| What are some general principles in bone pathology? | ➢ A bone tumour can manifest as a :
1. Painfull on palpation mass
2. Spontaneous Pain
3. Pathological fracture
4. Incidental finding.
➢ Diagnostic orientation depends on the clinical setting :
1. Age at Diagnosis
2. History
3. pre-existing bone injury
➢ Diagnostic orientation depends also radiological findings : Xrays, CT +++, MRI |
| How is contribution of imaging? | ➢ Imaging (exams must be interpreted by a radiologist specialized
in the osteo-articular system) Provides :
1. Arguments for the aggressiveness of a bone injury;
2. Diagnostic orientation based on: the aspect/the location/the patient condition.
➢ In some cases, it identifies some minor lesions that do not require a biopsy or surgical gesture;
➢ It is necessary for the assessment of local extension if surgery is needed
➢ MRI is used to determine the tumor limits and its relationship to adjacent structures. |
| How is bone biopsy? | ➢ Usually necessary for establishing the diagnosis : except for some cases of multiple bone metastases of a known progressive primary cancer or for some benign tumors of typical
radiological appearance.
➢ The biopsy can be performed either surgically or at the trocart with imaging guidance (CT).
➢ In our practice, the bone removal will most often have to be decalcified, which lengthens the response time |
| What are non neoplastic bone lesions? | Brown tumor, osteonecrosis (avascular necrosis), Infarct, osteomyelitis, Paget's disease, rheumatoid polyarthritis, gout, pseudogout, |
| What is brown tumor? | ➢ Symptomatic, untreated primary hyperparathyroidism manifests with three interrelated skeletal abnormalities: osteoporosis (generalized), brown tumors, and osteitis fibrosa cystica (generalized).
➢ Mass or nodular lesion of reactive reparative fibrous tissue with many Mp and multinucleated cells
➢ These lesions often undergo cystic degeneration.
➢ Generalized Osteitis Fibrosa Cystica: In case of severe HyperPTH; it includes:
• Increased bone cell activity
• Peritrabecular fibrosis,
• Cystic brown tumors |
| What are major causes of avascular necrosis? | Major causes
➢ Long lasting Corticosteroide treatments
➢ Vascular rupture or thrombosis
➢ Barotraumatism
➢ Vasculitis
➢ Sickle cell disease
➢ Radiothérapy |
| What is osteonecrosis? | ➢ Refers to infarction (ischemic necrosis) of bone and marrow cells.
➢ Diverse set of conditions predisposes to bone ischemia :
vascular injury (trauma, vasculitis), drugs (corticosteroids),
systemic disease (sickle cell crisis), and radiation.
➢ In about 25% of cases, the cause is unknown
➢ Microscopically, dead bone is recognized by empty lacunae surrounded by necrotic adipocytes that frequently rupture.
➢ In the healing response, osteoclasts resorb the necrotic
trabeculae.
➢ Trabeculae that remain act as scaffolding for the deposition of new bone in a process known as creeping substitution
➢ ostéocytes nuclei are absent
➢ Bone trabeculae irregular
➢ fibrous tissue with nuclear debris in the medullary spaces |
| What is osteomyelitis? | ➢ Can result from a penetrating injury with the introduction of organisms, usually bacteria, into the bones.
➢ Manifests as a primary solitary focus of disease.
➢ More commonly Osteomyelitis may be a complication of any systemic infection
➢ In children, most bone infections, happen mainly in the
metaphyseal region (the greatest blood flow)
➢ Osteomyelitis in adults most often begins in the epiphyseal and subchondral locations.
➢ It causes bone destruction with the appearance of a bone sequestration and a reactive bone on the periphery |
| How is tx and etiology of osteomyelitis? | ➢ Osteomyelitis is difficult to treat and may require surgical
drainage and antibiotic therapy.
➢ The most common causative organism is Staphylococcus
aureus.
➢ Newborns may have Haemophilus influenzae and group B streptococcus infections
➢ Sickle cell anemia patients are at risk for Salmonella
osteomyelitis.
