Diagnosis & Management

Molecular Cytogenetics

With the development of fluorescent in situ hybridization (FISH), genetic analyses of interphase nuclei became possible, even in fixed and paraffin-embedded material, by application of differentially labeled centromere-specific and sequence-specific probes to tissues and cells . Multicolor labeling techniques made it possible to identify more than one DNA sequence simultaneously . Break-apart probes, differentially labeled DNA fragments flanking, e.g., the EWS breakpoint region on chromosome 22q12 in Ewing sarcomas, indicate translocations by the splitting of the normally paired green and red (or fused yellow) signal . Because results can be obtained within 48 hours, FISH methods are increasingly used as diagnostic tools.


Cytogenetics is the morphologic study of chromosomes with the use of karyotyping.

Flow Cytometry

Flow cytometry (FCM) is a quantitative automated method used to analyze the DNA content and the proliferation rate of isolated cells . To determine the DNA content, the DNA is stained stoichiometrically with specific fluorescent dyes and the emitted fluorescent signal is measured as the nuclei pass one by one through a nozzle-equipped chamber (flow cell). The intensity of the signal is proportional to the amount of DNA in the isolated nuclei translocation of genetic material from chromosome 11 to chromosome 22, which is highly characteristic for Ewing sarcomas.

Enolases are enzymes of the glycolytic pathway. They consist of three different subunits: alpha, beta, and gamma. The functional enzyme is a dimer consisting of two identical subunits . The gamma subunit, or neuron-specific enolase (NSE), is found in neural and neuroendocrine cells. Aberrant expression, e.g., in smooth muscle cells, has also been observed . NSE positivity is found in PNETs belonging to the Ewing tumor family and in neuroblastomas and melanomas


A more recent method is immunohistochemistry (IHC), which demonstrates by immunologic methods specific antigens that serve as markers on the cell surface and its inner structures . By choosing the appropriate detection methods, including antigen retrieval techniques, almost any available antibody can be used to label a cell or a tissue . Studies using IHC are extremely helpful in differentiating among tissues that have similar morphology or whose histologic origins are uncertain

The histologic patterns are then compared and matched with similar or identical histologic patterns of known examples of bone tumors . For daily diagnostic requirements, standard hematoxylin and eosin (H&E) staining after decalcification is usually sufficient . Only for some histochemical and immunocytochemical methods does previous decalcification represent an obstacle. Acidic decalcifiers such as formic acid (5%–10% solutions) are ordinarily used. These agents provide good results within a short period of time. Because formic acid is not as rapid a decalcifier as nitric acid, the tissue structure is well preserved and good staining for H&E is retained . Most immunohistochemical protocols can also be applied. However, genetic analyses are often seriously hampered. Decalcification by EDTA, a chelating agent, does not pose these problems but is much more time-consuming . However, its use in combination with ultrasound leads to a reduction in time . Recently developed automated techniques of EDTA decalcification combined with ultrasound allow much more rapid decalcification, at least for small samples such as core biopsies . An earlier method, introduced about 20 years ago, of embedding the bone specimen in plastic and cutting it without previous decalcification, which is necessary for histomorphometric purposes, does not substantially contribute to bone tumor diagnostics.

Sessile osteochondroma Radiographic hallmarks include uninterrupted cortical and medullary continuity between the lesion and the host bone.

The radiographic hallmark of myositis ossificans is the so-called zonal phenomenon, characterized by a radiolucent area in the center of the lesion that indicates immature bone formation and a dense zone of mature ossification at the periphery. CT may demonstrate the classic zonal phenomenon of the lesion

Ossified parosteal (or periosteal) lipoma is a rare lesion, which in the majority of cases measures 5 to 7 cm at its greatest dimension . Pain is an unusual symptom; most patients give a history of a slow-growing, painless mass that has been present for many years . Consistent with fatty tumors generally, lobulation is the chief radiographic feature of the mass, which contains low-density fat in contrast to the surrounding muscle tissue that it displaces

Melorheostosis is a rare form of mixed sclerosing dysplasia that on radiography appears as a long segment of cortical thickening (flowing hyperostosis), often resembling wax dripping down one side of a candle . A typical focus of monostotic melorheostosis usually exhibits both parosteal and endosteal involvement and the lesion commonly extends into the articular end of the bone , features rarely present in a parosteal osteoma.

The heavily collagenous stroma of parosteal osteosarcoma is the key feature that distinguishes it from parosteal osteoma . In contrast, the presence of mature bone and the absence of an active fibrous stroma are the distinctive features of parosteal osteoma .

