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2 pathological diagnosis of cancer

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  • 1.
    • Learning is the beginning of wealth.
    • Learning is the beginning of health.
    • Learning is the beginning of spirituality.
    • Learning is where miracles begin.
    • – Jim Rohn
  • 2. Pathological Diagnosis of Neoplasm
    • Jing-Ping YUN, M.D., Ph.D.
    • 云 径 平
    • Professor in Department of Pathology Cancer Center of Sun Yat-sen University
  • 3. Pathological Diagnosis of Neoplasm
    • Recognize: roles of pathological diagnosis applied in clinical oncology
    • Understand: definition, morphology, nomenclature, differentiation, differences between benign and malignant neoplasm, Grading and staging, Precancerous lesions
    • Familiar with: principles and technologies of diagnostic pathology
  • 4.  
  • 5. The Key Points of Medical Science Disease To prevent To diagnose To treat
  • 6. Goals and Tasks of Diagnostic Pathology
    • Determine: Nature and name of disease (neoplasm)
    • Determine: grading and staging
    • Report: molecular changes and Biomarkers
  • 7. Main Contents of Pathological Diagnostic Report
    • Where: Organ and tissue involved by the lesion
    • Why: morphological characteristics, immunophenotypes, molecular changes, biomarkers
    • What: Nature and name of disease, Grading and staging, Comments
  • 8. Neoplasm: Contents
    • Definition
    • Nomenclature
    • Morphologic characteristics
    • Biologic change
      • Transformation
      • Growth rate
      • Benign vs Malignant neoplasm
      • Invasive and metastasis
      • Molecular basis
    • Grading and Staging
    • Precancerous lesion
    • Tumor-like lesion
  • 9. Definition of Neoplasm
    • Dr. DA Willis
    • A neoplasm is an abnormal mass of
    • tissue, the growth of which exceeds and
    • is uncoordinated with that of the normal tissues and persists in the same
    • excessive manner after cessation of the
    • stimuli which evoked the change.
  • 10. Terms for Neoplasm
    • Neoplasm — the new growth
    • Neoplasia — the process of “new growth”
    • Tumor — the term was originally applied to the swelling caused by inflammation, but by long precedent, the term is now equated to neoplasm
    • Cancer — the common term for all malignant tumors
    • Oncology — the study of tumors or neoplasm
  • 11. More Terms …
    • Dysplasia — recognizable morphologic changes in cells that indicate the presence of genetic mutations beginning the development of a neoplasm. Usually grading dysplastic changes based on the thickness of the involved epithelium: less than 1/3 mild atypical proliferation. less than 2/3 moderate atypical proliferation. more than 2/3 severe atypical proliferation.
    • eg: Dysplastic change of cervical epithelium infected by HPV
    • Anaplasia — recognizable morphologic changes in the tumor cells lack of differentiation; literally means “to form backward”, implying a ‘reverse differentiation’ of mature normal cells. It is considered a hallmark of malignant transformation.
    • eg: Anaplastic Rhabdomyosarcoma
  • 12. Dysplasia Dysplastic change in cervical epithelium
  • 13. Anaplastic tumor showing cellular pleomorphism
  • 14. Rhabdomyosarcoma: Anaplastic cells
  • 15. Proliferative Terms (Not Neoplastic)
    • METAPLASIA: One cell type is replaced by another cell type .
    • eg: cigarette smoking induced change of bronchial epithlelial cells to squamous; Barrett’s esophagitis--where the squamous epithelium of the esophagus is replaced by columnar epithelium.
    • HYPERPLASIA: An increase in the number of cells in an organ or tissue, which may then have an increased volume.
    • Physiologic hyperplasia: Proliferation of mammary glandular epithelium at pregnancy, compensatory hyperplasia of the liver after partial hepatectomy
    • HYPERTROPHY: An increase in size of cells and thus an increase in the size of the organ
    • eg: physiologic hypertrophy of uterus during pregnancy, hypertrophy of the cardiac muscle in hypertension or valvular disease, hypertrophy of skeletal muscles due to heavy exercise
  • 16. Differentiation
    • Differentiation — refers to the extent which neoplastic cells resemble comparable normal cells, both morphologically and functionally.
    • Tumors are often “ graded ” as to the extent of cellular differentiation or how closely they resemble the normal parent tissue that they are derived from.
  • 17. Grading of Differentiation
    • Well-differentiated means the cells are very similar in appearance and architectural arrangement to normal tissue of that organ
    • “ Poorly-differentiated” refers to tumors that show only minimal resemblance to the normal parent tissue they are derived from.
    • “ Anaplastic” (undifferentiated) means the tumor shows no obvious similarity to it’s parent tissue, usually associated with aggressive behavior
  • 18. Structure of Neoplasm
    • Parenchyma: Neoplastic cells.
    • Stroma: Non-neoplastic (Fibrous connective tissue and vasculature )
    • Fast growth  less stroma
    • Less stroma  more necrosis
  • 19.
    • Loss of normal architectural arrangement and polarity
    Morphological features of tumors Late Adenoma Normal Crypt Early Adenoma Adenocarcinoma
  • 20.
    • Pleomorphism – variation in size and shape of cells and nuclei within the neoplasm
    Morphological features of tumors
  • 21.
