Pathology of Bone and

Soft tissue
Dr. Nirmalya Chakrabarti
MD (Pathology), Gold Medalist [WBUHS]
Deptt. Of Pathology, Malda Medical college, Malda
Competencies:
Core Competencies:

PA-33.1: Classify and describe the etiology, pathogenesis, manifestations, radiologic and
morphologic features and complications of osteomyelitis.

PA-33.2: Classify and describe the etiology, pathogenesis, manifestations, radiologic and
morphologic features and complications and metastases of bone tumors. (Bone Tumors:
GCT, Osteosarcoma, Ewing’s Sarcoma).

PA-33.3: Classify and describe the etiology, pathogenesis, manifestations, radiologic and
morphologic features and complications and metastases of soft tissue tumors.

Non core Competencies: PA-33.4: Paget disease of Bone, PA-33.5: Rheumatoid Arthritis.
Microanatomy of Bone
 1. Osteoblasts: uninucleate cells along new bone-forming surfaces,
synthesize bone matrix, alkaline phosphatase is its marker.
 2. Osteocytes: those osteoblasts incorporated in bone matrix during its
synthesis, found in lacunae of bone matrix.
 3. Osteoclasts: large multinucleate cells of mononuclear-macrophage origin,
found along endosteal surface, cause bone resorption activity determind
by acid phosphatase
 4. Osteoid matrix: type 1 collagen, hydroxyproline and hydroxylysine.
 Bone remodeling = interactive balance between osteoblastic formation and
osteoclastic resorption [ under influence of Vit. D1, Parathyroid hormone
and calcitonin in calcium metabolism].
Osteomyelitis: inflammation of bone and marrow,
virtually always secondary to infection.
 Pyogenic osteomyelitis (caused by pyogenic organisms) – clinically 2
types: acute and chronic, histologically 3 types: acute, sub-acute and
chronic.
 Tuberculous osteomyelitis (caused by M. tuberculosis in low income
countries where there are cases of pulmonary and extrapulmonary
tuberculosis).
 Salmonella osteomyelitis (caused by Salmonella typhi after attack of
typhoid fever among children with sickle cell anemia).
Pyogenic osteomyelitis
 Patient Profile:
 Developing countries – hematogenous spread of infection, long bones of
infants and young children (5-15 yrs), after trivial mucosal injuries or from
minor skin infections.
 Developed countries – direct extension from a contiguous site, jaw and
skull involvement.
 Patient of all ages – compound fractures, surgical procedures, infection of
limbs in diabetics.
 Most dangerous among infants: can spread to a joint resulting septic
arthritis followed by cartilage destruction and permanent disability.
Pyogenic osteomyelitis
 Etiologic organisms:
 Most commonly Staphylococcus aureus.

 Less frequently

• H. influenzae and Group B Streptococci (in neonates),

• E. coli, Pseudomonas, Klebsiella ( in pts of UTI or i.v drug users),

• Mixed bacterial infections (direct spread/ inoculation during surgery/ open #).
Pathogenesis:
 Pyogenic organisms reach bone via blood circulation
 Bacteria get lodged in metaphysis due to stasis of blood resulting from hair-pin
arrangement of blood vessels.
 Host bone initiates inflammatory responses leading to bone destruction & pus
formation.
 Pus in medullary cavity spreads in:
1. Along medullary cavity: thrombosis of medullary vessels, loss of blood supply.
2. Out of cortex: i. pus travels via Volkmann’s canal to subperiosteal location, periosteum
is lifted, damage of periosteal vessels, loss of blood supply, segment of avascular
necrosed bone (sequestrum).
ii. Subperiosteal pus generates subperiosteal reactive new bone
formation (periosteal reaction), encases necrosed bone – known as involucrum (with
holes – cloacae for drainage of pus)
iii. Perforation of periosteum- pus comes out to muscular/ subcutaneous
plane the to skin forming discharging sinus.
3. Other directions: to joints (hip/shoulder) causing acute septic arthritis.
Gross Morphology:
Contd..
 Sequestrum:
 Sequestrum is a piece of dead bone, surrounded by infected granulation tissue
trying to ‘eat’ the sequestrum away.
 It appears pale and has a smooth inner and rough outer surface because the latter
is being constantly eroded by the surrounding granulation tissue
 Involucrum:
 Involucrum is the dense sclerotic bone overlying a sequestrum.
 There may be some holes in the involucrum for pus to drain out. These holes are
called cloacae.
 The bony cavities are lined by infected granulation tissue.
Histological features:
 Acute osteomyelitis: features of acute inflammation, edema & bone necrosis.