Fibrous Dysplasia

a fibroosseous lesion that may affect one bone (monostotic form, 70% to 80% of patients)
several bones (polyostotic form, 20% to 30%)characterized by the replacement of normal lamellar cancellous bone by an abnormal fibrous tissue that contains small, abnormally arranged trabeculae of immature woven bone , formed by metaplasia of the fibrous stroma.


Most commonly affecting the femur (with a predilection for the femoral neck), the tibia, the ribs (representing the most common benign lesion of the rib), and the base of the skull, the lesion of monostotic fibrous dysplasia arises centrally in the bone; it usually spares the epiphysis in children and the articular end of the bone in adults . The incidence in men and women is the same . Because these lesions are usually asymptomatic, most of them are discovered incidentally on radiographs obtained for other reasons. Rarely, pain accompanied by local swelling and deformity is present. The most common complication is a pathologic fracture through the structurally weakened bone. This may be the initial presentation, particularly for lesions located in the lower extremity.

The radiographic appearance of the lesion depends on the proportion of osseous to fibrous tissue. Lesions with higher degrees of ossification appear more dense and sclerotic. More fibrous lesions exhibit a greater radiolucency, with a characteristic “ground-glass” or even cystic appearance.

A solitary focus of fibrous dysplasia may be surrounded by a characteristic thick band of reactive bone, creating a “rind” sign . This appearance of fibrous dysplasia must be differentiated from the very similar presentation of a bone infarct.

In extremely rare instances, lesions of fibrous dysplasia may protrude from the bone (the so-called exophytic variant of fibrous dysplasia.

Polyostotic Fibrous Dysplasia

Although radiographically similar to the monostotic form, polyostotic fibrous dysplasia often exhibits a somewhat more aggressive appearance. Moreover, the lesions are distributed differently in the skeleton, showing a striking predilection (more than 90% of cases) for one side of the body. They often involve the pelvis, followed in frequency by the long bones, skull, and ribs; the proximal end of the femur is a common site of occurrence. In general, the lesions of polyostotic fibrous dysplasia progress in number and size until skeletal maturity is reached, after which they become quiescent. Only 5% of lesions continue to enlarge. Unlike the monostotic form, this variant of fibrous dysplasia is usually symptomatic. In most patients the presenting symptoms, such as a limp, leg pain, or a pathologic fracture, result from skeletal involvement. However, at a very early age, associated endocrine abnormalities (such as vaginal bleeding) usually appear first.

Polyostotic fibrous dysplasia that is associated with endocrine disturbances (i.e., premature sexual development, gigantism or acromegaly, hyperthyroidism, hyperparathyroidism, and Cushing syndrome) and skin pigmentation (café-au-lait spots) constitutes the disorder called McCune-Albright syndrome. This condition, which is caused by somatic mutations in the GNAS1 gene located in chromosome 20q13 , appears to predominantly affect girls, who exhibit true sexual precocity resulting from accelerated gonadotropin release by the anterior lobe of the pituitary. However, a recent study indicates that, in a substantial number of cases, children treated for isolated fibrous dysplasia actually have unrecognized McCune-Albright syndrome, which becomes apparent when appropriate tests are performed . Typically, the café-au-lait spots of McCune-Albright syndrome show irregular, ragged (“coast of Maine”) borders, in contrast to the smoothly marginated (“coast of California”) café-au-lait markings seen in neurofibromatosis. Mazabraud syndrome is a condition in which multiple fibrous and fibromyxomatous soft tissue tumors occur in association with polyostotic fibrous dysplasia.

The most common complication of polyostotic fibrous dysplasia is a pathologic fracture that, when it occurs in the femoral neck, frequently leads to a “shepherd’s crook” deform. Occasionally, accelerated growth of a bone or hypertrophy of a digit may be observed. The development of a sarcoma in fibrous dysplasia is extremely rare, but it may occur either spontaneously or, more commonly, after radiation therapy.

Massive formation of cartilage may be observed in the lesion, accompanied by secondary calcification and ossification patterns, known as fibrocartilaginous dysplasia or fibrochondrodysplasia.

The severe form of craniofacial fibrous dysplasia has been termed “leontiasis ossea,” because marked deformities combined with bone enlargement resemble a lion’s face.

Because of increased uptake on skeletal scintigraphy, radionuclide bone scanning is the most rapid way to determine the distribution of skeletal lesions.