted from these "lesions" is a red, jelly‑like substance. Microscopic examination shows it to consist of normal hematopoietic tissue as shown in slides #5 and #6. The pale globules are fat cells and the intervening cells are erythrocytes and leukocytes in various stages of maturation. Occasional multinucleated megakaryocytes (precursor cell of platelets) are

encountered (arrow)

Treatment

None required. This "non‑disease" is often incorrectly diagnosed as a cyst, an infection, or primary or metastatic tumor.

OSTEOSCLEROSIS

In sharp contrast to bone marrow defects, osteosclerosis is an area of dense bone (radiopaque) within the jaw without apparent cause. There are no signs or symptoms.

Radiographic Features

Osteosclerosis appears as a radiodense area within bone; the size ranges from a few millimeters to several centimeters. Most are less than 1.0 cm. The shape varies from round to oval, some are angulated or appear as linear streaks. They appear as a homogenous radiodense area that has a sharp interface with surrounding bone, although some may "trailoff" into surrounding bone. Osteosclerosis may occur in non‑tooth bearing areas (slide #7) between teeth (slide #8) and seemingly attached to teeth (slide #9). Their occurrence in areas of previous tooth extractions (slide #10) suggests that some cases of osteosclerosis may be old foci of condensing osteitis or perhaps the result of deposition of excessive bone during the course of bone repair. While some areas of sclerosis may be a reaction to past episodes of trauma or infection, others cannot be explained on that basis and may be developmental malformations.

Histologic Features

Osteosclerosis is seldom biospied because it is recognized radiographically. Suffice it to say that the sclerotic areas consist of dense but otherwise normal bone.

Treatment

No treatment is required. The principal reason for recognizing osteosclerosis is to guard against over‑diagnosis. benign bone lesions such as ossifying fibroma and even osteosarcoma may appear as radiodense lesions. Unlike true bone tumors, however, osteosclerosis does not displace teeth, does not expand bone and causes no symptoms.

Osteosclerosis is ordinarily a solitary lesion. In people with several areas of osteosclerosis, Gardner's syndrome should be suspected. This autosomal dominant inherited condition consists of multiple areas of bone sclerosis (called osteomas), supernumerary teeth, premalignant intestinal

polyps, and skin lesions that may be either fibromas or epidermoid inclusion cysts. The jaw osteomas of a Gardner syndrome patient are seen in slide # 11.

SUBMANDIBULAR SALIVARY GLAND DEFECT (Also lingual mandibular salivary gland depression ‑ static bone cyst ‑ latent bone cyst ‑ Stafne's bone cyst.)

The submandibular salivary defect is a developmental abnormality that appears as a radiolucent area in the mandible. It may by mistakenly diagnosed as a cyst or a tumor. There are no clinical signs nor symptoms.

Radiographic Features

The salivary gland defect is ordinarily found on panoramic dental x‑rays. It occurs as well‑defined radiolucent area and is oval to round and located below the inferior alveolar canal, above the inferior border of the mandible, and just anterior to the angle of the mandible. Slides # 12, # 13, and # 14 are typical. Although most are "enclosed" in bone, some seen to form a deep notch in the inferior border of the jaw. Often, a portion of the perimeter seems to have a radiodense border, but it seldom encircles the area completely.

One survey of almost 5,000 panoramic films uncovered 18 cases of salivary gland defect (0.4%). Rarely they are bilateral.

The cause of the radiographic "lesion" is a developmental defect in which a lobe of the submandibular salivary gland encroaches on the developing mandible. The mandible has a scooped‑out surface defect to accommodate the gland. Although the area appears as a hole in the bone, it is really a scoopedout depression on the lingual surface of the bone.

Rarely the sublingual gland will encroach on the anterior mandible to produce a radiographic defect. On even rarer occasions, salivary gland tissue may actually become entrapped in bone and lie dormant for years. In later years, the grandular tissue may become neoplastic and produce the paradoxical situation of a salivary gland cancer arising as a primary cancer within bone.

Treatment

No treatment required. Differential diagnosis is usually no problem because of the characteristic appearance and location of the defect.

SECTION 11

NON‑NEOPIASTIC DISEASES OF THE JAWS

OSTEOGENESIS IMPERPECTA (Also: Brittle bone disease,)

Osteogenesis imperfecta is an inherited disease of the skeleton and other connective tissues. Autosomal recessive and dominant forms have been described in four major subtypes. The cause is a deficiency in the synthesis of Type I collagen which is a component of bone matrix, joints, tendons, ligaments, sclera and teeth. Although the skeleton bears the brunt of the disease, other tissues are affected.

Clinical Features

The disease is apparent at birth or becomes evident in the first few days of life. The skeleton is reduced in size, is porous with thin cortices, has small and widely spaced trabeculae, and is extremely susceptible to fracture. The fractures heal, but with the same imperfect bone. A severely affected child experiences fractures with the slightest trauma and their skeleton cannot support their own weight. Hypermobility of the joints is another indication of the widespread nature of this disease. The sclera is thin and the pigmented cells of the retina and choroid show through. This gives a blue or slate grey color to the eye as seen in slide # 15. Paradoxically, there is a tendency toward solidification of the inner ear (otosclerosis) leading to deafness.

The gene for the dental defect known as dentinogenesis imperfecta apparently lies near to the defective gene that causes osteogenesis imperfecta because the two conditions are often inherited together. Slide # 16 is an illustration of the teeth of the patient shown in slide # 15.

Radiographic Features

Slide #17 illustrates the radiographic features of the disease; it is, the arm of a 4‑year‑old girl. No cortex is visible, and the deformity caused by multiple fractures is apparent. Full size, good quality radiographs show the bone to be unusually radiolucent, a result of the porous nature of the defective bone.

Laboratory Values

Serum values of calcium and phosphorus are normal as is the alkaline phosphatase.

Histologic Features

For obvious reasons, microscopic material is difficult to obtain. , We must rely on what others have reported. The bones show thin cortices and decreased numbers of trabeculae that are abnormally thin. Marrow spaces are correspondingly larger than normal.

Treatment

There is no cure for this disease. Complications, such as fractures, are treated as they occur. In severe cases, skeletal growth is greatly retarded and there is extensive deformity. In the type II autosomal recessive form, death

in‑utero or at a very young age is common.

