Deel 1 samenvatting t/m ewing sarcoma

Autopsy

• Hospital autopsy: performed by a clinical pathologist, requires permission from relatives, and is done in almost every hospital in the Netherlands
• Medico-legal autopsy: performed by a forensic pathologist, ordered by a district attorney, and does not require permission from relatives

Pathology

• Study of disease: focuses on functional and structural changes in cells, tissues, and organs
• Aspects of disease:
  • Etiology: cause of disease
  • Pathogenesis: mechanism of disease development
  • Morphologic and molecular changes: structural alterations in cells and organs
  • Clinical significance: relation to clinical picture

Histology and Cytology

• Histology: study of tissue structure
• Cytology: study of individual cells
• Formalin fixation: denatures DNA, making it unusable for analysis
• Target genes: examples include HER2 in breast cancer, KRAS/BRAF in colon cancer, and EGFR/KRAS in lung cancer

Nomenclature of Disease

• Importance of uniform nomenclature: enables accurate epidemiological studies and communication
• Eponymous names: commemorate discoverers or signify ignorance of cause or mechanism
• Neoplasm: literally means "new growth", can be benign or malignant

Prefixes and Suffixes in Terminology

• Prefixes:
  • Ana-: absence
  • Dys-: disordered
  • Hyper-: excess
  • Hypo-: deficiency
  • Meta-: change
• Suffixes:
  • -itis: inflammatory process
  • -oid: resembling
  • -penia: lack of
  • -ectasis: dilatation
  • -opathy: abnormal state

Neoplasia

• Definition: abnormal mass of tissue, growth exceeds and is uncoordinated with normal tissues
• Classification:
  • Behavioural: benign or malignant
  • Histogenetic: cell of origin
  • Precise classification of individual tumors
• Benign vs malignant:
  • Benign: small, slow-growing, non-invasive, well-differentiated
  • Malignant: large/small, fast-growing, invasive, poorly differentiated

Morphological and Cytological Features of Cancer

• Microscopic appearance:
  • Large, variably shaped nuclei
  • Increased number and abnormal mitoses
• Benign features:
  • Looks like normal cells
  • Low proliferation rate
  • No necrosis
• Malignant features:
  • Cells look "very" abnormal
  • Polymorphic cells
  • High N/C rate
  • High proliferation rate
  • Often necrosis

Staging of Cancer

• Definition: extent of cancer, such as tumor size and spread
• Purpose: understand seriousness of cancer and chances of survival
• TNM system:
  • T: tumor size and extent
  • N: affected nodes
  • M: metastasis

Molecular Pathology

• Diagnosis: detection of mutations, specific translocations, or amplifications
• Prognostic: detection of specific changes associated with prognosis
• Predictive: detection of mutations or amplifications that are druggable targets
• Hereditary syndromes: detection of (epigenetic) changes associated with somatic variations

Hallmarks of Cancer

• Molecular profile: tumor DNA
• Genomic alterations: copy number variations, nucleotide variations, and gene rearrangements
• Tumor microenvironment: surrounded by various cell types

Cellular Pathology and Inflammation

• Homeostasis: balance between cellular growth and death
• Cellular adaptations to stress:
  • Hypertrophy: increase in cell size
  • Hyperplasia: increase in cell number
  • Atrophy: decrease in cell size and number
  • Metaplasia: reversible change in cell type and function
• Cell death: necrosis, apoptosis, and autophagy

Inflammation

• Components:
  • Vascular
  • Cellular
  • Mediators
• Outcome:
  • Acute inflammation: resolution or abscess formation
  • Chronic inflammation: prolonged duration of inflammation

Tissue Repair

• Regeneration or scar formation
• Dependent on tissue, stem cells, and growth factors
• Scar formation: replacement with connective tissue (fibrosis)### Bone Structure and Formation
• Osteoblasts, osteoclasts, hematopoietic supportive stroma, marrow adipocyte, and hematopoietic stem cells are present in bone.
• Cortical bone has a dense layer with osteoblasts on the inside, osteocytes within the matrix, and canaliculi connecting them.
• Osteons are organized in a ring shape within cortical bone, with a canal for blood vessels.

