Bone pathology, soft tissue tumors

Zoltán Sápi MD, PhD

1st Department of Pathology and Experimental Cancer Research
 Non-neoplastic or metabolic disease
Hyperparathyroidism: parathyroid glands produce excess
parathyroid hormone, resulting in elevated levels of calcium associated with "leaching"
calcium from the bones.
Only 25% have bone disease, usually bone pain
Presents in young to middle-aged adults with recurring kidney stones, peptic ulcer,
vomiting, weakness, headaches
Affects entire skeleton, cortical bone more than medullary bone
Usually detected early, so osteitis fibrosa cystica (severe changes, also called
Recklinghausen’s disease) are rare
Skeletal abnormalities with secondary hyperparathyroidism are typically mild
Causes: parathyroid adenoma; rarely carcinoma or hyperplasia
Laboratory: marked hypercalcemia and hypophosphatemia
Gross: thin bone cortices, rarely associated with brown tumor of hyperparathyroidism
Micro: increased osteoclastic activity with tunneling of osteoclasts into bone matrix
(dissecting resorption)

Subperiosteal
resorption
 Achondroplasia

An inherited disorder in which there is reduced proliferation of the

chondrocytes in the epiphyseal plate of long bones.
The result is a form of dwarfism in which the trunk is of normal length,
but the extremities are short.
Normal mental ability.
Fibroblast growth factor receptor 3 (FGFR3) has a negative regulatory
effect on bone growth. Activating point mutation of FGFR3.
4 out of 5 are new spontaneous mutations.

normal growth plate

Osteogenesis imperfecta
One of the most common congenital connective tissue matrix diseases
Disease of type I collagen due to mutations in genes coding for
alpha 1-2 collagen chains, usually autosomal dominant
A type of osteoporosis with marked cortical thinning and
attenuation of trabeculae
Skeletal abnormalities may be mild or severe
associated with short stature and increased fractures
Blue sclera: due to translucent sclera and visualization
of choroid
Hearing loss: due to abnormalities of middle ear bones
Dental imperfections: small, misshapen, blue-yellow teeth,
due to dentin deficiency
Paget’s disease
Also called osteitis deformans
Late-onset disorder (90% are over age 55) characterised by focal areas of increased
bone turnover containing enlarged hyperactive osteoclasts.
“Collage of matrix madness”, with furious osteoclastic bone resorption (osteolytic phase),
hectic bone formation (mixed osteoclastic/osteoblastic phase), burnt-out osteosclerotic
stage (gain in bone mass, but bone is disordered)
Symptoms: often mild; localized pain due to microfractures and nerve compression
Associated neoplasms: sarcoma (5% with severe polyostotic disease), giant cell tumor
Micro: diagnostic features are increased osteoclastic and osteoblastic activity ;
primarily woven bone; focal mosaic pattern of lamellar bone, osteoclasts may have up to
100 nuclei

polished
 Bone Tumors
WHO classification

Osteogenic tumors Notochordal tumors

Osteoid osteoma Chordoma
Osteoblastoma
Osteosarcoma
Tumors of undefined neoplastic nature
Cartilage tumors Aneurismal bone cyst
Osteochondroma Simple bone cyst
Chondromas Fibrous dysplasia
Chondromyxoid fibroma Osteofibrous dysplasia
Synovial chondromatosis Langerhans cell histiocytosis
Chondrosarcoma

Hematopoietic tumors
Giant cell tumors Plasma cell myeloma
Giant cell tumor
Malignant lymphoma
Malignancy in giant cell tumor

