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differential diagnosis of hypercalcemia
Parathyroid-related, malignancy-related, vitamin D- related, associated with high bone turnover, or associated with renal failure.
Sx of hypercalcemia
Hypercalcemia can account for the nephrolithiasis and lethargy. Other manifestations include: mental confusion, fatigue, arrhythmia, etc.
Hypercalcemia can also be asymptomatic (~50%).
Symptoms depend on Ca level:
above symptoms more common with levels > 11.5,
> 13 parenchymal organ calcification is more common; > 15mg/dl can produce coma or cardiac arrest.
Causes of Hypercalcemia
Hemoconcentration
Malignancy - paraneoplastic syndrome
Malignancy - secondary to bone destruction by tumor
Primary hyperparathyroidism
Milk-alkali syndrome
Drug effect
Other endocrine abnormalities (thyroid disease, acromegaly)
What labs would help you differentiate between primary
hyperparathyroidism and malignancy-associated
hypercalcemia?
PTH and PTHrP. Both entities result in hypercalcemia, but in primary hyperparathyroidism this is
accompanied by elevated PTH, whereas in malignancy
associated hypercalcemia the PTHrP is elevated.
List the Main Causes of Primary Hyperparathyroidism
Parathyroid adenoma (80%)
Parathyroid carcinoma (5%)
Primary parathyroid hyperplasia (15%)
Many patients are asymptomatic and are diagnosed by finding an increased calcium and low (or low normal) phosphate while undergoing routine laboratory testing
Parathyroid adenoma: Histo
Stromal fat, present in normal parathyroid, is absent (A).
Proliferation of cells in nests and gland-like structures (B).
Hyperparathyroidism Bone effects
Central part of trabeculae tunneled out by PTH-activated osteoclasts (dissecting osteitis) – safest way for body to resorb bone, i.e. outer shell of each trabeculum remains intact and able to bear weight. Eventually, tunnel composed of fibrous tissue (osteitis fibrosa). Accumulation of hemosiderin secondary to bleeding at the site of bone reabsorption commonly gives these lesions a brown color (“brown tumors”).
Von Recklinghausen disease of bone
With progression, increased resorption and fibrosis, cysts form within the fibrotic marrow --known as osteitis fibrosa cystica
What is secondary hyperparathyroidism??
Hyperparathyroidism that occurs in patients with chronic hypocalcemia due to:
renal failure, vitamin D deficiency, malabsorption
Diffuse hyperplasia (secondary hyperplasia) of the parathyroid glands is typical
What is Renal Osteodystrophy?
Term that describes bone changes secondary to chronic renal failure. These changes include:
1. Osteitis fibrosa cystica
2. Osteomalacia
3. Bone disease secondary to aluminum deposition in patients undergoing renal dialysis
How does renal osteodystrophy develop?
Decreased GFR, damaged tubules don’t excrete phosphorus
and decreased synthesis of 1,25 OH vitamin D > hypocalcemia > increased PTH > osteitis fibrosa cystica and osteomalacia or rickets
What is osteopenia
Osteopenia is "decreased bone mass" (seen radiologic or histologic)
What is Osteoporosis
Osteoporosis is the clinical syndrome that occurs when osteopenia becomes symptomatic (bone pain or fractures).
By DEXA they can also be differentiated by the degree of bone mass reduction (>2.0 sd in osteopenia, >2.5 sd in osteoporosis).
What are the clinical
manifestations of compression fractures?
Pain and muscle spasm
if acute, kyphosis if
gradual.
Epidemiology: Osteoporosis
Epidemiologic data:
54% of women post-
menopause are
osteopenic, 30% are
osteoporotic, 27% have
sustained a vertebral compression fracture by age 65. Of the 300,000 hip fractures/year in the USA, 90% are osteoporotic and 24% are fatal within a year.
Histologic Features: osteoporosis
Thin cortex (arrow)and thin bone trabeculae (circles).