➢ Patients with urinary tract infections and injection drug users are at risk for osteomyelitis with the species Escherichia coli and Pseudomonas and Klebsiella. |
| How is osteomyelitis microscopy? | ➢ Ingrowth of fibrous tissue
➢ Chronic inflammatory infiltrate
➢ Deposition of reactive bone at the periphery.
➢ The newly deposited bone can form a shell of living tissue
➢ The dead bone is known as a sequestrum |
| What is paget's disease? | ➢ Increase in bone turnover
➢ Asynchronism of OB and OC activity in bone turnover :
Osteoclastic activity and osteoblastic activity are prominent
➢ The result is a thicker but weaker bone that has irregular cement lines, producing a mosaic pattern instead of the organized lamellar pattern.
➢ This proliferating bone is very vascular and increased vascular flow can lead to high flow congestive heart failure
➢ Localized disease may not require treatment other than occasional use of pain relievers.
➢ Wider polyostotic disease can be treated with osteoclastinhibiting bisphosphonates |
| What is rheumatoid polyarthritis bone pathology? | ➢ May start insidiously with general discomfort, fever, and
aches and pains
➢ Followed by swelling, warmth and tenderness of the joints.
➢ It has a cyclical evolution with alternating remissions and
exacerbations.
➢ Significant morning stiffness is often present.
➢ Aspiration of joint fluid generally shows :
o increased turbidity,
o reduced viscosity,
o increased protein,
o leukocytosis with a predominance of neutrophils |
| How is presentation of rheumatoid arthritis? | ➢ Firm, non-tender nodules occur in about a quarter of RA patients, usually those with more severe disease
➢ They appear in the soft tissue under the skin on bony protrusions like the elbow.
➢ They sometimes appear in the visceral organs, especially the lungs and the heart.
➢ RA affects about 1% of the population.
➢ Women are more often affected than men.
➢ Onset often occurs between the second and fourth decade, but RA occurs in a wide age range.
➢ Genetic predisposition in About half the cases. |
| What is gout? | ➢ Disease marked by transient attacks of acute arthritis initiated by urate crystals
➢ Articular and sometimes soft tissue déposition of urate cristals
➢ In most cases there is a hyperuricémia.
➢ Several joints can be involved.
The first metatarsophalangeal joint (big toe) is most often affected by acute attacks characterized by:
o severe pain,
o swelling
o erythema of the involved joint |
| How is gout presentation? | ➢ Chronic gout occurs approximately 12 years after the initial acute attack.
➢ It is marked by the deposit of urate crystals in a chalky mass called tophi: can appear around a joint.
➢ Joint aspiration during an acute gouty attack shows increased turbidity, reduced viscosity and leukocytosis with many neutrophils.
➢ On microscopy, monosodium urate crystals needle-shaped birefringent appear in the liquid.
➢ The inflammation in gout is triggered by precipitation of urate crystals in the joints, stimulating the production of cytokines that recruit leukocytes
➢ Chronic Tophaceal gout results from the repetitive
precipitation of uraye crystals during acute gout attacks.
➢ MSU crystals cause surrounding destructive inflammatory response
➢ Tophi most commonly forms around joints, in soft tissue, including tendons and ligaments, and less commonly in visceral organs.
➢ The tophi can erode and destroy the adjacent bone.
➢ Urate can also form in the kidneys, and around 20% of gout patients may eventually develop kidney failur |
| What is pseudogout? | ➢ Calcium Pyrophosphate Crystal Deposition Disease
➢ More common in patients over 50
➢ Causes acute, subacute or chronic arthritis
➢ Affects Knees, wrists, elbows, shoulders and ankles
➢ The knee can show significant chondrocalcinosis lesions even reaching the meniscus and articular cartilage
➢ Most cases are idiopathic
➢ Some cases may occur in people with thyroid disease,
hyperparathyroidism, diabetes mellitus or hemochromatosis
Morphology:
➢The crystals first develop in the articular cartilage
➢Under polarized microscopy : Individual crystals are rhomboid, 0.5 to 5 μm in greatest dimension and are positively birefringent
➢Inflammation is usually milder than in gout |
| What are different types of bone tumors? | 1. Primary bone tumors :
➢ Benign
➢ Malignant
2. Secondary tumors which are by definition always malignant (hematogenous metastases).
3. Hematopoietic tumors |
| What are primitive bone tumors? | ➢ The classification of primary bone tumors according to the World Health Organization (WHO), counts more than 50 benign and malignant tumor entities.