Ewing sarcoma/PNET
Ewing sarcoma
Osteoid osteoma
Rare; benign tumor, nidus measures 1.5-2.0 cm or less
75% under age 25; 2/3 male; 50% in femur/tibia;
Intense localized pain, particularly at night, due to production of prostaglandin E2 or
nerve fibers in reactive zone; pain relieved dramatically by aspirin
Xray: small, round lucency with variable mineralization surrounded by
extensive sclerosis
Micro: central nidus is sharply circumscribed, anastomosing bony trabeculae with
variable mineralization, plump osteoblasts, vascularized connective tissue
Treatment: CT localization of nidus and excision or radiofrequency ablation;
recurrence is unusual
Osteosarcoma
Most common primary bone tumor after myeloma
Definition: malignant bone tumor that produces osteoid directly from tumor cells and
unconnected with cartilage
60% male; usually ages 10-25 years, associated with Paget’s disease after age 40
Not associated with trauma, although trauma may lead to discovery of tumor
Sites: metaphysis of long bones
Xray: large, destructive, lytic or blastic mass with permeative margins
Codman's triangle: shadow between cortex and raised ends of periosteum
(due to reactive bone formation), non-specific
Sites of metastasis: lung (98%, 20-80% at diagnosis)
Note: excision of metastatic lung nodules may
prolong survival
5 year survival: 70%
Treatment: preoperative chemotherapy is helpful to spare
limbs
Micro: high grade spindle cell tumor that produces
osteoid matrix
Chondroma
Benign cartilaginous tumor
Either enchondroma (arise from diaphyseal medullary cavity), subperiosteal/juxtacortical
chondroma or soft tissue chondroma
Usually asymptomatic or pain due to pathologic fracture
Age 20-49 years, no gender preference; may be due to displaced growth plate
Sites: small bones of hands and feet; 70% solitary; 30% multiple
Molecular: 12q13-15 (HMGA2 / HMGI-C)
Maffuci’s syndrome: multiple enchondromas and soft tissue hemangiomas;
Ollier’s disease: nonhereditary disease of multiple enchondromas of long bones
and flat bones
Treatment: excision, may recur if incompletely excised; often leave alone
Chondrosarcoma
Malignant cartilage forming tumor that does not produce osteoid
May arise from osteochondroma
Third most common bone malignancy after myeloma and osteosarcoma
Usually ages 30-60 years, 75% males
Often large painful tumors of long bones or ribs that grow rapidly
Grading: based on cellularity and nuclear changes in chondrocytes; well, moderate or
poorly differentiated correspond to grades 1-3
Prognostic features: grading important for 5 year survival: well differentiated-78%,
moderate-53%, poorly differentiated-22%
Gross: pearly white or light blue, often with focal calcification
Micro: tumor cells produce cartilaginous matrix, may have only minor or focal atypia,
but consider malignant if malignant radiologic features
 Giant cell tumour of bone
Definition
Giant cell tumour of bone is a benign, locally aggressive neoplasm which is
composed of sheets of neoplastic ovoid mononuclear cells interspersed
with uniformly distributed, large osteoclast-like giant cells

Clinical feature
4-5% primary bone tumors

peak: 20-45 years

very rare below 10 years

female predominance (slight)

end of long bones – typical

5% flat bones

pain, swelling, lim. joint movement

path. fracture: 5-10%

 Imaging/macro
expanding, eccentric, lytic area

epiphysis and adjacent metaphysis

well-defined margin with sclerosis

well-defined margin without sclerosis
ill defined margin with cort. destr.

soft and reddish brown

blood filled spaces

 Classification of GCTB - WHO

GCTB with benign histological appearance: sheets of mononuclear cells

admixed with numerous osteoclastic giant cells

Metastasizing GCTB: the same as above, but distant metastasis

Malignancy in GCTB: a sarcoma appears at the site of previously

documented GCTB; progression in the same tumor

Malignant GCTB/giant-cell rich MFH: a high grade sarcoma arises

within the GCTB
 Ewing’s sarcoma / primitive neuroectodermal tumor (PNET)
Terms usually used interchangeably; some suggest to call PNET if neural
morphologically or a soft tissue tumor and Ewing’s if undifferentiated or a bone tumor
#2 bone sarcoma in children
May present with pain, fever, weight loss, leukocytosis and increased erythrocyte
sedimentation rate mimicking osteomyelitis
Sites: marrow of femur, tibia, humerus, fibula, pelvis, ribs, vertebra
Xray: destructive, lytic tumor with reactive periosteal bone resembling onion skin
Treatment: preoperative chemotherapy, surgery, radiation therapy
5 year survival: 75%; 50% are cured; metastases to lung, skull, pleura
Poor prognostic factors: high stage, direct extension into soft tissue, aneuploidy