Ossification

• There are two types of ossification:
  • Intramembranous ossification: direct bone formation without a cartilage step (minority of bone formation).
  • Endochondral ossification: cartilage model is replaced by bone.
• Intramembranous ossification occurs in the cranial vault, facial bones, clavicles, and cortical bone, mainly for appositional bone growth.
• Endochondral ossification occurs in the axial and appendicular skeleton, resulting in longitudinal bone growth, joint cartilage, and fracture healing.

Regulation of Longitudinal Growth

• Regulation of longitudinal growth is complex and involves paracrine and systemic regulation.

Differences between Articular and Growth Plate Cartilage

• Articular cartilage:
  • Located at distal ends of bones.
  • Involved in joint formation and motility.
  • Resistant to resorption.
  • Associated with osteoarthritis (osteoarthritis).
• Growth plate cartilage:
  • Entrapped between epiphyseal and metaphyseal bone.
  • Involved in longitudinal bone growth.
  • Disappears at the end of puberty.
  • Associated with growth disorders.

Non-Neoplastic Pathology of Bone

• Bone fracture:
  • Loss of bone integrity due to mechanical injury and/or diminished bone strength.
  • Types: normal (acute trauma), stress or fatigue fracture (repetitive mechanical stress), and pathological fracture (weakened bone due to pre-existing lesion/tumor).
• Fracture healing:
  • Involves the formation of a callus, which unites the fractured bone ends.
  • Stages: inflammatory, soft callus, and hard callus formation.

Mesenchymal Stem Cell Differentiation

• Mesenchymal stem cells (MSCs):
  • Multipotent progenitor cells.
  • Reside in bone marrow, adipose tissue, and cord blood.
  • Undifferentiated, with self-renewal capacity.
  • Can differentiate into bone, cartilage, and adipose tissue.
• Identification of MSC markers:
  • CD73, CD90, CD105.
• Osteoblast differentiation:
  • CBFA1/RUNX2 transcription factor induces RANK ligand, blocking adipocyte differentiation.
  • RUNX2 is essential for osteoblast differentiation and bone formation.

Wnt Signaling

• Wnt signaling pathway:
  • Important for bone development and homeostasis.
  • Defects in Wnt genes lead to hereditary bone pathologies.
  • β-Catenin translocation into the nucleus activates genes.

Mesenchymal Stem Cells in Research and Therapy

• MSCs are present in bone marrow, easy to obtain, and can differentiate in vitro.
• MSCs can be transfected with foreign DNA and frozen for later use.
• MSCs are immunosuppressive and can inhibit alloreactive T-cell proliferation.

Cartilage Tumors of Bone

• Classification of cartilage tumors:
  • Benign: osteochondroma, enchondroma.
  • Malignant: peripheral chondrosarcoma, central chondrosarcoma.
• Histological grading:
  • ACT/grade I: low cellularity, lot of matrix, mitoses absent.
  • Grade II: increased cellularity, cytonuclear atypia, mitoses sparse.
  • Grade III: high cellularity, atypia, myxoid, mitoses.

Osteochondroma

• Benign cartilage tumor:
  • Located at the bone surface.
  • Has a cartilage cap and marrow cavity continuous with the underlying bone.
• Multiple osteochondromas (MO):
  • Hereditary, autosomal dominant.
  • Mutations in EXT1 and EXT2.

Ewing Sarcoma and Molecular Diagnostics

• Sarcoma genesis:
  • Ewing sarcoma: specific translocation.
  • Chondrosarcoma: specific mutation, multistep model.
  • Osteosarcoma: complex karyotype.
• Age-specific incidence of bone sarcomas:
  • Ewing sarcoma: peaks in adolescence and young adulthood.
  • Chondrosarcoma: peaks in adulthood.
  • Osteosarcoma: peaks in adolescence and young adulthood.

Case Study: Ewing Sarcoma

• Diagnosis:
  • Small blue round cell tumor in bone.
  • Immunohistochemistry: CD99, FLI1.
  • Molecular diagnostics: EWSR1-FLI1 fusion (NGS analysis).
• Treatment:
  • Resection, chemotherapy, radiation.
  • 5-year survival: about 60-65%.
• EWSR1-ETS target genes:
  • Involved in cell proliferation, evading growth inhibition, escape from senescence, angiogenesis, and invasion and metastases.