Microfracture with callus
What is primary osteoporosis?
An overall loss of bone mass
Begins during middle age years; accelerates in women after menopause (senile and postmenopausal types)
Factors leading to an increased bone mass:
Calcium intake in early life and
Exercise
Factors increasing the rate of bone loss:
Decreased estrogen
Decreased physical activity
Discuss the pathogenesis of primary osteoporosis.
Gradual and overall loss of bone mass over many years due to osteoclastic activity > osteoblastic activity.
Begins during 4th decade – rate of bone loss/year is 0.3% in males and 0.5% in females.
List at Least 5 Causes of Secondary Osteoporosis
The main reason: **Glucocorticoids excess (suppress osteoblasts)//

Immobilization
Cushing’s syndrome
Thyrotoxicosis
Hyperparathyroidism
Hypogonadism
Diabetes mellitus
Protein malnutrition
Malabsorption
Alcoholism/Cirrhosis
Ascorbic acid deficiency
Postgastrectomy
Multiple myeloma
Leukemia/Lymphoma
Ehlers-Danlos syndrome
Osteogenesis imperfecta
Drugs(corticosteroids, heparin, methotrexate, GnRH analogues, lithium, cyclosporine)
(Table 21-1, Robbins Basic Pathology)
How Does Osteoporosis Affect the Levels of Serum Calcium, Phosphate and PTH?
In spite of the marked decrease in mineral content in bone, serum calcium, phosphate and PTH are normal
Since there is no increase in osteoblastic activity, serum alkaline phosphatase is normal
What are Heberden’s nodes?
Subcutaneous nodules (osteophytes) at the distal interphalangeal joints.

Think Rheumatoid Arthritis
Case: Case History:
A 65 year-old woman complains of pain in her back and both knees for several years
The pain is worse when she is standing up or walking and relieved by rest
There is no swelling or redness of the joints
Physical examination reveals Heberden’s nodes

What would be your main consideration if she complained of joint swelling and redness?
Rheumatoid arthritis, the most common inflammatory arthritis.
Define osteoarthritis.
A primary degenerative disorder of the articular
cartilage in which progressive loss of cartilage and
overgrowth of bone spurs (osteophytes) combine to
limit joint motion.

You have articular cartilage loss and 2o bone changes
(osteophytes, cysts, subchondral sclerosis)
What bones are affected most commonly in osteoarthritis?
Weight bearing joints, such as the intervertebral joints, the hips and the knees.
For unknown reasons, the distal interphalangeal joints of the hands are often affected; the osteophytes at that location form “Heberden's nodules.”
Gross and Radiologic Features:Osteoarthritis
Cysts (synovial fluid enters subchondral bone, forming fibrous-walled cysts)
Loss of articular cartilage, results in friction of exposed bone surfaces resembling polished ivory (“eburnation”)
Histologic features:Osteoarthritis
Extensive loss of articular cartilage, with “fibrillation” or “flaking” of the surface. Small fragments of cartilage may break off and form loose bodies. Cysts may form when granulation tissue undergoes myxomatous change
What Demographic Features and Predisposing Conditions are Associated With Osteoarthritis?
Typically > 50 years of age
Radiographic evidence of DJD is very common
Symptoms do not correlate with severity of radiologic changes.
Clinical symptoms attributed to the disease occur in a minority of radiologically affected persons.
Conditions predisposing to this disease include any factor causing increased strain on the joint:
Frequent injury (ball players!)
Obesity (doesn’t explain why ankle involvement is rare)
Abnormal weight bearing (irregular leg length, scoliosis, etc.)
What is osteoid?
Osteoid is the organic matrix of bone that has not
undergone mineralization (or just has a little of it).
What is an osteosarcoma?
A neoplasm in which osteoid is synthesized by
malignant cells.
Gross and radiologic Features:Osteosarcoma
“Codman's triangle” on X-ray: the angle formed by the elevation of periosteum by the tumor
Grossly, they are large, bulky, gritty grey-white tumors often with hemorrhage and cystic degeneration.
List the different types
of osteosarcoma.
90% = conventional, 10% = variants:
telangiectatic, small-cell, parosteal, periosteal, well
differentiated intramedullary, intracortical, multifocal
and high grade surface osteosarcomas.
In Which Bones Does Osteosarcoma Typically Arise?
It is commonly seen in the femur and tibia, especially
around the knee, where ~50% are found
What Is the Most Common Location for a conventional
Osteosarcoma Within a Bone?
Within the bone, the metaphysis is the favored site of origin
What is most common primary tumor of bone?
Osteosarcoma is the most common primary tumor of bone, exclusive of hematopoietic neoplasms
What is the age, location and sex predominance of osteosarcoma?
Two age peaks
Under the age of 20 years, around the knee area
And in the elderly, secondary to Paget's disease, osteochondromatosis, enchondromatosis and radiation exposure, most involve flat bones
More common in males
Discuss the Genetic Influences in Development of Osteosarcoma.
Genetic mutations are fundamental to the development of osteosarcoma
Patients with hereditary retinoblastomas have several hundred-fold greater risk of subsequently developing osteosarcomas, due to Rb gene mutations
P-53 mutations are frequently present in sporadic osteosarcoma
Discuss the pathogenesis of Paget disease of the bone.
It is a chronic disease caused by exaggerated and non-physiologic bone remodeling. It begins as a wave of bone resorption that is followed by a rapid and disorganized osteoblastic response producing dense and brittle bones.
Gross and Radiologic Features:Paget Disease of Bone
** Jigsaw appearance **