OSTEOPETROSIS (Also: Marble bone disease, Albers‑Schonberg disease)

Osteopetrosis is an inherited disease of bone in which there is failure of normal osteoclastic resorption. Autosomal dominant and recessive forms exist; the latter is more serious and affected infants may be stillborn or die soon after birth.

Although osteoclasts fail to resorb bone, osteoblasts exhibit normal function. The imbalance between osteoblastic apposition of bone and osteoclastic resorption leads to increasing bone density throughout the skeleton.

Clinical Features

There are several consequences of a dense skeleton. Surprisingly, affected bone fractures more easily, probably because trabeculae are not properly molded and aligned along planes that buttress the bone against stress.

As the bone becomes more dense, the marrow volume is correspondingly reduced. This accounts for the major hematologic complication of pancytopenia. Patients may be severely anemic with erythrocyte levels of less than I million per cubic millimeter. Comparable reductions in platelets may lead to a hemorrhagic diathesis with potentially fatal bleeding. Similarly, reduction of leukocytes leads to increased risk of infection. Extraction of teeth or bone injury may lead to osteorayelitis.

Radiographic Features

The radiographic changes are so characteristic they are virtually pathognomonic. Bones exhibit a homogeneous, fine grain density throughout the skeleton. Normal landmarks may be obscured. Slide # 18 is a lateral skull film of an affected patient. At first glance it appears to be poor quality film. Normal suture lines cannot be seen in the cranium and teeth and sinuses are not seen. The reason is that the extremely dense bone obscures normal structures. Slide # 19 is a panoramic view of the jaws of an 11 ‑year‑old girl with osteopetrosis. The bone is homogeneously and finely opaque, and several teeth that should be erupted, or nearly erupted, are entrapped deep within bone. Radiographs of other bone of the skeleton would show the same dense changes.

Laboratory Values

Cellular elements of the blood may be markedly decreased as discussed above. Serum calcium, phosphorus and alkaline phosphatase levels are normal.

Histologic Features

Because the disease is rare and the diagnosis usually made by history and x‑rays, it is uncommon for pathologists to have the opportunity to examine bone from these patients.

Recall that much of the skeleton is first formed in cartilage that mineralizes and is then resorbed (by osteoclasts) and replaced with bone. Throughout life, bone is constantly remodeled and osteoblastic and osteoclastic activity is balanced. In tissue sections of those affected early in life, residual islands of unresorbed mineralized cartilage are found throughout the skeleton, evidence of osteoclastic inactivity. Bone is not remodeled and shaped to body needs and marrow spaces are small and contain inadequate hematopoietic tissue.

Treatment

If a bone marrow donor with a histocompatibility match is available, bone marrow transplantation may correct the disease. The donor's marrow provides the functional osteoclasts that the recipient lacks.

PAGETS DISEASE (osteitis deformans)

Paget's disease is a skeletal disease of unknown cause that may affect a single bone (monostotic form) or multiple bones (polyostotic form). Traces of the measles and repiratory synctial viruses have been found within the osteoclasts

in the disease. This suggests Paget's may be a viral "osteoclastitis".

In the early phase, osteoclastic resorption of normal bone is accelerated. As normal bone is removed, new and abnormal bone is formed by heightened osteoblastic activity. In the late phase; osteoclastic resorption wanes and osteoblastic apposition predominates. The disease may "burn‑out" leaving enlarged and dense bone comprised of atypical trabeculae of "Paget's bone".

Clinical Features

It is uncommon for Paget's to occur before age 40. Men and women are affected equally (or nearly so). The incidence has been estimated to be as high as 3% of the adult population. It is a chronic disease which in its worst form may cause severe pain. Weight bearing bones break easily or may slowly bend under pressure to produce crippling, bowing deformities or compression of spinal nerves. If the base of the skull is affected, occlusion of cranial foramina may produce deafness and blindness.

Although any bone may be affected, the disease favors bones in the midline. Sacrum, spine, skull, pelvis and the large tubular bones of arms and especially the legs are most commonly affected. Facial bones, jaws, ribs and those bones distal to the elbow and knee are far less often involved. The frequency of jaw involvement is uncertain, but one study cites an incidence of 17%. The maxilla is more often involved than the mandible.

Involved bones become progressively larger; flat bones become thicker and round bones increase in circumference. Hats and dentures may no longer fit and in medical lore, these signs have become classics. Teeth may drift apart as the jaws enlarge. Slide #20 is of a 50‑year‑old female with involvement of the right maxilla and base of the skull. Notice the bulky expansion of the patient's right maxilla compared to her left. (Please consult your text for other pictures.)

Patients with Paget's disease have an increased risk of developing sarcoma of bone, chiefly osteogenic sarcoma. The incidence of sarcomatous change in Paget's disease ranges from a low of .95% to 12.5%. The clinical severity of the Paget's disease and age of the patients appear to affect the transformation rate.

Radiographic Features

Early Stage ‑ Osteolysis dominates and the lesion is radiolucent.

Middle Phase ‑ Apposition of "Paget's bone" creates islands of density within the radiolucent lesions. These islands lack the normal trabecular pattern and are homogeneously dense. Because they resemble tufts of cotton, they have been called "cotton wool" densities. Slide #21 illustrates this in the skull. Slide #22 shows Paget's of the mandible in a patient with an edentulous, but normal mwdlIa.

Late Phase ‑ Osteoblastic apposition of atypical bone continues as osteoclastic activity subsides, The bone becomes homogeneously dense. Slide #23 illustrates late stage Paget's of the maxilla. The quality of the film is not great, but the density on the patient's right (arrow) is obvious when compared to the opposite side.

When jaws are involved, the teeth often show hypercementosis.

Laboratory Values

Serum calcium and phosphorous levels are normal, but the serum alkaline phosphatase level is greatly increased to levels not seen in any other disease.

Histologic Features

Microscopic features vary with the stage of the disease. The disease is a struggle between osteoclasts and osteoblasts. In the early stages, osteoclastic resorption outpaces osteoblastic activity. Slide #24 illustrates numerous osteoclasts in resorption lacunae (Howship's lacunae). Slide #25 shows osteoblastic activity recognized as a simple layer of cells lying adjacent to a trabeculae of atypical bone. As resorption and apposition wax and wane, the trabeculae become abnormally shaped. They are small, angulated and often terminate in sharp points or scimitar shape. Episodes of resorption and apposition result in numerous "reversal" lines which make each trabeculae appear to be composed of several smaller pieces fitted together. This is known as the "Chinese character", "jigsaw puzzle" or "mosaic" pattern, and is highly suggestive of Paget's. This is best seen in sections heavily stained with hematoxylin as shown in slide #26. The marrow of Paget's bone shows fibrous replacement, lymphocytic infiltration and vascular dilation.