➢ The name of these tumors is based on:
1. the line of differentiation of the supposed cell of origin:
osteoblast / chondrocyte
2. The benign or malignant nature of tumor proliferation:
osteoblastoma / osteosarcoma
➢ More common in children
➢ Mainly metaphyseal.
➢ Malignant tumors are rare: the most common primary bone tumor is osteosarcoma (all forms) |
| How is biopsy of primitive bone tumors? | ➢ Biopsies are preferably surgical (in non-hematopoietic primary bone tumor) because these tumors are often heterogeneous.
➢ The biopsy must be done in a specialized center because they are rare tumors requiring a multidisciplinary team work
(radiologists, surgeons and pathologists).
➢ The biopsy should preferably be done by the surgeon who will then take charge of the patient for any subsequent surgical treatment.
➢ The biopsy area must be removed with the primary bone tumor in case of malignancy
➢ Morphology is to be interpreted according to the clinic (age ++, history, pre-existing bone lesion) and imaging +++. Ex: a fracture callus may be morphologically similar to a high grade osteosarcoma on a biopsy.
In the absence of clinical and imaging information, the pathologist may miss the right diagnosis. |
| What is done in surgical excision of primitive bone tumors? | ➢ On the surgical excision of a primary tumor, the pathologist must confirm the histological nature of the lesion, and specify, other characteristics of the tumor:
o Extension of invasion (soft parts, joint)
o Quality of the excision with histological margins.
o If neoadjuvant CT: also assess the response of the tumor to
chemotherapy by quantifying tumor necrosis.
o In both cases of osteosarcoma and Ewing's sarcoma, a patient is considered a good responder if the tumor necrosis is greater than or equal to 90% |
| What are secondary bone tumors? | ➢ The most used diagnostic procedure is a trucut biopsy; Less often a surgical biopsy will be done for diagnosis
➢ Indications :
o When there is a strong clinical suspicion of bone metastasis (known carcinoma, multiple bone lesions)
o In the context of a pathological fracture, a sample for
histological confirmation can be performed during the
therapeutic surgical procedure
The biopsy allows:
➢ The Histological diagnosis of the tumor (ex:
adenocarcinoma) with quite often, but not in all cases,
orientation towards a primitive (ex: breast origin? Pulmonary? Prostatic?…)
➢ Possible identification of therapeutic targets. (meta of breast AK [HR/HER], primary pulmo meta [EGFR mutations...] |
| How is histologic dx of secondary bone tumors? | The histological diagnosis of a metastasis is based on:
➢ The origin of the malignant cells (epithelial / melanocytic, etc.)
➢ The expression of certain proteins and / or the secretion of certain substances by tumor cells, most often demonstrated by immunohistochemistry or histochemistry:
Mucines, HR, Neuroendocrine secretory grains…
➢ The choice of the antibodies for an immunohistochemical study depends on the diagnostic hypotheses
➢ The diagnostic hypotheses are made On the morphological appearance of the tumor observed on the standard staining (HE) On clinical / biological and radiological information.
➢ The choice of Ab also depends on the possible therapeutic incidence. |
| What are benign primitive bone tumors? | Can behave in a variable way:
➢ Quiescent
➢ Active
➢ Locally Aggressive
Osteoid osteoma: ➢ Relatively common, young patient (child, adolescent, young adult).
➢ Severe nocturnal pain that is relieved by aspirin and other nonsteroidal anti- inflammatory agents.
➢ Typical imaging in standard radiography and CT show the <<nidus » : clear gap with central condensation
➢ Size less than 2 cm, surrounded by reactive bone sclerosis (CT) and by edema (MRI).
➢ Most often, a biopsy is not necessary for diagnosis
Osteoid osteomas most commonly arise in the second
or third decade. They involve most often the femur or
tibia |
| How is tx of osteoir sarcoma? | ➢ Osteoid osteoma is frequently treated by radiofrequency
ablation, or cryotherapy
➢ During therapeutic procedure a biopsy is taken for histology study
➢ Confirmation possible in 30 to 60% of cases only.