 Subacute osteomyelitis: the inflammatory infiltrate contains more lymphocytes and

plasma cells.

 Chronic osteomyelitis: fibrosis and creeping substitution are prominent. [Abundant

plasma cells – Plasma cell osteomyelitis; abundant foamy macrophages:
Xanthogralumatous osteomyelitis.]

 Osteomyelitic sinus tracts are lined by squamous epithelium. This squamous

epithelium may give rise to epidermal inclusion cyst in underlying bone or rarely
squamous cell carcinoma.
Acute osteomyelitis: inflammatory infiltrate consists of mainly neutrophils and necrotic
bone is resorbed by osteoclasts.
Clinical features:
1. Acute osteomyelitis:
Presenting complaints: acute onset of pain and swelling at the end of a bone, systemic
f/o infection – fever etc, primary focus of infection elsewhere in body.
For secondary osteomyelitis – H/O wound infection from an open # or surgery.
Examination: febrile, dehydrated, classical features of inflammation localised to
metaphysical area of bone.
Later stage – abscess at muscular or subcutaneous plane.
 Swelling of adjacent joint due to sympathetic effusion.
2. Chronic osteomyelitis:
Presenting complants: a chronic discharging sinus, discharge of sero-purulent to thick
pus, H/O extrusion of small bone fragments from sinus, minimal pain aggravated during
acute exacerbation with fever.
Examination: chronic discharging sinus fixed to underlying bone, sequestrum may be
seen through sinus opening, puckered scar, thickened irregular bone, tenderness on deep
palpation, stiffness of adjacent joints.
Investigations:
 Acute osteomyelitis:
 Blood: neutrophilic leucocytosis, elevated ESR, blood culture – organism may be
identified.
 X-Ray: earliest sign- periosteal new bone deposition at metaphysis ( it takes 7-10
days to appear). Features of bony destruction.
 Bone scan: increased uptake of Tc-99 by bone at metaphysis (seen before X-Ray
apeearence).
 Aspiration of Pus using thick needle: to confirm presence of Pus, its Culture and
therapeutic aspect.
Radiographs of Acute osteomyelitis:
Investigations contd….
 Chronic Osteomyelitis:
 Blood: is of no help. ESR may be mildly elevated.
 X – Ray:
 Thickening & irregularities of cortices,
 Patchy sclerosis resulting honey-combed appearance,
 bony cavity – an area of rarefaction surrounded by sclerosis,
 sequestrum appears denser than surrounding bone,
 granulation tissue surrounding sequestrum gives rise to a radiolucent zone around
it,
 Clocaca may be visible.
 CT scan and MRI
Complications:
 General complications: in early stage – septicaemia.
 Local complications:
• Chronic osteomyelitis: commonest complication of acute osteomyelitis. Occurs due
to delayed and inadequate t/t leading to spread of pus with in medullary canal &
subperiosteally and sequestrum formation, highly virulent organisms, reduced host
resistance due to malnutrition or immunosuppression.
• Acute pyogenic arthritis.
• Pathological fracture.
• Growth plate disturbances: shortening, lengthening or deformity of limb.
• Development of squamous cell carcinoma in long standing cases.
• Secondary amyloidosis in long standing cases.
• Vertebral osteomyelitis may cause vertebral collapse, spinal cord compression &
neurologic deficits.
Tuberculous osteomyelitis:
 Common condition in underdeveloped & developing countries.

 M. tuberculosis reaches bone by hematogenous route most commonly from lungs.

 The disease affects adolescents & young adults.

 Spine and bones of extremities: most frequently involved.

 More destructive & resistant to control than pyogenic osteomyelitis.

 Histologic findings of granulomatous inflammation & caseous necrosis are typical.