Molecular: t(11,22)(q24;q12)
22q12 is EWS, a transcription factor;
11q24 is FL-1;
EWS-FL1 is a transactivator of the c-myc promoter
 Micro: sheets of small, round, uniform cells 10-15 microns with scant clear cytoplasm,
divided into irregular lobules by fibrous strands; indistinct cell membranes;
round nuclei with indentations, small nucleoli

t(11;22)
CD99
 SOFT TISSUE TUMORS
(GENERAL)

* LARGE AND HETEROGENEOUS GROUP (MORE

THAN 200 ENTITY)
* CLASSIFIED ACCORDING TO A HISTOGENETIC
CONCEPT (E.G. FIBROSARCOMA FROM
FIBROBLAST)
* PRIMITIVE MULTIPOTENTIAL MESENCHYMAL
CELLS --> DIFFERENTIATION ALONG ONE OR
MORE LINES
* INCISIONAL BIOPSY OR FNA (INITIAL DIAGNOSIS)
* LIGHT MICROSCOPIC EVALUATION (H&E),
ANCILLARY TECHNIQUES
 SOFT TISSUE TUMORS
BENIGN: WELL CIRCUMSCRIBED (PUSHING
BORDER), UNIFORM CELL MORPHOLOGY,
RARE MITOSES, NO RECURRENCE AFTER
REMOVAL, METASTASIZING POTENTIAL
INTERMEDIATE MALIGNANCY: INFILTRATIVE
GROWTH PATTERN, MONOMORPH CELL
MORPHOLOGY, RARE MITOSES FREQUENT
RECURRENCE AFTER REMOVAL, NO
METASTASIZING POTENTIAL
MALIGNANT: INFILTRATIVE GROWTH
PATTERN, ATYPICAL-POLYMORPHIC
TUMOR CELLS, FREQUENT MITOSES,
FREQUENT RECURRENCE,
METASTASIZING POTENTIAL

BORDERLINE: UNABLE TO DETERMINE

WHETHER THE TUMOR IS BENIGN OR
MALIGNANT BY MORPHOLOGY AND/OR
PROGNOSTIC FACTORS
 SOFT TISSUE TUMORS,
ANCILLARY TECHNIQUES

* ELECTRON MICROSCOPY
* IMMUNOHISTO- OR
CYTOCHEMISTRY
* CYTOGENETICS
* DNA PLOIDY
* PROGNOSTIC FACTORS ( P-53,
MDM-2, CDK4, Her2, etc.)
t(12;16)
 SOFT TISSUE TUMORS;
THERAPY
* Small clearly benign STT (on clinical grounds) can
be removed directly with a rim of uninvolved
normal tissue
* If the tumor is benign by FNA, can be safely
enucleated („shelling out” the tumor)
* If the tumor is intermediate and/or low grade
malignant by FNA, a wide excision is
recommended (often myectomy!), because of the
existance of microsatellite tumor tissue
* If the tumor is high grade malignant by FNA, a
combination of surgery, radiation therapy and
multidrug chemotherapy is necessary
 TUMORS AND TUMORLIKE
LESIONS OF FIBROUS TISSUE
BENIGN: FIBROMA
NODULAR FASCIITIS
ELASTOFIBROMA
NASOPHARINGEAL FIBROMA
KELOID
FIBROMATOSIS COLLI
INFANTILE DIGITAL FIBROMATOSIS
FIBROMATOSES, SUPERFICIAL AND DEEP
MALIGNANT: FIBROSARCOMA