➢ Microscopically, it is a benign osteoforming tumor, well
circumscribed and composed of randomly interconnecting
delicate trabeculae, of woven bone that are prominently
rimmed by a single layer of osteoblasts.
➢ The stroma surrounding the neoplastic bone consists of loose connective tissue that contains many dilated and congested capillaries |
| What is cartilaginous benign tumors? | ➢ Chondromas are benign tumors of hyaline cartilage that
usually occur in bones of endochondral origin
➢ When They arise within the medullary cavity, they are called enchondroma
➢ When They arise on the cortical surface they are called
juxtacortical chondroma.
➢ Diagnosis of enchondroma is usually made on standard
radiography Biopsy is not necessary
➢ The rule is therapeutic abstention;
➢ Surgical treatment will be done if symptomatic or in case of suspected transformation into low-grade chondrosarcoma
➢ Enchondromas are true neoplasms, with mutations in the IDH1 and IDH2 genes.
➢ Solitary lesions are usually less than 3 cm in size and typically arise in metaphyseal regions of tubular bones, such as the distal femur here, but more likely in the hands and feet
➢ Cellularity is greater than that of normal cartilage, but the cells are not highly atypical |
| What is osteochondroma? | ➢ Osteochondroma, known clinically as exostosis, is a benign cartilage-capped tumor that is attached to the underlying skeleton by a bony stalk.
➢ This abnormal growth in OC enlarges very slowly and usually stops growing when the epiphyseal plate closes.
➢ In some cases there is multiple lesions : enchondromatosis (Ollier Disease and Maffucci syndrome).
➢ Risk of malignant transformation into chondrosarcoma,
specially in the enchondromatosis (rare in osteochondroma).
➢ Microscopy : they are composed of well-circumscribed
nodules of hyaline cartilage containing benign chondrocytes |
| What is giant cell tumor? | ➢ Almost exclusively affects adults
➢ Locally aggressive neoplasm
➢ Arise in the epiphyses of long bones, most commonly the
distal femur and proximal tibia.
➢ lytique eccentric tumor with deformation of the contours of the bone.
➢ Limited by a thin bony shell (no real soft tissue infiltration).
➢ Sometimes lung implants considered “benign”
➢ Microscopically, the tumor conspicuously lacks
bone or cartilage, consisting of numerous
osteoclast-type giant cells with 100 or more nuclei
with uniform, oval mononuclear tumor cells in
between. |
| What are other benign primitive bone tumors? | ➢ Angioma
➢ Essential bone cyst
➢ Aneurysmal Bone Cyst :
Generally occurs during the first 2 decades of life / no sex predilection Most frequently develops in the metaphysis of long bones and the posterior elements of vertebral bodies.
Microscopy :
✓ Consists of multiple blood-filled cystic spaces separated by thin, tan-white septae.
✓ The septae are composed of plump uniform fibroblasts,
multinucleated osteoclast-like giant cells, and reactive woven bone, but they are not covered by endothelium
✓ Recure rarely after resection
✓ Rarely behaves agressively |
| What is conventional osteosarcoma malignant bone tumor? | • Distal femur +++, proximal tibia, proximal humerus, pelvis.
• R/O Hematogenous spread (Pulmonary metastases).
• Osteolytic, osteocondensing or mixed radiological appearance.
• Histological confirmation essential before treatment.
• Malignant tumor cell proliferation (atypical osteoblasts)
developing, at least centrally with an osteoid matrix formation This tumor can produce malignant cartilage and malignant fibrous tissue.
High grade conventionnal Osteosarcoma:
➢Dense proliferation
➢Atypical cells
➢Osteoid matrix formation ; Very important diagnostic element |
| How is tx of conventional osteosarcoma? dx features? | ➢ The usual treatment includes neoadjuvant chemotherapy, followed by a surgical resection in block of the tumor: with wide surgical margins, leaving a layer of healthy tissue around the piece of resection
➢ an eventual chemotherapy after adjuvant will depends on the histological response of the tumor.
➢ Post-chemotherapy tumor necrosis is an essential element of the pathologist report of the resection piece, for the evaluation of the effectiveness of the chemotherapeutic treatment.