 Spinal tuberculosis (Pott’s disease): infection breaks through IVD to involve

multiple vertebrae & surrounding soft tissues, discal & vertebral destruction leads
to compression # , gives rise to kyphosis, scoliosis & neural deficits.

 TB osteomyelitis may cause tuberculous arthritis, sinus tract formation, psoas

abscess and amyloidosis.
Bone Tumors: WHO classification, 2017.
 Chondrogenic tumors:
 Benign:
 Osteochondroma
 Chondroma including Enchondroma and Periosteal chondroma
 Osteochondromyxoma
 Intermediate ( Locally aggressive):
 Chondromyxoid fibroma
 Atypical cartilaginous tumor/ Chondrosarcoma grade I
 Malignant:
 Chondrosarcoma grade II and III
 Mesenchymal chondrosarcoma
 Dedifferentiated chondrosarcoma
 Clear cell chondrosarcoma
 Osteogenic tumors:
 Benign:
 Osteoma and Osteoid osteoma
 Intermediate (Locally aggressive):
 Osteoblastoma
 Malignant:
 Low-grade central osteosarcoma
 Conventional osteosarcoma – Chondroblastic/Fibroblastic/Osteoblastic
 Telangiectatic osteosarcoma
 Small cell osteosarcoma
 Secondary osteosarcoma
 Periosteal osteosarcoma
 Parosteal osteosarcoma
 High-grade surface osteosarcoma
 Osteoclastic giant cell rich tumors:
 Benign:
 Giant cell lesion of small bones
 Intermediate( Locally aggressive, rarely metastasizing):
 Giant cell tumor of bone
 Malignant:
 Malignancy in giant cell tumor of bone
 Fibrogenic tumors:
 Intermediate:
 Desmoplastic fibroma
 Malignant:
 Fibrosarcoma of bone
 Fibrohistiocytic tumors:
 Benign fibrous histiocytoma/No-ossifying fibroma
 Hematopoietic tumors:
 Malignant:
 Plasma cell myeloma
 Solitary plasmacytoma
 Primary NHL
 Notochordal tumors:
 Benign:
 Benign notochordal tumor
 Malignant:
 Chordoma
 Vascular tumors: Hemangioma, Angiosarcoma
 Lipogenic tumors: Lipoma, Liposarcoma
 Myogenic tumors: Leiomyoma of bone, Leiomyosarcoma of bone
 Tumors of undefined neoplastic nature:
 Benign:
 Simple cyst
 Fibrous dysplasia
 Osteofibrous dysplasia
 Rosai Dorfman disease
 Intermediate:
 Aneurysmal bone cyst
 Langerhans cell histiocytosis
 Erdheim Chester disease
 Miscellaneous tumors:
 Ewing Sarcoma
 Adamantinoma
 Undifferentiated high grade pleomorphic sarcoma
 Osteosarcoma:
 Most common primary malignant tumor of bone
 Age distribution: Bimodal – 75% occurs before age of 20 yrs, smaller peak in
older adults (>45 yrs of age).
 Predisposing conditions: Paget disease of bone, bone infarcts, prior radiation,
chemotherapy, foreign bodies (secondary osteosarcoma) in older adults.
 Men> Women
 Originating site: Arises from metaphyseal region of long bone (Femur, tibia,
humerus). Most commonly around knee joint.
 Other site of involvement: jaw, skull, axial skeleton.
 Pathogenesis: during adolescent growth spurt –> occurs in growth plate of rapidly
growing bones –> increased proliferation predispose to mutation driving
oncogenes.
 70% have acquired genetic abnormalities including chromosomal aberrations.