Summary of histopathology:

1.Osteoclastic resorption and osteoblastic apposition,sometimes in the same field

2."Mosaic" trabeculae

3.Fibrous connective tissue replacement of the normal fatty marrow

4.Vascular dilation

5.Lymphocytic infiltration suggesting an inflammatory basis for the disease

Treatment

Mild cases are asymptomatic and require no treatment. Pain may be controlled with aspirin or indomethacin. Steroids have been reported to suppress the disease, but require large doses with the risk of Cushinoid syndrome. Large doses of sodium fluoride (up to 120 mg/day) may ameliorate symptoms and subcutaneous injections or nasal sprays of calcitonin may reduce the rate of osteoclastic resorption. More recently disodium etidronate has been found to reduce bone resorption an symptoms.

FIBROUS DYSPIASIA

Of all bone diseases, fibrous dysplasia is one of the most mysterious. Diagnostic criteria are not firmly established. The basic defect appears to be a benign proliferation of fibroblasts arising within bone marrow. Normal trabeculae of bone undergo osteoclastic resorption to make room for the expanding cellular mass. Some of the growing fibroblasts undergo metaplasia to become osteoblasts. New bone is formed within the cellular mass. The new bone is abnormal, however, and consists of small and highly irregularly‑shaped trabeculae of embryonic or "woven" bone. The net result is a tumor‑like enlargement of the affected bone which is weakened and liable to pathologic fracture.

Clinical Features

This disease appears more often in‑youth and there is no sex preference. A single bone may be involved (monostotic form) or multiple bone involvement may occur (polyostotic form). In the polyostotic form, other organ system abnormalities may be seen. Multiple bone lesions of fibrous dysplasia accompanied by large patches of melanotic skin pigmentation had been referred to as the "Jaffe" variant. Bone lesions with skin pigmentation and endocrinopathy are referred to as "Albright's syndrome". The main endocrine disturbance in Albright's syndrome consists of precocious puberty in females and hyperthyroidism in males.

Affected bone(s) becomes enlarged with cortical thinning. Although, ordinarily painless, this growth may encroach on other structures (maxillary sinus) or cause pathologic fractures.

Slide #27 is a 19‑year‑old female with a history of slow, painless, enlargement of the mandible which proved to be fibrous dysplasia.

Radiographic Features

The radiographic features are so variable that one wonders if all reported cases are examples of the same disease. Purely radiolucent forms have been described, but the most common appearance is that of a finely trabeculated radiodensity, the so‑called "ground glass" appearance. Occasionally localized areas of density appear on a background that is more radiolucent. This pattern may mimic Paget's disease of bone.

Most authors believe that fibrous dysplasia lacks a sharply demarcated border. Instead, the disease tends to blend into surrounding normal bone so that on the radiograph, the clinician may not see a definite junction between normal and abnormal. Ossifying fibroma may clinically and histologically resemble fibrous dysplasia but it typically has a sharp border. Slide #28 illustrates fibrous dysplasia of the mandible and #29 shows finely trabeculated density of the maxilla encroaching on the sinus.

Laboratory Value

Fibrous dysplasia causes no significant abnormalities in blood calcium, phosphorus or serum alkaline phosphatase.

Histologic Features

Slide #30 is of normal bone and slide #31 is fibrous dysplasia; magnifications are approximately equal. Note the large smooth bordered trabeculae and fatty marrow of normal bone compared to the network of small and irregularly shaped trabeculae in fibrous dysplasia. The marrow is replaced by cellular fibrous connective tissue that shows few mitoses and no nuclear pleomorphism.

Slide #32 is a higher power view of fibrous dysplasia. Some authors state that the trabeculae are often "C" shaped. Analysis of the arrangement of collagen fibers within these abnormal trabeculae shows that the fibrils to be deposited haphazardly whereas in normal bone, collagen fibers tend to lie parallel.

Treatment

Surgery is the only treatment. Small lesions may be adequately treated by simple curettage or cosmetic shaving, but larger lesions may require resection of the involved part.

Radiation therapy is contraindicated. Several patients who have been irradiated have developed osteogenic sarcoma. Radiation may convert a benign lesion into a malignant one.

Differential Diagnosis

Some features of fibrous dysplasia may resemble Paget's, but there are important differences.

Fibrous Dysplasia

Age Youth

Serum No abnormality

X‑Ray Homogeneous density "Ground glass" pattern with ill‑defined borders.

Histology Abnormal trabeculae of immature (woven) bone in a fibrous marrow

Paget's

Over 40

Alkaline phosphatase increased

Lucent to dense depending on stage. "Cotton‑wool" pattern is classic

Extensive osteoclastic and osteoblastic activity surrounding "mosaic" trabeculae with vascular dilation & lymphocytic infiltration of marrow.

CHERUBISM

This rare, inherited disease is characterized by marked fullness of the face. Involvement of the maxilla causes expansion with upward displacement of the eyes producing the so‑called "heavenly gaze". The name "cherubism" comes from the cherubic facial appearance depicted in angelic children commonly seen in Renaissance art.

Clinical Features

The jaws show firm, bilateral painless swellings as shown in slide #33. It is uncommon for the disease to be unilateral, but such a patient is seen in slide #34. The disease occurs mainly in the mandible, but may also involve the maxilla. The swelling usually begins in the posterior regions of the jaws, classically the mandibular rami. No other bone in the body is affected with rare exception. Occasionally, enlarged submandibular lymph nodes are present.

Cherubism has an early onset, usually by age five. It progresses steadily during the childhood years. It is usually inherited as a autosomal dominant trait, but sporadic cases have been reported. Primary and secondary teeth of the affected child may be absent, irregularly shaped, impacted, displaced and/or may have an abnormal eruption sequence.

Radiographic Features

Cherubism appears as radiolucent multiocular lesions with fairly welldefined borders as seen in slide #35. Typically, lesions begin in the mandibular rami and advance anteriorly. A patient with beginning lesions in both rami is illustrated in slide #36. The radiographic features are virtually pathognomonic. No other disease of the jaws is bilaterally symmetrical and begins at such an early age.