➢ The formation of osteoid matrix or mineralized bone by malignant tumor cells is diagnostic of osteosarcoma
➢ Fine, lacelike pattern of neoplastic bone produced by anaplastic malignant tumor cells in an osteosarcoma |
| What is Ewing sarcoma? | ➢ Very poorly differentiated malignant tumor that is included in the group of peripheral neuroectodermal tumors
(neuroectoderm = embryonic nerve tissue)
➢ t (11; 22) causing the fusion of the EWS-FLI1 gene
➢ Tumor develops essentially in the medullary cavity of the
diaphysis of the long bones and the pelvis
➢ Occurs during the 2 first decades with slight male
predominance.
➢ The clinical manifestations of these bone locations can be: local pain / warmness/ edema.
More rarely fever and leukocytosis mimicking an infection.
Brown hemorragic and necrotic bone tumor rupturing the cortex
Sheets of uniform small, round cells that are slightly larger and more cohesive than lymphocyte. They have scant cytoplasm, which may appear clear because it is rich in glycogen. The tumor cells do not produce bone or cartilage |
| What is chondrosarcoma? | Intramedullary tumor, made of confluent greyish-white nodules, which extends from the superior femoral metaphysis to the diaphysis.
The tumor is necrotic in the center (greenish-yellow coloration)
Nodules of hyaline and myxoid cartilage permeating throughout the medullary cavity, growing through the cortex, and forming a relatively well-circumscribed soft tissue mass
Conventional chondrosarcoma entraps native lamellar bone as a confluent mass of cartilage |
| What are lesions simulating primary neoplasms? | Nonossifying Fibroma, Fibrous Dysplasia, Metastatic Tumors |
| What is non ossifying fibroma? | ➢ Benign, likely reactive, mesenchymal proliferation
➢ May be present in as many as 50% of children and young adults aged 2–25 years.
➢ It is synonymous with fibrous cortical defect or metaphyseal fibrous defect if localized to the cortex or medulla, respectively.
➢ The findings are sufficiently specific on plain radiography that biopsy is rarely necessary.
➢ Fibroblastic cells arranged in a storiform (pinwheel) pattern admixed with lymphocytes and macrophages with foamy cytoplasm or multinucleated cells |
| What is fibrous dysplasia? | ➢ Frequent lesion.
➢ At any age, discovered in children and young adults.
➢ Single (70%) or multiple (30%) lesion.
➢ Long bones, skull and face bones, ribs.
➢ Clinical signs: bone deformation, fracture for long bones.
➢ Imaging diagnosis (standard X-ray ± CT): well
circumscribed lesions, intramedullary, vary greatly in
size
➢ The lesional tissue is composed of curvilinear
trabeculae of woven bone surrounded by a
moderately cellular fibroblastic proliferation.
➢ The trabeculae lack prominent osteoblastic rimming;
➢ Cystic degeneration, hemorrhage, and foamy
macrophages are other common finding |
| What are metastatic tumors? | ➢ These are the most common bone tumors
➢ To think of first in adults
➢ Bone is the third most common metastatic site after the liver and lung
➢ The most frequent histological type: carcinomas
➢ The most osteophilic cancers: breast, prostate, thyroid, kidney, lung.
➢ Bone metastases can be inaugural (revealing) or not.
➢ A biopsy with pathologoical examination is often necessary. The most accessible lesion will be biopsied.
➢ Any bone lesion presenting elements of discrepancy between the clinic, the imagery, and the primitive should be biopsied. |
| What are purposes of biopsy of metastatic tumors? | ➢ Histological diagnosis of the lesion (lymphoma? Sarcoma? Adenocarcinoma? ...);
➢ Orientation towards a primary neoplasia when it is not known or found;
➢ Possible identification of therapeutic targets (RH, HER-2, search for molecular anomalies predictive of response or non-response to socalled "targeted" treatments).
➢ Histological evidence (diagnostic certainty) is necessary because:
✓ Treatments are potentially toxic;
✓ Treatments depend on histological types and primary cancer;
✓ Some treatments are "targeted"
In about 10% of cases primitive neoplasm is not found : They are generally so-called “metastasis from unknown primary” adenocarcinomas and they have a poor prognosis |