Autopsy

• Hospital autopsy: performed by a clinical pathologist, requires permission from relatives, and is done in almost every hospital in the Netherlands
• Medico-legal autopsy: performed by a forensic pathologist, ordered by a district attorney, and does not require permission from relatives

Pathology

• Study of disease: focuses on functional and structural changes in cells, tissues, and organs
• Aspects of disease:
  • Etiology: cause of disease
  • Pathogenesis: mechanism of disease development
  • Morphologic and molecular changes: structural alterations in cells and organs
  • Clinical significance: relation to clinical picture

Histology and Cytology

• Histology: study of tissue structure
• Cytology: study of individual cells
• Formalin fixation: denatures DNA, making it unusable for analysis
• Target genes: examples include HER2 in breast cancer, KRAS/BRAF in colon cancer, and EGFR/KRAS in lung cancer

Nomenclature of Disease

• Importance of uniform nomenclature: enables accurate epidemiological studies and communication
• Eponymous names: commemorate discoverers or signify ignorance of cause or mechanism
• Neoplasm: literally means "new growth", can be benign or malignant

Prefixes and Suffixes in Terminology

• Prefixes:
  • Ana-: absence
  • Dys-: disordered
  • Hyper-: excess
  • Hypo-: deficiency
  • Meta-: change
• Suffixes:
  • -itis: inflammatory process
  • -oid: resembling
  • -penia: lack of
  • -ectasis: dilatation
  • -opathy: abnormal state

Neoplasia

• Definition: abnormal mass of tissue, growth exceeds and is uncoordinated with normal tissues
• Classification:
  • Behavioural: benign or malignant
  • Histogenetic: cell of origin
  • Precise classification of individual tumors
• Benign vs malignant:
  • Benign: small, slow-growing, non-invasive, well-differentiated
  • Malignant: large/small, fast-growing, invasive, poorly differentiated

Morphological and Cytological Features of Cancer

• Microscopic appearance:
  • Large, variably shaped nuclei
  • Increased number and abnormal mitoses
• Benign features:
  • Looks like normal cells
  • Low proliferation rate
  • No necrosis
• Malignant features:
  • Cells look "very" abnormal
  • Polymorphic cells
  • High N/C rate
  • High proliferation rate
  • Often necrosis

Staging of Cancer

• Definition: extent of cancer, such as tumor size and spread
• Purpose: understand seriousness of cancer and chances of survival
• TNM system:
  • T: tumor size and extent
  • N: affected nodes
  • M: metastasis

Molecular Pathology

• Diagnosis: detection of mutations, specific translocations, or amplifications
• Prognostic: detection of specific changes associated with prognosis
• Predictive: detection of mutations or amplifications that are druggable targets
• Hereditary syndromes: detection of (epigenetic) changes associated with somatic variations

Hallmarks of Cancer

• Molecular profile: tumor DNA
• Genomic alterations: copy number variations, nucleotide variations, and gene rearrangements
• Tumor microenvironment: surrounded by various cell types

Cellular Pathology and Inflammation

• Homeostasis: balance between cellular growth and death
• Cellular adaptations to stress:
  • Hypertrophy: increase in cell size
  • Hyperplasia: increase in cell number
  • Atrophy: decrease in cell size and number
  • Metaplasia: reversible change in cell type and function
• Cell death: necrosis, apoptosis, and autophagy

Inflammation

• Components:
  • Vascular
  • Cellular
  • Mediators
• Outcome:
  • Acute inflammation: resolution or abscess formation
  • Chronic inflammation: prolonged duration of inflammation

Tissue Repair

• Regeneration or scar formation
• Dependent on tissue, stem cells, and growth factors
• Scar formation: replacement with connective tissue (fibrosis)### Bone Structure and Formation
• Osteoblasts, osteoclasts, hematopoietic supportive stroma, marrow adipocyte, and hematopoietic stem cells are present in bone.
• Cortical bone has a dense layer with osteoblasts on the inside, osteocytes within the matrix, and canaliculi connecting them.
• Osteons are organized in a ring shape within cortical bone, with a canal for blood vessels.