Histologic Features

Multinucleated giant cells distributed among spindle shaped fibroblasts is the characteristic finding. These are demonstrated in slides #37 and #38.

Treatment

The disease may be self‑limiting. The lesions may stop growing and regress during the teens. Surgical curettage may achieve cosmetic improvement in those patients with unsightly jaw enlargement. Radiation therapy is contraindicated since it may interfere with facial growth and may also induce sarcomatous change.

FLORID OSSEOUS DYSPIASIA

(Also: Osseous Dysplasia; Sclerotic Cemental Masses of the Jaws,)

The several names for this disease reflect the uncertainty of its origin. Although many regard this as a disease of bone, others think it is of cementum.

We are taught that cementum is a tissue different from bone. However, in chemical composition and structural organization, they are similar. Additionally, there are two diseases of bone that have a profound effect on cementum: (1) hypophosphatasia produces a severe rickets‑like defect of the entire skeleton and cementum is deficient or absent; and (2) Paget's disease of the jaws often causes hypercementosis of the teeth, just as it increases the bulk of bones. If bone and cementum are distinctily different, why do these two bone diseases have an effect on cementum? We believe that cementum may be a variant of bone. If this is true, diseases of cementum are in reality diseases of bone.

Clinical Features

This disease exhibits a strong predilection for middle‑aged, black females. In one reported series of 34 patients, 33 were female and 32 were black. The age ranged from 26 to 59 with a mean of 42 years. Duration was from 6 months to 29 years. Twenty‑three patients were without symptoms, the others complained of intermittent dull pain.

Approximately half of the 34 patients had expansion of the involved bone, but expanision is rarely sufficient to produce facial swelling. Fluid containing bone cavities (cysts) were found in 14 patients, a feature not seen in most University of Missouri patients.

Approximately 50% of patients have involvement of both maxilla and mandible, others have only a single jaw involved. Unilateral disease is rare.

Radiographic Features

The typical case of florid osseous dysplasia shows radiodense masses with surrounding halos of radiolucency. This is easily seen in slide #39 in which lesions are seen throughout the mandible in a 44‑year‑old AfricanAmerican female. In some cases, the lesions seem to originate around the roots of teeth (arrow, slide #40). As the dense material grows, it may attach to the roots of teeth; these observations are taken as evidence the material is cementum. Slide #41 shows large, sclerotic masses in both quadrants of the mandible in a 75‑year‑old African‑American female.

Extraction of teeth in areas of sclerosis may present a problem since some of the hard tissue may cling to the tooth. Slide #42 is a whole mount of a decalcified molar tooth with the roots submerged in lesional tissue.

Laboratory Values

There are no abnorinalities in serum minerals or enzymes.

Histologic Features

Slide #43 illustrates the microscopic features. In the upper left, trabeculae of newly formed matrix resemble bone whereas in the lower right, round and acellular deposits resemble cementum. We regard all this material as bone.

The intervening stroma is cellular and benign fibrous connective tissue. In slide #44, fibrous connective tissue fills the marrow. Osteoblasts line the trabeculae and vascular dilation is evident. The histology has several features in common with fibrous dysplasia and Paget's disease. Paget's bone shows more osteoclastic activity and each trabeculae has more reversal lines. Fibrous dysplasia produces immature (woven) bone.

Treatment

Uncomplicated florid osseous dysplasia requires no treatment. 'The natural course of this disease is slow growth for a number of years. Eventually, most cases become arrested. Surgical entry into this abnormal bone is often followed by osteomyelitis. Therefore, teeth should not be extracted without good reason. Traumatic ulceration of overlying mucosa also predisposes to infection; denture fit should be carefully monitored to avoid this sequelae.

In those cases with superimposed infection, sequestrectomy with primary closure and antibiotics are the accepted treatment.

SECTION III

BONE TUMORS

CENTRAL GIANT CELL GRANULOMA

CGCG is a controversial growth arising centrally within bone. This lesion is seldom found outside the jaws although a histologically similar (if not identical) tumor occurs in other bones of the skeleton. This latter tumor is called "true giant cell tumor" and is regarded as a true neoplasm in contrast to the CGCG which is regarded by many as an exuberant hyperplasia. The term reparative is often used to describe this condition but the absence of previous trauma and the destructive nature of this lesion casts doubt on the reparative theory.

Clinical Features

The "rule of two‑thirds" will remind you that approximately two‑thirds of patients are female, two‑thirds are under age 30, and two‑thirds occur in the mandible. Pain, expansion or a feeling of fullness may call attention to the tumor. The middle and anterior segments of the jaws are most frequently involved.

Radiographic Features

The lesion is purely radiolucent. It may be unilocular or more often multilocular with classic "soap bubble" appearance. Root resorption has been reported in approximately 40% of the cases. Almost an equal number of cases showing root displacement. Slides #45, #46 and #47 are examples of CGCG. In slide #47, the clinician did root canals because the lesion was mistakenly diagnosed as periapical cysts. Although large tumors cause considerable jaw expansion, it is uncommon for the tumor to penetrate the cortex. Multilocular lesions may be confused radiographically with ameloblastoma, myxoma, aneurysmal bone cyst and hemangioma.

Histologic Features

The tumor consists of a solid, cellular proliferation of oval to spindle fibroblasts which lack pleomorphism and have a low rate of mitoses. Scattered throughout these stromal cells are numerous multinucleated giant cells that give this tumor its name. The giant cells presumably are derived from fusion of the mononuclear stromal cells. Erythrocytes percolate through the tumor in poorly formed vascular channels. Slides #48 and #49 are medium and high power views of this tumor. In slide #48 giant cells are identified with arrows and in slide #49, a giant cell dominates the field. Mononuclear stromal cells surround the giant cell.

Treatment

Curettage is usually curative, but recurrence rate aprroaches 20%. Jaw resection may be necessary in some cases.

Differential Diagnosis

Microscopically, CGCG is similar to cherubism, aneurysmal bone cyst and "brown" tumors of hyperparathyroidism. The bilateral nature and genetic aspects of cherubism help in differentiating it from reparative granuloma. Aneurysmal bone cyst (ABC) ordinarily has blood filled cavernous spaces helpful in the diagnosis. Patients with hyperparathyroidism have elevated serum calcium, a feature not seen in patients with giant cell granuloma.