2013.04.25.
 ELASTOFIBROMA

* POORLY CIRCUMSCRIBED
TUMOR OF SUBSCAPULAR
REGION
* MAINLY SPORADIC BUT
FAMILIAL CASES HAVE
BEEN DESCRIBED
* COLLAGEN BUNDLES
ALTERNATE WITH
DEGENERATED ELASTIC
FIBERS
* NOT TRUE NEOPLASM BUT
RATHER REACTIVE
HYPERPLASIA INVOLVING
ABNORMAL
ELASTOGENESIS
* ORCEIN STAIN
 NODULAR FASCIITIS
• SUBCUTANEOUS
PSEUDOSARCOMATOUS
TUMOR

* YOUNG ADULTS

* UPPER EXTREMITIES, TRUNK

AND NECK

* HISTORY OF RAPID GROWTH

(USUALLY A FEW WEEKS)

* SMALL SIZE

* CELLULAR SPINDLE-CELL
GROWTH SET IN A
LOOSELY TEXTURED
MUCOID MATRIX
 FIBROMATOSES
* PROLIFERATION OF WELL-
DIFFERENTIATED FIBROBLASTS,
MYFIBROBLASTS
* INFILTRATIV GROWTH PATTERN
* LACK OF CYTOLOGIC FEATURES
OF MALIGNANCY, SCANTY
MITOSIS
* OFTEN ARISE IN MUSCULAR
FASCIA
* FREQUENT LOCAL RECURRENCE
BUT NO METASTASIZING
POTENTIAL
* PROMPT RADICAL EXCISION WITH
A WIDE MARGIN OF INVOLVED
TISSUE
FIBROSARCOMA
* CELLULAR,
FIBROBLASTIC
SPINDLE CELL
PROLIFERATION WITH
A LOT OF MITOSES
* DIAGNOSIS OF
EXLUSION (NO
SPECIAL
IMMUNOSTAINING)
* MAY BE CONGENITAL;
ARISE FROM
SUPERFICIAL AND
DEEP CONNECTIVE
TISSUES
 FIBROHISTIOCYTIC TUMORS
BENIGN: FIBROUS HISTIOCYTOMA
(DERMATOFIBROMA)
JUVENILE XANTHOGRANULOMA
INTERMEDIATE:
DERMATOFIBROSARCOMA PROTUBERANS
MALIGNANT:
MALIGNANT FIBROUS HISTIOCYTOMA (MFH)
- myxoid
- giant cell
- inflammatory
- storiform-pleomorphic
2013.04.25.
FIBROUS HISTIOCYTOMA
(DERMATOFIBROMA)

* VERY COMMON
* VARIABLE MIXTURE
OF FIBROBLASTIC
AND HISTIOCYTE-
LIKE CELLS
(FOAMY,
MULTINUCLEATED
CELLS)
* MAINLY
SUBCUTANEUS
DEMATOFIBROSARCOMA
PROTUBERANS

* TYPICAL STORIFORM hard bumps over the skin;