 RB mutation: 70% in sporadic os, germline mutation -> 1000 fold risk
 TP53 mutation: sporadic os, germline mutation in Li-Fraumeni syndrome
 CDKN2A: inactivation of p16 & p14
 Overexpression of MDM2 & CDK4 9 (which inhibits p53 & RB function).
Osteosarcoma contd….
 Clinical features: pain followed by swelling, pathological #.
 Pain – constant, boring, worsening with increase of size of swelling.
 incidental h/o trauma.
 On examination: warm, tender swelling at metaphysis, overlying skin: shiny with
prominent veins, margin of swelling: ill defined, movement of adjacent joint –
limited, compression of neuro-vascular structures of limb.
 Radiologic features: an area of irregular destruction in metaphysis,
 cortex – eroded,
 new bone formation in matrix of tumor
 Periosteal reaction: tumor lifts periosteum->incites intense irregularperiosteal
reaction
 Codman’s triangle: a triangular area of subperiosteal new bone at tumor-host
cortex junction at the end of tumor.
 Sunburst appearance: breach of periosteum-> tumor grows into overlying soft
tissues->bone is laid down along blood vessels within tumor growing centrifugally.
 Elevated serum alkaline phosphatase.
 Gross morphology:
 bulky, gritty, gray-white tumors that often contain hemorrhage and cystic degeneration.
 The tumor frequently destroys the surrounding cortices to produce soft tissue masses
 spread extensively in the medullary canal and replace hematopoietic marrow.
 Tumors infrequently penetrate the epiphyseal plate or enter the joint, where they may
grow along tendo-ligamentous structures or through the attachment site of the joint
capsule.
 Osteoblastic osteosarcoma: grayish white, hard, gritty feeling when cut.
 Chondroblastic type: plalescent and bluish-gray.
 Fibroblastic type: fish-flesh like sarcomatous appearance
 Telangiectatic type: large areas of tumor necrosis & blood filled spaces within tumor
mass.
Gross morphology:
 Microscopic features:
 Microscopically, osteosarcoma is defined by the direct production of immature bone
or osteoid by neoplastic cells.
 Osteoid: glassy, eosinophilic, amorphous appearance following decalcification
(resembling collagen or amyloid), lace-like/ sheet-like appearence, direct contact with
neoplastic tumor cells.
 highly atypical malignant cells (polyhedral/spindle shaped/oval/round/small blue cells
in diffuse, nested or pseudo-papillary arrangement) with significant nuclear
pleomorphism, large hyperchromatic nuclei, bizarre tumor giant cells, and abundant
abnormal mitotic figures.
 Extensive necrosis and intravascular invasion are also common.
 Predominant matrix produced by tumor cells: osteoid/cartilaginous/fibrous.
 Telangiectatic osteosarcoma: numerous blood-filled spaces separated by septa
containing highly pleomorphic mononuclear and multinucleated giant cells
accompanied by abundant mitotic activity.
Natural history:

 All osteosarcoma pts are assumed to have occult metastasis at the time of
diagnosis.
 Route of metastasis: via hematogenous route to lungs, bones, brain & other sites.
 5 year survival rate for those pts without overt mets – 70%
 5 year survival rate for those with clinically evident mets/recurrent ds/secondary
osteosarcoma - <20%
 Treatment options: Neoadjuvant chemotherapy, surgery & post-operative
adjuvant chemotherapy.
Giant cell tumor (Osteoclastoma):
 Common bone tumor with variable growth potential.
 1/3 rd benign, 1/3rd locally aggressive, 1/3rd malignant.
 Peak incidence between 20-40 yrs of age.
 Female>Male.
 Located at epiphysis. Tumor originated at epiphyseis & may extend into
metaphysis.
 Bones affected: lower end of femur, upper end of tibia, lower end of radius.
 Pathogenesis: Neoplastic cells are primitive osteoblast precursors expressing
high level of RANKL-> promotes proliferation of osteoclastic precursors->
differentiate into mature osteoclasts.
 Absence of feedback between osteoblasts & osteoclasts-> localized but highly
destructive bone resorption.
 Acquired mutation in gene encoding histone 3.3-> mechanism unknown.
Presenting features:
 Swelling & vague pain, pathological #.
 On examination: bony swelling, eccentrically located at the end of bone.
 Surface of swelling – smooth.
 Tenderness on deep palpation.
 Deformity of limb if pathological # occurs.
 Radiological features:
 Radiolucent, expansile, eccentric solitary lytic lesion.
 Soap-bubble appearance: tumor is homogenously lytic with trabeculae of remnants
of bone traversing it, giving rise to a loculated appearance.
 No calcification within tumor.
 No periosteal reaction.
 Thinned out cortex.
Expansile lytic lesion with thinned out cortex and soap-bubble appearance
at distal end of radius: GCT
Gross morphology: GCT
 cut surface is solid or friable
 variegatedred–brown and yellow appearance.
 Hemorrhage, necrosis and cystic change may be prominent.
 When the cortex is thinned or destroyed, a thin rim of reactive bone may surround
the tumor.
Microscopic features:
 Two main components:
 1. sheets of round, oval or elongated mononuclear stromal cells with an open
chromatin pattern (there are actual neoplastic cells).
 2. Osteoclast-like large multinucleate giant cells with nuclei (more than 20-30
nuclei) similar to those of the mononuclear stromal neoplastic cells. There are
evenly interposed with stromal mononuclear neoplastic cells.
 Variable number of mitotic figures.
 Secondary changes: haemorrhage, necrosis, cystic change, fibrohistiocytic
change.
Prognosis:
 Treated by curettage.
 40-60% recur locally.
 4% metastasize to lung: may regress spontaneously, seldom fatal.
 RANKL inhibitor Denosumab is recent promising adjuvant therapy.
 Malignant GCT:
 Sarcomatous lesion arising within a GCT, or as a sarcoma that appears in the
same area in which a bona fide GCT was treated.
Giant cell containing lesions of bone:
 1. Giant cell tumor of bone
 2. Fibrous cortical defect/ Non-ossifying fibroma
 3. Chondromyxoid fibroma
 4. Chondroblastoma
 5. Langerhans cell histiocytosis
 6. Brown tumor of hyperparathyroidism
 7. Giant cell reparative granuloma
 8. Aneurysmal bone cyst
 “One of the main microscopic differences between true giant cell tumor and these
mimics resides in the spatial relationship between the giant and stromal cells.
Giant cells tend to be distributed regularly and uniformly in giant cell tumor
whereas in the lesions that simulate it, foci containing numerous, clumped giant
cells alternate with large areas completely lacking this component.”
Ewings sarcoma:
 2nd most common bone sarcoma in children.
 Age: 5 – 20 yrs of age
 occurs most often in long bones (femur, tibia, humerus, and fibula) and in bones of
the pelvis, ribs, vertebrae, and clavicle.
 Location: diaphysis of long tubular bones.
 Pathogenesis: Balanced translocation t(11;22)-> creating EWSR1/FLI1 fusion
gene-> encodes EWS/FLI1 protein->binds to chromatin-> dysregulates
transcription-> uncontrolled growth & abnormal differentiation.
 Cell of origin: mesenchymal stem cells & primitive neuroectodermal cells.
 Clinical features:
 Presents with a painful enlarging mass.
 On examination: affected site – tender, warm, swollen.
 Systemic features – fever, leucocytosis, elevated ESR [mimics Pyogenic
osteomyelitis].
Radiological findings:
 destructive lytic tumor.
 permeative, or moth-eaten margins extending into surrounding soft tissues.
 The characteristic periosteal reaction produces layers of reactive bone deposited in an
onion-skin fashion.
Gross morphology:
 Involves large area, or even entire medullary cavity.
 Cut section – gray white, soft, thin; sometimes like pus.
 Bone is expanded.
 Periosteum elevated with subperiosteal new bone formation
 Tumor ruptures through cortex-> extends into adjacent soft tissue.
Microscopic features:
 Solid sheets of cells divided into irregular nests by fibrovascular septa.
 Individual cells are primitive, small, and uniform.
 The cell outlines are indistinct, resulting in a “syncytial” appearance.
 The nuclei are round, with frequent indentations, small nucleoli,
 variable mitotic activity.
 There is a well-developed vascular network. Some of the tumor cells may arrange
themselves around the vessels in a pseudorosette fashion.
 Necrosis is common.
 IHC: tumor cells are positive for CD99.
 Molecular genetics: detection of reciprocal translocation of t(11;22)(q24;q12) or
t(21;22)(q22;q12).
Spread & metastasis:
 The metastatic spread of ES/PNET is to the lungs and pleura, other bones
(particularly the skull), central nervous system, and (rarely) regional lymph nodes.
 About 25% of patients have multiple bone and/or visceral lesions at the time of
presentation.
 Prognosis:
 Neoadjuvant chemotherapy+surgery+Post op adjuvant chemotherapy with or
without radiation -> 5 year survival is of 75%.
 Chemotherapy induced necrosis – positive prognostic indicator.