OSSIFYING FIBROMAXEMENTIFYING FIBROMA

These two tumors are generally regarded as variants of the same process and will be discussed as a single entity. This is a benign tumor arising centrally within bone. It is composed of fibroblasts sometimes exhibiting a compact whirled appearance with variable amounts of collagen between tumor cells. Small droplets of calcified material may be produced. This bears a resemblance to cementum and such a lesion is designated "cementifying" fibroma. Other tumors produce trabecuale of bone; this type is called "ossifying" fibroma. They are identical in radiographic appearance and clinical behavior.

Clinical Features

Although this tumor is not rare, neither is it common. No single author has published a large series. It occurs in both jaws, but the molar‑premolar region of the mandible is the most common site. As in many other jaw tumors, the most common symptom is slow and painless expansion of the affected jaw.

This is a tumor that occurs primarily in the third and fourth decades with a

female prepondance.

Radiographic Features

The appearance is variable and depends on the amount of cementum or bone produced. Those tumors with little calcified material are radiolucent. Those with much calcified matrix are radiodense. Naturally, intermediate degrees of radiolucency‑radiodensity may be seen.

The border of the tumor is usually sharply circumscribed which helps in distinguishing this tumor from fibrous dysplasia which it may resemble microscopically. Unilocular and multilocular forms exist. Expansion in all directions may occur, but perforation of overlying bone rarely occurs. Slides #50, #51, #52 and #53 illustrate ossifying/cementifying fibroma.

Histologic Features

The tumor consists of a compact mass of benign fibroblasts. Tumor cells are oval to spindle shape and secrete variable amounts of collagen. In the variant known as cementifying fibroma, acellular droplets of calcified matrix are produced. This is illustrated in slide #54. Slide #55 is a higher power view. In the "ossifying" fibroma variant, trabeculae of bone are produced. This is illustrated in slide #56. This tumor does not have a capsule around it, but the interface between tumor and surrounding bone is sharp.

Treatment

The treatment is curettage, recurrence is infrequent. Slide #57 is an ossifying fibroma in a 16‑year‑old girl. Slide #58 is the same patient 10 months following curettage. Several teeth were sacrificed, but notice how bone ' has filled in the surgical site. A variant of this lesion called a "juvenile ossifying fibroma" may behave in a more aggressive fashion.

EWING'S SARCOMA

Ewing's sarcoma is the most malignant tumor arising in bone. The cell of origin is a primitive nerve cell that has a 11:22 reciprocal chromosome translocation. Microscopically, the tumor consists of compact masses of small, round cells with uniform nuclei and scant cytoplasm. To the surgical pathologist, Ewing's tumor is difficult to distinguish from other tumors composed of small, round cells such as lymphocytic lymphoma, Burkitt's lymphoma, metastatic neuroblastoma, and metastatic embryonal rhabdomyosarcoma.

Clinical Features

This tumor is seen chiefly in youth. Most patients are under age 30, and many are under age 10. Pain and swelling are the most common complaint. The patient may have fever, leukocytosis, and increased erythrocyte sedimentation rate leading to an incorrect diagnosis of an infection rather than tumor. No bone is immune to Ewing's tumor, but 60% occur in pelvis and legs. Unlike many bone tumors which favor the ends (epiphysis and metaphysis) of tubular bones, Ewing's is often found in the shaft (diaphysis). Ewing's tumor in the jaws is a rarity.

Radiographic Features

The tumor produces no mineralized matrix and therefore appears as a pure radiolucency. The border may be indistinct in contrast with benign tumors which often are sharply demarcated. As the tumor breaks through cortex, the periosteum may lay down successive layers of reactive bone to produce the classic "onionskin" appearance. Radiating spicules from the tumor surface may also mimic the sunburst appearance of osteosarcoma. Slide #59 is an occlusal radiograph of a large Ewing's tumor in the midline of the anterior maxilla. The patient presented with swelling and epistaxis. Slide #60 is an intraoral film of the same patient illustrating the destructive nature of the tumor with resorption of the roots of the teeth.

Histologic Features

The tumor is composed of sheets of compact, small, round tumor cells with uniform nuclear size and scant cytoplasm. Trabeculae of fibrous stroma may course through the tumor dividing sheets of tumor cells into smaller aggregates. Slide #61 and #62 are medium and high‑power views of a Ewing's sarcoma. Approximately 80% of Ewing's tumors will have tumor cells whose cytoplasm is rich with glycogen, This can be demonstrated with the PAS (periodic acid‑Schiffl stain in which glycogen stains bright pink to red. This is helpful in distinguishing Ewing's tumor from other small cell tumors, most of which lack glycogen. Other markers of nerve cell origin such as S‑100 and neuron specific enolase (NSE) are positive and help distinguish Ewings from other small round cell tumors.

Treatment

Ablative surgery, high dose irradiation and chemotherapy are combined

in the treatment of this dreadful tumor.

Sixty‑six patients with Ewing's tumor treated at the National Cancer Institute with combined radiation therapy and intensive chemotherapy (adriamycin, cyclophosphamide and vincristine) had a 52% five year survival in those who had no detectable metastases at the time of diagnosis. Not many years ago, virtually all patients with this tumor died.

OSTEOGENIC SARCOMA

(Osteosarcoma)

Osteosarcoma is a tumor in which malignant osteoblasts produce an atypical product, either osteoid or bone. Mutations are thought to be the major cause of osteosarcomas. Mutations associated with retinoblastoma and P53 suppressor gene are frequently found. A prior history of radiation therapy

is also suspected as a etiologic factor. Osteosarcomas frequently develop in sites of active mitotic activity. Common sites include femoral growth plates and in bone tumors such as Paget's disease that exhibit active osteoid production.

Clinical Features

Osteosarcoma occurs in all bones of the skeleton. The distal metaphysis of the femur is the most common site. They are a tumor of youth and peak in the second and third decades. A patient over age 40 with osteosarcoma in the long bones should be suspected of having underlying Paget's disease.

The chief signs and symptoms are swelling pain of the affected site. Growth of the tumor is rapid and 20% have metastases to the lungs at the time of diagnosis. Although hematogenous metastasis is the primary pathway, lymphatic spread does occur. Lung metastases result from hematogenous spread and regional lymph node metastases are the result of lymphatic dissemination.