Thickened cortex and trabeculae, often quite coarsened and irregular.
Enlargement of the affected bone, due to bone overgrowth.
Over the span of 10-20 years the x-ray appearance may change from lytic, to more dense, to entirely dense
85% polyostotic, 15% monostotic
Histology: Paget Disease of Bone
uncontrolled remodeling, likened to a jigsaw puzzle appearance it prominent cement line, forming a “mosaic” pattern.


Paget disease is divided into
initial osteolytic stage,
mixed osteolytic-osteoblastic stage
burnt-out quiescent osteosclerotic stage
The microscopic picture depends upon the state of the disease process in the bone from which the specimen was taken.

Osteoblastic and osteoclastic activity
Presence of chiefly woven bone initially, eventually becoming disorganized lamellar bone.//

When new bone formation predominates over reabsorption, massive trabecular plates are built up to a density that is neither cortical nor cancellous in its architecture. Note the marked osteoclastic multinucleation
Discuss the Population Distribution of Paget Disease
Usually begins during mid-adulthood, common in Caucasians in England, France, Austria and regions common to Australia, New Zealand and U.S.
Rare in Scandinavia, China, and Japan
What laboratory tests may help you support a diagnosis of Paget disease of the bone?
Serum calcium and phosphate are normal
Because of the marked increase in osteoblastic activity, serum alkaline phosphatase is elevated and often over 5 times the upper reference limit. The levels tend to be proportional to the extent of skeletal involvement.
In asymptomatic patients, increased alkaline phosphatase of bone origin may call attention to the presence of the disease
Describe the complications/clinical manifestations
of Paget bone disease.
Fractures, bone deformities, osteoarthritis (altered
biomechanics cause uneven wearing of articular
cartilage), cardiac enlargement or failure, cranial or
peripheral nerve impingement and neoplasms.
What neoplasms arise in pagetic bone?
Both benign and malignant lesions occur
The worst of these, a sarcoma (osteosarcoma, MFH, or chondrosarcoma), can develop in 5-10% of patients with polyostotic disease
Explain the occurrence of heart failure and hearing loss in Paget disease.
Though Paget disease may involve any bone, it more commonly affects the skull, the tibia and the bones of the pelvis
While many times clinically silent, the disease may manifest as skeletal deformities (skull enlargement, tibial bowing), nerve compression (hearing loss) and less commonly, increased vascularity, causing A-V shunting leading to cardiac failure
Case history:
A 45-year-old man presented with a history of hip pain lasting several months
Imaging studies revealed a destructive lesion involving the body of the left ischium
-------