PATTERN, HIGH flesh-colored
CELLULARITY
* LOCAL
AGGRESSIVENESS
(HIGH TENDENCY FOR
LOCAL RECURRENCE)
* VERY RARELY TURNS TO
FIBROSARCOMA
DURING RECURRENCE
MALIGNANT FIBROUS
HISTIOCYTOMA
* MOST COMMON TYPE OF
SOFT TISSUE SARCOMA
* HIGHLY PLEOMORPHIC
TUMOR CELLS,
STORIFORM GROWTH
PATTERN
* VIMENTIN AND CD-68
POSITIVITY OF TUMOR
CELLS
* LOCAL RECURRENCE AND
CAPACITY TO
METASTASIZE TO
DISTANT SITES
vimentin
 TUMORS OF ADIPOSE TISSUE
BENIGN: LIPOMA
ANGIOMYOLIPOMA
MYELOLIPOM
HIBERNOMA
MALIGNANT: LIPOSARCOMA
- Well-differentiated
- Myxoid
- Round-cell
- Pleomorphic
 LIPOMA
* BENIGN FATTY TUMOR WHICH
CAN ARISE IN ANY LOCATION,
VERY COMMON
* MAINLY SUPERFICIAL RARELY
DEEP-SEATED
* OFTEN GROW TO A LARGE SIZE
AND ARE USUALLY pseudoathletic appearance
ENCAPSULATED
* MAY BE SINGLE OF MULTIPLE
* MATURE FATTY TISSUE; OFTEN
MIXED WITH VESSELS,
SMOOTH MUSCLE
(ANGIOMYOLIPOMA IN
KIDNEY)
* CHROMOSOMAL ABBERATION
OF 12q, 6p BUT NOT RING OR
GIANT CHROMOSOMES
 LIPOSARCOMA
* SECOND MOST FREQUENT SOFT TISSUE SARCOMA IN
ADULTS
* USUALLY LARGE AND OCCUR MOST FREQUENTLY IN
THE LOWER EXTREMITIES
* DIFFERENT SUBTYPES BUT THE CLUE IS THE
LIPOBLAST
* MYXOID LIPOSARCOMA:
t(12;16)(q13;p11)
Different lipoblasts
S-100
RHABDOMYOMA

* ADULT TYPE (IN THE ORAL

CAVITY), FETAL FORM
(HEAD AND NECK AREA
AND HEART) AND
GENITAL TYPE
(VULVOVAGINAL Rhabdomyoma in a 3-month-old
REGION); VERY RARE boy with tachycardia.

* WELL DIFFERENTIATED
LARGE, ROUNDED OR
POLYGONAL TUMOR
CELLS WITH ABUNDANT
ACIDOPHILIC
CYTOPLASM; CROSS
STRIATION
 RHABDOMYOSARCOMA
* MOST FREQUENT SOFT TISSUE SARCOMA OF CHILDHOOD
* HEAD AND NECK REGION, RETROPERITONEUM, UROGENITAL
TRACKT
* SPINDLE OR PLEOMORPHIC TUMOR CELLS WITH
EOSINOPHILIC CYTOPLASM AND WITH CROSS STRIATION
* ALVEOLAR TYPE: t(2;13)(q35;q14) VERY POOR PROGNOSIS
* OTHER TYPES: GOOD RESPONSE FOR THERAPY
Myf-4
 Synovial sarcoma
Usually a deep seated mass present for years around
large joints (80% in knee and ankle) in young adults (age 20-40);
only 10% actually involve the joint
Represent 10% of adult soft-tissue tumors
5 year survival is 50-70%; 10 year survival 40%; recurs locally,
10-15% metastasize to lung and pleura, bone, regional nodes
Treatment: wide local excision plus radiation
Gross: well circumscribed, firm, gray-pink; focal calcifications on Xray
Micro: biphasic or monophasic or undifferentiated;
Spindle cells are arranged in plump fascicles ; biphasic have spindle cells and plump
epithelial cells forming glands/cords
 Genetic findings
t(X;18)(p11.2;q11.2)

SYT on chromosome 18

SSX1,SSX2 and SSX4

on chromosome X

SYT-SSX chimeric protein

oncogenic effect
keratin Aspiration cytology

ABL
SYT-SSX1

18q11.2
break apart ABL
SYT-SSX2
 Prognostic factors
Low risk for metastasis
Patient age < 25 years
Heavily calcified sc. better pr.
Tumor size < 5cm
Mono-biphasic type ?
Absence of poorly diff.
Extensive tu. necrosis adverse pr.
areas
High MI (> 10 m/10 HPF) adverse pr.
Aneuploidy adverse pr ?
High risk for metastasis
Increased apoptotic index adverse pr.
Patient age > 25 years
p53 mutation adverse pr. ?
Tumor size > 5cm
SYT/SSX2 fusion transcript better pr. ?
Poorly diff. areas
YB-1protein (P-glycopr.) adverse pr.
p27 low expression adverse pr. ?