It is estimated that approximately 6% of osteosarcomas arise within the jaws. The tumor affects both sexes equally and the mean age of patients with jaw tumors is in the early thirties, 10 years older than for osteosarcomas that arise in other bones. The most common symptoms in descending order were swelling, pain, loose teeth and paresthesia.

Slide #63 illustrates a somewhat unusual presentation. An elderly man had a loose maxillary left second molar tooth. The dentist believed the tooth to be loose because of periodontitis and the tooth was extracted. Within days, a tan mass of tissue grew from the extraction socket.

Microscopic study showed this tissue to be osteosarcoma that had simply exited through the extraction socket. Radiographs were taken revealing a large area of bone destruction. The tumor was removed and a picture of the surgical specimen is shown in slide #64.

Radiographic Features

As with many bone tumors, both benign and malignant, the radiographic appearance is variable and depends on the amount of tumor bone synthesized by the malignant osteoblasts. In those tumors with little "tumor bone", the radiographic appearance will be radiolucent; whereas those tumors with much tumor bone will be radiodense. Mixed lucent‑dense lesions indicate an intermediate degree of tumor bone formation. There are 3 features of osteosarcoma that are classics: (1) small streaks of bone radiate outward from approximately 25% of these tumors. This produces a sunray (sunburst) pattern. This is shown in a resected osteosarcoma of the mandible seen in slide #65; (2) in the jaws, this tumor may grow within the periodontal membrane space causing resorption of the adjacent bone resulting in uniform widening of the space. This is seen in slide #66. Widening of the periodontal membrane space may also be seen in other conditions such as chondrosarcoma and scleroderma so it is not pathognomonic; and (3) in long bones affected with osteosarcoma, the periosteum is elevated over the expanding tumor mass in a tent‑like fashion. At the point on the bone where the periosteum begins to lift (edge of the tent), an acute angle between the bone surface and the periosteum is created. This is called Codman's triangle and is highly suspicious for osteosarcoma.

Slide #67 is a film of a radiodense "osteoblastic" osteosarcoma in the anterior maxilla of an 1 1‑year‑old girl. With a little imagination, you can see a slight "sunburst" appearance on the superior aspect.

Laboratory Values

No significant abnormalities.

Histologic Features

The single feature necessary for the diagnosis of osteosarcoma is the formation of osteoid by a sarcomatous stroma. Osteoid (bone matrix) appears as eosinophilic (pink) trabeculae as shown in slide #68 and #69. Much of the osteoid calcifies to become bone. Calcification is recognized microscopically by increased basophilia (blueness) which usually starts in the central areas of the osteoid, leaving a rim of eosinophilic uncalicified matrix as illustrated in slide #69.

The stomal cells show considerable nuclear abnormalities, such as atypical mitoses, enlarged nuclei, with hyperchromasia and great variation in nuclear size and shape (pleomorphism). These features are illustrated in slides #68 and #69, but are best seen in slide #68.

Three common histologic varieties of osteosarcoma are identified; formation of tumor osteoid (bone) is the common denominator. Some tumors synthesize large amount of osteoid (osteoblastic variety), others secrete considerable malignant cartilage matrix (chondroblastic variety), and others secrete little matrix material (fibroblastic variety). In the jaws, the chondroblastic variety is most common.

Treatment and Prognosis

Treatment is ablative surgery. This tumor arises in the medullary portion of bone, infiltrates adjacent tissues and readily metastasizes. Improved treatment regimens have increased the overall five year survival rate to approximately 60%. Chemotherapy is beneficial and combinations of cyclophosphamide, vincristine, L‑phenylalanie mustard, and adriamycin are often used as an adjunct to surgery.

Osteogenic sarcoma arising in Paget's disease is especially malignant, the 5‑year survival is approximately 8%.

Occasionally, sarcomas arise in the outer cortex of bone (parogteal osteosarcoma) or in the periosteum (periosteal osteosarcoma). These variants are rare, usually show a high degree of differentiation and carry a more favorable prognosis.

Osteosarcomas of the jaws require radical resection, hemimandibulectomy or hemimaxillectomy. In large tumors the recurrence rate is high and overall five year survival is approximately 40%. Radiation therapy is of little benefit. Osteosarcomas of the jaws usually do not metastasize, however they do recur locally. This is the major cause of death.

CHONDROSARCOMA

The malignant neoplasm of chondrocytes has much in common with osteosarcoma. This section will therefore be brief and will point out the major differences between the two tumors.

Clinical Features

This tumor is about one half as common as osteosarcoma with most occuring in those fifty or older. Common sites include the pelvis, ribs, shoulder, and long bones. Approximatley 12% occur in the head and neck region. Jaw lesions typically occur 10‑20 years earlier than other skeletal lesions and present as a painless enlargement or widening diastema. Widening of the periodontal ligament space is often seen radiographically.

Radiographic Features

The tumor may be purely radiolucent, radiodense or a mixture of radiolucency and radiodensity. The malignant chondrocytes secrete hyaline cartilage matrix that calcifies. The degree of radiodensity reflects the amount of calcified matrix. We have no good clinical photographs of this tumor in the jaws.

Histologic Features

Atypical chondrocytes that secrete cartilage matrix are the diagnostic features of this tumor. Slides #70 and #71 illustrate this. Note the variability of the size, shape and staining intensity of the chondrocyte nuclei that occupy the large lacunae within the cartilage matrix. Some chondrosarcomas are extraordinarily well‑defferentiated and the pathologist may have difficulty distinguishing such a tumor from a benign chondroma.

Treatment

Total sugical resection is the best treatment. The tumor is radioresistant and chemotherapy has limited value. Most patients who die of this tumor will die of local recurrence; distant metastasis occurs late in the course of the disease. Unusual behavior has been reported in this tumor. Chondrosarcoma arising near a major vein (eg. iliac or femoral veins) may penetrate the vessel wall. Without losing attachment to the main body of the tumor, a solid "plug" (tumor thrombus) will fill the vein and literally grow "downstream". Rare cases may even have a tumor thrombus with a tail so long it reaches the heart. With radical surgery, the five year survival rate is 40‑60%. Some references report that 60% of patients have recurrence within 5 years and many have recurrences 10‑20 years later.

