Whole pathology of bone tumors and MSC differentiation

Osteochondroma and Chondrosarcoma

• Mutant cells grow out and form an osteochondroma with some normal cells.
• Osteochondroma is not entirely clonal.
• Osteochondromas can progress to secondary peripheral chondrosarcoma.
• Chondrosarcoma is clonal, and some cells may not have EXT mutations.
• Other mutations that inactivate cell cycle genes, such as INK4 or Trp53, can also occur.

Central Cartilaginous Tumors

• Enchondromatosis (Ollier disease) is a rare, non-hereditary condition with a unilateral predominance.
• It occurs during skeletal formation in young patients and has a 40% risk of malignant transformation.
• IDH1 or IDH2 mutations are often found in Ollier, secondary chondrosarcoma, and primary central chondrosarcoma.
• These mutations convert α-KG to D2HG, affecting DNA methylation and histone modifications.

Ewing Sarcoma and Molecular Diagnostics

• Pathological diagnosis involves immunohistochemistry, molecular analysis, morphology, and clinical and radiological information.
• Ewing sarcoma has a specific translocation, EWSR1-ETS, which is essential for tumor formation.
• Immunohistochemistry is used to detect antigens in tissue sections, determine diagnosis, and predict prognosis.
• Molecular testing is necessary to confirm the diagnosis, as immunohistochemical profiles may overlap.
• Techniques for translocation detection include conventional cytogenetic, RT-PCR, FISH, and next-generation sequencing.

Molecular Alterations in Small Blue Round Cell Tumors

• Ewing sarcoma specific translocations involve EWSR1-ETS fusion proteins.
• Specific translocations in sarcomas involve chimeric gene formation, promoter swap, and truncation.
• These translocations lead to transcriptional deregulation, deregulated signaling, and altered expression.

Diagnosis and Treatment

• Diagnosis involves a combination of immunohistochemistry, molecular analysis, and radiological information.
• Treatment for Ewing sarcoma involves resection, chemotherapy, and radiation, with a 5-year survival rate of about 60-65%.
• Genetic testing is essential for diagnosis, but not sufficient on its own, as some tumors share the same fusion but are entirely different.
• Antibodies against chimeric proteins, such as SS18-SSX, can be used for diagnosis.

Giant Cell Containing Tumors of Bone

• Giant cells in bone tumors are not necessarily indicative of a giant cell tumor.
• GCTB (giant cell containing tumors of bone) is a specific type of tumor with a distinct biology and therapy.
• GCTB is characterized by the presence of giant cells and mononuclear cells.
• Treatment for GCTB involves understanding its biology and therapy.

Height Measurement and Definition

• Height is measured in relation to the standard deviation (SDS) from the mean height
• Tall stature: height > 2 SDS or > 1.6 SDS above target height based on parent's height
• Short stature: height < -2 SDS or > 1.6 SDS under target height based on parent's height

Guideline for Measuring

• Measure height, weight, head circumference, arm span, and sitting height
• Measure parents' height only when armspan and sitting height are abnormal in the child

Height Determinants

• 60-80% of height is determined by genetics
• Feeding, health, and medication are other important factors influencing height

Syndrome Definition and Recognition

• A syndrome is a group of signs and symptoms that occur together and characterize a particular abnormality or condition
• Syndrome recognition involves pattern recognition

Causes of Short Stature

Primary Growth Disorders

• Syndromes
• SGA (small for gestational age) without catch-up growth
• Skeletal dysplasia
• Disorders of bone metabolism

Secondary Growth Disorders

• Malnutrition
• Celiac disease
• Hormonal disorders
• Metabolic disorders
• Idiopathic short stature (unknown cause)

Syndromes with Short Stature

• Down syndrome (trisomy 21)
• Turner syndrome
• Noonan syndrome

Turner Syndrome

• Occurs only in girls
• Characterized by a single X chromosome or an isochromosome X (missing short arm)
• Often have heart conditions and are infertile
• Benefit from growth hormone therapy

Noonan Syndrome

• Caused by a gene mutation, affecting both boys and girls
• Short stature (mean height: 169 cm in males, 154 cm in females)
• Developmental delay (mean IQ: 86)
• Facial features: hypertelorism, ptosis, low-set ears, and broad neck
• Congenital cardiac anomaly, pectus deformity, lymphatic abnormalities, coagulation defects, and cryptorchidism
• Genetics: mutations in genes in the RAS-MAPK pathway

Skeletal Dysplasia

• Frequency: 1:3000 live births, 1:110 perinatal mortality
• Characterized by short limbs for trunk, epiphysis, metaphysis, and/or diaphysis abnormalities
• Causes disproportionate short stature
• Heterogeneity (clinical and genetic), non-uniform terminology

Skeletal Dysplasia: Achondroplasia

• Frequency: 1:15,000 - 1:40,000
• Clinical features: short stature with large head, short arms and legs, skin creases, pronounced lumbar lordosis, and short hands with trident fingers
• X-ray features: normal or small bone size, no increase in bone width with age

Objectives

• Define short stature and tall stature
• Recognize and describe the clinical features of common syndromes with short stature
• Understand the molecular background of specific syndromes
• Interpret the inheritance pattern of a specific syndrome and its implications for the patient and their family