Her-2 over-expression better pr.

 Muscle biopsy
A doctor is likely to call for a muscle biopsy after looking at
preliminary blood tests, performing an electromyogram
(EMG) and physical examination, and determining that the
patient’s symptoms indicate an underlying neuromuscular
disorder. The muscle biopsy can help distinguish between
muscular and neurological problems and can help pinpoint
the exact neuromuscular disorder present.

A muscle biopsy is a surgical procedure in which one or

more small pieces of muscle tissue are removed for further
microscopic or biochemical examination. The procedure,
often used in the diagnosis of a neuromuscular disorder, is
considered „minor” surgery and is usually performed
under local anesthetic.
Dermatomyositis (DM): DM is an auto immune muscle disease which
occurs in children and adults. The cardinal sign of this disorder is the
presence of a rash commonly over the upper chest and back or shoulders.
Occasionally, a purplish (heliotrope) discoloration is present over the
eyelids. Along with the rash, muscle weakness in the hips and shoulders
is noted. The disease develops over weeks to months. The cause is
unknown but involves inflammation of the blood vessels in the skin and
muscle. Diagnosis is clinical with supportive evidence from blood levels
of muscle enzymes ( creatine kinase), and EMG findings. Many people
undergo muscle biopsy for a definitive diagnosis. The disease responds
well to oral steroids but is sometimes resistant.
Polymyositis (PM): PM is similar to DM but doesn’t
have the rash. Symptoms develop over weeks to
months in most cases. The cause is usually unknown
but occasionally, PM and DM are associated with
cancer or rheumatoid conditions. Treatment is similar
to that of DM.

Drug-induced myositis: Several medications may

lead to muscle damage. These include certain
cholesterol lowering agents, colchicine, and some
other drugs.
Duchenne’s muscular dystrophy (DMD): DMD is a progressive
hereditary disease that presents in boys during infancy or early childhood.
Affected children will be slow to walk and may fail to master certain motor
activities by the appropriate age. Initially, patients have weakness in
shoulder and hip girdle muscles but, over years, weakness appear in hand
and foot muscles as well as respiratory and cardiac muscles. The disease
progresses to death often by the age of 20 due to heart failure or respiratory
compromise. A severe deficiency or absence of the protein dystrophin
underlies this disease but the exact mechanism is unknown. Diagnosis is
clinical with supportive evidence from EMG and CK elevation.
Definite diagnosis is now possible
by muscle biopsy or by genetic
testing of blood. The disease
partially responds to high doses of
oral steroids but there is no cure. A
milder form of DMD is known as
Becker dystrophy and results from
a partial loss of dystrophin. In
some cases, women who carry the
abnormal gene have some mild
symptoms of muscle disease
(cramps, slight weakness, mildly
elevated CK) and are known as
manifesting carriers.
Myotonic dystrophy :
Unlike most muscular
dystrophies, MD usually shows
severe distal weakness prior to
the development of proximal
weakness. It is inherited in a
dominant fashion. Symptoms can
be evident at birth or not be
noticeable until adulthood.
Drooping of the eyelids (ptosis)
and cataracts are other frequent
features of the disease. No cure
or effective treatment is
available.
Myasthenia gravis (MG): Auto immune disease where the target of
inflammation are the acetylcholine receptors on the muscle membrane.
MG may occur at any age and common early symptoms are double
vision, droopy eyelids, difficulty swallowing, or generalized weakness.
The onset may be gradual over months or develop rapidly over several
days or weeks. Diagnosis is clinical with supportive evidence including
presence of acetylcholine receptor antibodies, positive tensilon test, or
abnormal electrodiagnostic testing. A number or therapeutic agents are
available and include steroids, plasmapheresis, azathiorpine,
pyridostigmine and surgical removal of the thymus gland.