MULTIPLE MYELOMA

Multiple myeloma is a malignant neoplasm of plasma cells. Myeloma is a functional tumor that secretes large quantities of immunoglobulin. These proteins are readily detected in the serum by electrophoresis and are referred to as the M (myeloma) component. Any of the 5 classes of antibodies may be produced, but IgG is the most common. Light chains may be produced in excess of heavy chains and are excreted in the urine where they are referred to as Bence Jones proteins. Myeloma has several variants, all of which secrete excess immunoglobulins. Collectively they are referred to as plasma cell dyscrasias, gammopathies, dysproteinemias or paraproteinemias.

Clinical Features

Bone pain caused by mulitple plasma cell tumors within bone marrow is often the earliest symptom. Normal hematopoietic tissue is replaced by expanding plasma cell tumors leading to nonnocytic, normochromic anemia. Hypercalcemia develops as bone is resorbed. Approximately 10% of myeloma patients develop amyloidosis caused by the precipitation of immunoglobulin light chains within organs and tissues. Myelophthisic leukopenia and the inability to elaborate normal antibodies leads to increased susceptibility to bacterial infections. Kidney failure is a late sequelae of myeloma. Hypercalcemia may lead to in metastatic calcification of renal interstitial tissue. Amyloid deposition in the renal glomeruli causes glomerulosclerosis leading to the nephrotic syndrome. Pathologic fracture of involved bones is a feature of late stage disease. Although myeloma affects many organs and tissue, the plasma cell tumors in bone marrow are the dominant feature. They occur in any and all bones, but favor bones in or near the midline (skull, vertebrae, pelvis, ribs).

Radiographic Features

Multiple "punched‑out" 1 to 4 cm radiolucent lesions in bone are the characteristic features. Slide #73 is a skull film showing numerous lesions and Slide #74 is an edentulous jaw film with a tumor in the mandible. Similar radiographic lesions may be seen in histiocytosis X and metastatic carcinoma.

Histologic Features

Diagnosis rests on the microscopic identification of plasma cell tumors within bone. The tumor cells may exhibit a high degree of differentiation and be remarkably normal appearing or they may be so poorly differentiated that they bear little resemblance to plasma cells. (Recall that plasma cells are differentiated B lymphocytes). Slide #75 is a medium power view that shows a plasma cell tumor. Slide #76 is a high power view. Cells are easily identified as plasma cells because of the abundant cytoplasm with eccentric nuclei. In some cells, nuclear chromation appears in small clumps which resemble numbers on a clock (so‑called clock‑face appearance.)

Treatment

Remission may be achieved with systemic chemotherapy. The median

survival time with multiple myeloma is approximately three years.

Variants of Myeloma

A. Solitary Myeloma (Plasmacytoma)‑ single plasma cell tumor in the bone or soft tissue with minimal M‑component in serum. Progression to multiple myeloma is rare in soft tissue plasmacytomas whereas most solitary bone plasmacytomas progress to classic myeloma.

B. Plasma Cell Leukemia ‑ a rare variant of MM in which the malignant plasma cells are released from marrow and flood the circulation.

Diseases closely related to myeloma

A. Waldenstroms Macroglobulinemia ‑ a malignancy of B lymphocytes in which the degree of cellular differentiation lies halfway between lymphocyte and plasma cell. These tumors secrete mostly IgM and many of the clinical symptoms of the disease are caused by the resultant hyperviscosity of the blood (retinal and cutaneous hemorrhage, confusion & paresis). Tumor masses are not confined to bone marrow, but may also occur in lymph nodes and spleen.

B. Benign Monoclonal Gammopathy ‑ a small number of adults will be found to have a slight increase in circulating monoclonal (single type) antibody, but no evidence of plasma cell tumors. These patients are prone to amyloidosis, but few if any progress to myeloma.

C. Heavy Chain Disease (Franklin's disease) ‑ a plasma cell dyscrasia resembling Waldenstroms except only heavy chains are produced.

LANGERHANS' CELL GRANULOMATOSIS

(histiocytosis x)

This is an uncommon disease of variable behavior caused by proliferation of a special type of histocyte called a Langerhans' cell. In some patients, it behaves as a neoplasm whereas in others it may undergo spontaneous remission. It has recently been reported to be a monoclonal growth indicating that it is neoplastic rather than reactive (NEJM 7‑94). Clinical Features

Patients with Langerhans' cell Histiocytosis (LCH) tend to fall into three categories, each of which has an eponym.

1. Letterer‑Siwe Disease (Acute Disseminated LCH) – the severe form. Onset is usually before age 3 and is often fatal. Lesions are found throughout the skeleton, viscera and skin.

2. Hand‑Schuller‑Christian Disease (Unifocal or Multifocal

LCH) ‑ less severe than Lettere‑Siwe disease with fewer lesions. Occurs in late childhood and teens, and has better prognosis. In rare cases, may produce diabetes insipidus, exophthalmos, and multiple radiolucent lesions in bone known collectively as the Hand‑Schuller‑Christian triad.

3. Eosinophilic Granuloma (Unifocal or multifocal LCH) – the mildest form of the disease often presenting as a solitary lesion of bone. Occasionally, patients may have multiple bone lesions; skull and femur as the most common locations. It occurs chiefly in young adults and has a good prognosis.

The signs and symptoms of LCH naturally vary with the severity of the disease. The younger the patient at onset, the more serious the disease. Generalized skin rash results from skin infiltration. Ear drainage may signal involvement of the ear and temporal bone. Spleenomegaly and hepatomegaly due to cellular infiltrates are common in the disseminated form of the disease. Multiple lesions in bone marrow may elicit skeletal pain. Polyuria seen in the HSC triad is attributable to histiocytic infiltrates in the hypothalamic‑posterior pituitary axis which impairs secretion and storage of antidiuretic hormone. Exophthalmos is due to histiocytic accumulations behind the globe.

In dental practice a solitary lesion of the jaw (eosinophilic granuloma) is the usual presenting sign. They are frequently painful.

Radiographic Features

Figures 77, 78 and 79 illustrate LCH of the jaws. The lesions are purely radiolucent and may occur anywhere within the jaws. The mandible is more frequently involved than is the maxilla and the middle and anterior segments are the usual site. The rami are infrequently involved. In tooth bearing areas, LCH may resemble dental and periodontal infections. The classic textbook description is that of destruction of bone around a tooth (teeth) leaving the tooth "floating" in a radiolucent "blackhole" or "air".