Discuss the significance of the clinical findings.
Chondrosarcoma should be suspected at this site
and pain is an omnious symptom. Tumors in
the axial skeleton have a worse prognosis than
more peripheral tumors.
Gross radiologic and Pathologic Features: Chondrosarcoma
Lobules of gray-white translucent, gelatinous appearing tumor
Radiographs show destructive masses of low radiodensity
Spotty calcifications may be seen grossly and on radiographs, but are due to dystrophic calcification (not to the formation of osteoid)
Chondrosarcoma: Histology
Proliferation of malignant cells forming cartilage in a lobular pattern
Malignant osteoid is not formed.

Characteristically, there are 2 or more cells per lacuna
Cells disorganized in their distribution
If deposits of calcium are present, these are due to dystrophic calcification and not to the formation of osteoid
Which portions of the skeleton are more commonly
involved by chondrosarcomas?
The central (axial) skeleton (ribs, shoulder (13%) and
pelvis (31%), femur involved in 21%.
What age group and gender is more commonly affected
by this tumor?
Most common in persons in their forties and fifties; as with most other bone tumors, however, it is more common in males than in females. Only 3.8% occur before the age of 20 years.
How do you treat chondrosarcoma tumors?
Surgery is the main form of treatment, radiotherapy and
chemotherapy have more limited roles.
Discuss the potential for metastasis and compare
to osteosarcoma.
In chondrosarcoma, there is a direct correlation between grade and biologic behavior
Chondrosarcoma is typically a relatively slow growing tumor which tends to expand locally for many years before distant metastases develop
In contrast, Osteosarcoma at the time of diagnosis is associated with pulmonary metastasize in 20% of cases
In patients with poorly differentiated chondrosarcomas, (grade 3) however, metastases develop rapidly (75%).
Other metastatic sites are bone and brain
Case history: A 12 year-old boy had been complaining of pain, swelling and tenderness of the right lower thigh

Differential diagnosis?
Neoplasia and osteomyelitis, even if there is no fever or leukocytosis.
What age group is most commonly affected by Ewing Sarcoma tumor? Is there any sex/race predilection?
Average age at presentation is 10-15 years of age, 80% of cases are <20 years.

Slightly more common in males, whites > blacks
Ewing Sarcoma: Some features
Ewing's sarcoma involving the diaphysis of the humerus
Periosteal bone reaction may produce an “onionskin layering effect”, best seen with x-rays

The tumor can grow very fast, thus with minimal normal
bone reaction and a deceptively normal appearance.
Histologic features:Ewing Sarcoma
Ewing's sarcoma, a proliferation of small, dark, round cells which appear to have no differentiation. Necrosis is common in these neoplasms.

Uniform, small round blue cells with extremely scant cytoplasm.
Other small round blue cell tumors?
include neuroblastoma, small cell carcinoma of the lung, lymphoblastic lymphoma, and Burkitt's lymphoma, leukemia, small cell osteosarcoma, rhabdomyosarcoma, mesenchymal chondrosarcoma, etc.
Ewing sarcoma most commonly involves the long bones of the extremities, especially the femur and tibia. What part of these bones does this tumor involve most frequently?
Diaphysis

While osteosarcoma is metaphysis.
What is the natural history of Ewing sarcoma? What is
the effect of therapy?
Ewing sarcoma develops systemic metastases early,
particularly to lung and to other bones
Surgery does little, by itself, to prevent metastases;
however, the 5 year survival is about 40-75% with a
combination of surgery, chemotherapy and radiation
therapy
Ewing sarcoma enters in the differential diagnosis of the small, round and blue cell neoplasms, on what would you base your diagnosis? i.e. genetic findings
A t(11;22) translocation is commonly seen in these neoplasms, which appear to arise from primitive neuroectodermal tissue, hence their inclusion within a family similar neoplasms referred to as “primitive neuroectodermal tumors” (PNET). Also these neoplasms overexpress the MIC2 gene (short arm of X chromosome). The product of this gene, CD 99 can be identified immunohistochemically. All these special studies are interpreted within the overall clinico-radiologic context.
Giant cell tumor (osteoclastoma)
Multilobular red-brown mass on cut surface
Areas of hemorrhage, cyst formation and necrosis