Ossification

• There are two types of ossification:
  • Intramembranous ossification: direct bone formation without a cartilage step (minority of bone formation).
  • Endochondral ossification: cartilage model is replaced by bone.
• Intramembranous ossification occurs in the cranial vault, facial bones, clavicles, and cortical bone, mainly for appositional bone growth.
• Endochondral ossification occurs in the axial and appendicular skeleton, resulting in longitudinal bone growth, joint cartilage, and fracture healing.

Regulation of Longitudinal Growth

• Regulation of longitudinal growth is complex and involves paracrine and systemic regulation.

Differences between Articular and Growth Plate Cartilage

• Articular cartilage:
  • Located at distal ends of bones.
  • Involved in joint formation and motility.
  • Resistant to resorption.
  • Associated with osteoarthritis (osteoarthritis).
• Growth plate cartilage:
  • Entrapped between epiphyseal and metaphyseal bone.
  • Involved in longitudinal bone growth.
  • Disappears at the end of puberty.
  • Associated with growth disorders.

Non-Neoplastic Pathology of Bone

• Bone fracture:
  • Loss of bone integrity due to mechanical injury and/or diminished bone strength.
  • Types: normal (acute trauma), stress or fatigue fracture (repetitive mechanical stress), and pathological fracture (weakened bone due to pre-existing lesion/tumor).
• Fracture healing:
  • Involves the formation of a callus, which unites the fractured bone ends.
  • Stages: inflammatory, soft callus, and hard callus formation.

Mesenchymal Stem Cell Differentiation

• Mesenchymal stem cells (MSCs):
  • Multipotent progenitor cells.
  • Reside in bone marrow, adipose tissue, and cord blood.
  • Undifferentiated, with self-renewal capacity.
  • Can differentiate into bone, cartilage, and adipose tissue.
• Identification of MSC markers:
  • CD73, CD90, CD105.
• Osteoblast differentiation:
  • CBFA1/RUNX2 transcription factor induces RANK ligand, blocking adipocyte differentiation.
  • RUNX2 is essential for osteoblast differentiation and bone formation.

Wnt Signaling

• Wnt signaling pathway:
  • Important for bone development and homeostasis.
  • Defects in Wnt genes lead to hereditary bone pathologies.
  • β-Catenin translocation into the nucleus activates genes.

Mesenchymal Stem Cells in Research and Therapy

• MSCs are present in bone marrow, easy to obtain, and can differentiate in vitro.
• MSCs can be transfected with foreign DNA and frozen for later use.
• MSCs are immunosuppressive and can inhibit alloreactive T-cell proliferation.

Cartilage Tumors of Bone

• Classification of cartilage tumors:
  • Benign: osteochondroma, enchondroma.
  • Malignant: peripheral chondrosarcoma, central chondrosarcoma.
• Histological grading:
  • ACT/grade I: low cellularity, lot of matrix, mitoses absent.
  • Grade II: increased cellularity, cytonuclear atypia, mitoses sparse.
  • Grade III: high cellularity, atypia, myxoid, mitoses.

Osteochondroma

• Benign cartilage tumor:
  • Located at the bone surface.
  • Has a cartilage cap and marrow cavity continuous with the underlying bone.
• Multiple osteochondromas (MO):
  • Hereditary, autosomal dominant.
  • Mutations in EXT1 and EXT2.

Ewing Sarcoma and Molecular Diagnostics

• Sarcoma genesis:
  • Ewing sarcoma: specific translocation.
  • Chondrosarcoma: specific mutation, multistep model.
  • Osteosarcoma: complex karyotype.
• Age-specific incidence of bone sarcomas:
  • Ewing sarcoma: peaks in adolescence and young adulthood.
  • Chondrosarcoma: peaks in adulthood.
  • Osteosarcoma: peaks in adolescence and young adulthood.

Case Study: Ewing Sarcoma

• Diagnosis:
  • Small blue round cell tumor in bone.
  • Immunohistochemistry: CD99, FLI1.
  • Molecular diagnostics: EWSR1-FLI1 fusion (NGS analysis).
• Treatment:
  • Resection, chemotherapy, radiation.
  • 5-year survival: about 60-65%.
• EWSR1-ETS target genes:
  • Involved in cell proliferation, evading growth inhibition, escape from senescence, angiogenesis, and invasion and metastases.

This quiz covers the different types of autopsies, including hospital autopsy and medico-legal autopsy, and their respective procedures and requirements.