In the widely disseminated form occurring in children, the jaws may have horizontal loss of alveolar bone in one or all quadrants and thus be easily confused radiographically with prepubertal periodontitis, and Burkitt's lymphoma.

Histologic Features

Regardless of the severity of the disease, the microscopy is the same. It is characterized by the proliferation of Langerhans' cells that infiltrate and replace normal tissue. The proliferation is often accompanied by eosinophils. (You are urged to remember that the Langerhans' cell is the cell of origin. Students often mistakenly believe that the eosinophil is the cell of origin.) Areas of necrosis may be present and in a minority of cases, eosinophils may be so numerous that "eosinophilic abscesses" may form. Slide #80 is a medium power view of a typical lesion. The most numerous cells are Langerhans' cells (Arrows). Nuclei are round to oval with occasional indentation or fold to produce a bean shape. There is no pleomorphism and mitoses are few. 'The cytoplasm is moderate in amount and is eosinophilic. Cytoplasmic boundaries are indistinct where cells are closely packed, but may be easily seen in cells lying apart. Unique cytoplasmic organelles called Birbeck granules are found with electron microscopy. The eosinophils are easily recognized by their red, granular cytoplasm and nuclei that are often bilobed or trilobed.

Treatment

In mild, localized disease, curettement or low dose irradiation (1800 rads or less) are usually sufficient for cure. In severe, disseminated disease, systematic chemotherapy in indicated. Prednisone, vinblastine, vincristine and methotrexate have been used with some success. The death rate from acute disseminated disease still is nearly 50%.

Before ending this study set on bone diseases, there are several other diseases sufficiently common or "classic" to deserve a few comments. They are:

1. Osteoporosis

2. Rickets and osteomalacia

3. Caffey's disease

4. Vanishing bone disease

5. Aneurysmal bone cyst

6. Osteoid osteoma

7. Achondroplasia

8. Hyperparathyroid bone disease

OSTEOPOROSIS

A reduction in skeletal mass may be seen in a variety of diseases such as hyperparathyroidism, Cushing's disease and dietary deficiency. Such reductions are referred to as "secondary" since they are a consequence of another disease. Reduction in skeletal mass with no known cause is referred to as "Primary" osteoporosis. It affects 15 million adults in the United States and is the chief underlying cause of bone fractures in the elderly. Although it occurs in males, postmenopausal females are the principal victim. There is some controversy about the pathogenesis. Long considered to be caused by reduced synthesis of bone matrix, a recent review article indicates that osteoblastic activity is normal, but osteoclastic activity is increased. The imbalance leads slowly, but inexorably to diminished bone mass although the bone is qualitatively normal.

Weight bearing bones bear the brunt of the disease. The vertebrae and head of the femur are especially vulnerable. Of the 200,000 hip fractures each year in the United States 80% of the patients have pre‑existing osteoporosis.

Radiographs show diminished bone density with thin cortices. Microscopically, trabeculae are few and thin and marrow space is correspondingly increased.

Replacement estrogen therapy is beneficial in women, but benefits must be weighed against the increased risk of adenocarcinoma of the endometrium caused by the hormone. High dietary calcium intake (1500 mg/day), increased fluoride intake (20 mg/day) and exercise is recommended.

Rickets and Osteomalacia

Deficiant mineralization of bone. matrix (osteoid) produces a weak skeleton known as rickets in children and osteomalacia in adults. Weight bearing bones are bowed and easily fractured. There are three main pathways leading to these conditions:

1. simple dietary deficiency of minerals (Ca & P) and vitamin D.

2. intestinal malabsorption of minerals and vitamin D because of a variety of intestinal diseases.

3. kidney disease in which loss of renal tubular cells lead to deficiant. hydroxylation of 25‑OH‑D3 to 1,25 – dihydroxy D3, the active form of vitamin D. Deficient "active" vitamin D leads to reduced intestinal absorption of calcium with resulting mineralization defects. Additionally, hypocalcemia triggers the parathyroid glands to increased PTH secretion which promotes osteoclastic resorption of an already weakened skeleton, a double‑barrel effect. Osteomalacia which has its origin in the kidney has been referred to as "renal osteodystophy."

Caffey's Disease

(also: infantile cortical hyperostosis)

This is a disease of unknown origin usually occuring in the first, few months of life. Affected bones develop thick cortices and overlying soft tissue and skin are swollen and warm. Patients may have fewer and leukocytosis suggesting an infection, but no pathogen has been isolated, and it is unresponsive to antibiotics. It is said to be self‑limiting, burning out in a few months.

Vanishing Bone Disease

(also: Gorham's disease, phantom bone disease and massive osteolysis)

A rare and very mysterious disease in which a bone(s) or portion of a bone simply disappears and is replaced by moderately vascular fibrous connective tissue. A few cases have been reported in the jaws.

Aneurysmal Bone Cyst

A tumor‑like growth in bone which histologically appears to be one‑half giant cell tumor and one‑half hemangioma. Large blood‑filled cavernous spaces with intervening "giant cell‑like" stroma is the characteristic histologic finding. Some consider ABC to be simply a variant of giant cell tumor. Treatment is curettage and the prognosis is good.

Osteoid osteoma

A rare bone tumor with a doughnut appearance on radiograph i.e., a circle of radiodensity with a central hole of radiolucency. They are painful and peculiarly, the pain is most responsive to aspirin. Large osteoid osteomas are called "osteoblastoma".

Achondroplasia I

A form of autosomal dominant dwarfism in which the head and trunk are of normal size, but arms and legs are very short and bowed. It is an unkind, but they are said to be typical "circus" dwarfs.

Hyperparathyroid bone disease

Increased secretion of parathyroid hormone may occur as a "primary" or secondary" disease. Primary hyperparathyroidism is usually attributable to functional parathyroid tumors most of which are benign adenomas. Inappropriate secretion of PTH by non‑parathyroid tumor, such as oat cell carcinoma of the lung and renal cell cacinoma account for a small percentage of cases. Regardless of the etiology, hyperparthyroidism causes resorption of bone which reduces skeletal mass. In severe cases, bone cavities develop which become filled with fibrous tissue loaded with giant cells and hemosiderin pigment. These have been referred to as "brown tumors."

Secondary hyperparathyroidism is usually the result of chronic renal disease as discussed in item 3 under section on rickets.