Proliferation of uniform appearing mononuclear cells, their nuclei resemble those of the giant cells.
Is there any age predilection in Giant Cell Tumor? What sex is affected by this tumor most commonly?
It occurs most commonly between the ages of 30-40 years old and, in contrast to most bone tumors, it is MORE COMMON IN FEMALES.
What part of the bone is involved most commonlyin Giant cell tumor?
The epiphysis of long bones, especially, the area about the knee.

Metaphysis: osteosarcoma

Diaphysis: Ewing
What is the biologic behavior of Giant Cell tumor?
This tumor develops distant metastases very rarely (1-2 % to lungs), although it can recur if not completely excised. It is a locally aggressive neoplasm and the histology is not predictive of biologic behavior.
Case History:
A 25-year-old male with sickle cell disease with a non-healing, draining sinus tract.

What etiologic agent is most likely associated with
osteomyelitis in sickle cell disease?
Salmonella is very characteristic of osteomyelitis associated with sickle cell disease, found in more than ½ of cases
Staphylococcus aureus is most common
What bone complication is most likely associated with
sickle cell disease?
Infarcts
Name a complication (non-infectious) of the draining
sinus tract.
Developing a squamous cell carcinoma.
Gross Features:Osteomyelitis
The metaphysis is the typical site of involvement
There are areas of dead bone, the sequestrum
There is periosteal new bone formation, the involucrum
Histological features:Osteomyelitis
spicules of bone in which there are no nuclei. These fragments have apparently died as a result of the inflammation-mediated reduction in vascular supply. At the right of the photograph, numerous neutrophils fill the marrow space

Dead fragments - recognizable because the osteocyte nuclei are no longer visible in the lacunae, a sign that the osteocytes, the living cells of the bone, have died.
If this happens to a large area of bone, it would form what is referred to as a sequestrum, which may serve as an inflammatory focus and prevent healing, thus leading to the complication of chronic osteomyelitis.
addiontal Histological features:Osteomyelitis
A characteristic finding on x-ray later in the course is that there is periosteal new bone formation (involucrum), part of the reaction of bone to injury. The bony trabeculae are surrounded by a rim of osteoblasts, indicating that new bone formation is taking place.

Most commonly, especially in children, bacteria may reach bone by the hematogenous route; often without any obvious source of bacteremia. Alternatively, they may be introduced directly into bone (i.e. open fracture or a gunshot wound).
Osteomyelitis: Epidemiological garbage
Osteomyelitis as a clinical problem in this country is relatively uncommon
When it does occur, it frequently occurs spontaneously, usually in persons whose bones are still growing, and is usually caused by pyogenic bacteria, most commonly staphylococci
Staphylococcus species, especially S. aureus, is the most common agent in children
Infection with Salmonella species is particularly common in patients with sickle cell anemia
Chronic osteomyelitis is one of the more common antecedent causes of secondary amyloidosis
How would you expect a 60 year-old male with osteomyelitis to present?
Back pain due to vertebral osteomyelitis (spondylitis);
only ½ have fever and 1/3 leukocytosis, so an elevated ESR is a helpful lab finding.
Most are caused by Staph aureus, but think about gram negative bacteria if there is history of GU tract surgery or infection.
Case History:
This 3-year-old boy, from a socio-economically underprivileged family, has widening of the wrists, knees and ankles, beading of the ribs and bowing of legs.

How do you explain these bone changes?
Failure of calcification of osteoid formed by growing metaepiphyseal cartilage.
The metaphyseal portion of the bone becomes widened and thickened.
Bones under stress are affected: neonates show deformities of the skull and the ribs.
As the child begins to crawl, the arms bear much of the body's weight and become deformed.
In older children, the legs are deformed for identical reasons.
Gross Features:rickets
Widened epiphyseal growth plate; diminished mineralization of the bone in general.
Bowing of legs, rachitic rosary of ribs at costochondral junctions, flattening of the skull, pectus carinatum (pigeon chest).
Pseudofractures of Milkman-Looser: radiolucent transverse defects on concave side of long bones, medial side of the neck of the femur, ischial and pubic rami, ribs and scapula.
Histo Features:rickets
B.Section of a costochondral junction in rickets. Notice overgrowth and disorganization of osteoid tissue (non-mineralized bone matrix).
What is the underlying pathophysiology of rickets?
The fundamental defect is failure in bone mineralization due to deficiency of Vitamin D; this results in excess unmineralized matrix, increased amounts of osteoid and overcompensatory growth of the epiphyseal plates
Discuss causes of vitamin D deficiency
Dietary deficiency, inadequate exposure to sunlight, intestinal malabsorption, renal failure, chronic liver disease and vitamin D-resistant rickets
Compare osteomalacia and rickets
In adults, osteomalacia occurs due to deficiency of Vitamin D and is seen as an abnormal softening of bone, seen as “osteopenia” radiologically
This increases the risk of bone “fracture”
There is no cartilaginous growth plate in adults and the metaphysis of bone is not actively growing
Therefore the deformities seen in rickets are not present
Vitamin D deficiency: Osteomalacia
Weak bones, fractures and
osteopenia in adults

Decreased mineralization
and pseudofractures
Contrast osteomalacia and osteoporosis.
Osteomalacia is a defect in mineralization. The collagen structure is there, but calcium is not being deposited.
Osteoporosis - due to an overall loss of bone mass.
It is mostly a disease of aging, although it also occurs in the context of mineral deficiencies, abnormal collagen synthesis, endocrine abnormalities and immobilization.
It is probably the most common metabolic bone disease in this country affecting women more commonly than men.
Case history:
A 21-year-old man complains of pain in his right thigh for several months
The pain is relieved by aspirin, is worse at night and has increased in intensity gradually
X-rays of the right femur show a round lucency with sclerosis around the periphery.

Gross Features: Osteoid Osteoma
The lesion is red with a nidus surrounded by reactive and sclerotic bone
Usually less than 1 cm in diameter and are well circumscribed
The actual tumor, the “nidus,” is radiolucent on x-ray
Histologic Features: Osteoid Osteoma
Cross section of the bone with the central nidus and the corresponding low-power view demonstrating a central nidus surrounded by sclerotic bone.
List at least 3 other benign bone neoplasms
Osteoblastoma
Osteochondroma
Chondroma (enchondroma)
Chondroblastoma
Giant cell tumor of bone
Fibrous dysplasia
Benign fibrous histiocytoma
Benign vascular tumors
Aneurysmal bone cyst
What Is the Significance of Multiple chondromas (enchondromas)?
Multiple enchondromas (enchondromatosis) is known as Ollier disease
25-50% of patients with this syndrome eventually develop low-grade chondrosarcoma
If associated with soft tissue hemangiomas, it is known as Maffucci syndrome
Maffucci syndrome carries an additional risk for developing other malignancies including ovarian, liver and pancreatic carcinoma and brain gliomas
What is fibrous dysplasia of bone?
A benign, tumor-like lesion of bone involving one (monostotic) or more (polyostotic) bones
Occurs in early adolescence and represents a localized, developmental arrest of the normal growing bone
Monostotic lesions are usually asymptomatic and discovered incidentally on x-ray
Polyostotic lesions may cause deformities and may be associated with a variety of endocrinopathies
Fibrous Dysplasia: Histo
Loose spindle-cell tissue
surrounds irregular woven
bone trabeculae

Like 'chinese letters'