    • Mitotic activity - Increased in more malignant tumors and often abnormal in shape
    Morphological features of tumors
  • 22. Functional Alterations of Neoplastic cells
    • Loss of functions
    • Loss of responsiveness to and dependence upon normal regulatory pathways
  • 23. Nomenclature of Neoplasm
    • Cell of origin + Suffix
    • Neoplasms are named according to a binomial system denoting their histogenetic origin of the parenchymal component and biological behavior
    • Histogenetic origin refers to the tissue or cell type from which the tumor arose
    • Biological behavior includes the degree of tumor cell deffirentiation and patterm of growth: benign and malignant
  • 24. Nomenclature of Neoplasm
    • Cell of origin + Suffix
    • Benign tumors: Cell of origin + ‘ ~ oma’, e.g., adenoma, osteoma
    • Malignant tumors: Cell of origin + ‘ ~ carcinoma, ~ sarcoma’ , e.g., adenocarcinoma, osteosarcoma
    • Mixed Tumors – originated from more than one germ layer, or created by a divergent differentiation of a single pluripotential or totipotential cell into another tissue; benign or malignant
    • e.g., teratoma, pleomorphic adenoma or mixed tumor
  • 25.
    • Malignant tumors: suffix ‘ ~ oma’ or others
    • e.g., Glioma, Melanoma, Seminoma, Hepatoma, Leukemia
    • Non-neoplastic lesions: suffix ‘ ~ oma’
    • e.g., Granuloma, hamartoma
    • Morphology: e.g., Signet-ring cell carcinoma
    • Personal names: e.g., Ewing’s sarcoma, Brenner tumor, Hodgkin’s lymphoma
    Nomenclature of Neoplasm Exceptions
  • 26. Classification of neoplasms
    • Epithelial tumors
      • Benign forms – aden oma , papill oma
      • Malignant forms – carcinoma , eg adenocarcinoma, squamous cell carcinoma
    • Mesenchymal tumors
      • Benign forms – fibr oma , leiomy oma ,
      • Malignant forms – sarcoma , eg fibro sarcoma , leiomyo sarcoma
  • 27. Classification continued
    • Tumors of lymphocytes are always malignant – called lymphoma
    • Tumors of melanocytes
      • Benign – nevus
      • Malignant - melanoma
  • 28. Benign vs Malignant Tumor Characteristics Benign Malignant Morphology and Differentiation Well-differentiated appearance Structure similar to tissue origin Little or no anaplasia Usually some lack of differentiation Structure often atypical Variable degree of anaplasia Rate and pattern of growth Slow, progressive expansion Rare mitotic figures Normal-appearing mitotic figures Slow to rapid growth; erratic growth rate Mitotic figures often numerous Mitotic figures sometimes abnormal Local invasion No Invasion Cohesive and expansile growth Capsule often present Local Invasion Infiltrative growth Usually no capsule Metastasis No metastasis Frequent metastasis (definitive criteria for malignancy) Damage to human body Relatively smaller Relatively bigger Prognosis Good Bad
  • 29. Tumor spread
    • Features of tumor spread
    • invasion and metastasis
    • Invasion and metastasis are biologic hallmarks of malignant tumors
  • 30. Invasion and Metastasis
    • Pathways of tumor spread
        • Direct Spread
        • Body cavities
        • Blood vessels
        • Lymphatic vessels
    • Metastatic cascade: two phases
      • Invasion of Extracellular Matrix
      • Vascular Dissemination and Homing of Tumor Cells
  • 31. Invasion and Metastasis
    • loss of tumor cell-cell adhesion
    • invasion of basement membrane and extracellular matrix
    • invasion of blood vessels and lymphatics
    Steps of invasion Steps of Extravasation
    • circulating tumor cells
    • formation of tumor clumps
    • adhesion to endothelium
    • penetration of basement membrane
    • Metastatic deposit and growth
  • 32. Invasion and Metastasis Mammary carcinoma in a lymphatic in the lung
  • 33. Grading & Staging of neoplasm
    • Grading – Cellular Differentiation (Microscopic)
    • Staging – Progression or Spread (clinical)
  • 34. Grading of neoplasms
    • Grade I: Well-differentiated, cells look like normal cells
    • Grade II: Moderately differentiated
    • Grade III: Poorly-differentiated
    • Grade IV : Nearly anaplastic
    Grading of neoplasms assigned by the pathologist to reflect the cancer's degree of differentiation, the four grades are generally divided for malignant tumors
  • 35. Staging of neoplasms
    • The most common systems for staging employs the TNM classification.
      • "T" - based upon the size and/or extent of invasion.
      • "N" -indicates the extent of lymph node involvement.
      • "M" - indicates whether distant metastases are present.
    • The TNM forms are filled out using clinical and pathologic criteria and aid in determination of therapy, estimating the prognosis, and developing statistics useful for determining outcomes.
  • 36. TNM : Staging of tumor
  • 37. Staging of Malignant Neoplasms Stage Definition Tis In situ, non-invasive (confined to epithelium) T1 Small, minimally invasive within primary organ site T2 Larger, more invasive within the primary organ site T3 Larger and/or invasive beyond margins of primary organ site T4 Very large and/or very invasive, spread to adjacent organs N0 No lymph node involvement N1 Regional lymph node involvement N2 Extensive regional lymph node involvement N3 More distant lymph node involvement M0 No distant metastases M1 Distant metastases present
  • 38.
    • UICC( 国际抗癌联盟 ) TNM staging system
    • T 0 ~ 4 primary tumor size and invasive spectrum
    • N 0 ~ 3 lymph node metastasis
    • M 0 , 1 organ metastasis
          • I . T 1 N 0 M 0
          • II . T 2 N 0 M 0
          • T 0-2 N 1 M 0
          • III . T 3 N 0 M 0
          • T 0-3 N 2 M 0
          • V . T 4 N 0 M 0
          • T 0-4 N 3 M 0
          • T 0-4 N 0-3 M 1
  • 39. Tumor-like Lesions
    • Hamartoma – disorganized but mature mesenchymal or epithelial tissues found their normal anatomic location. It represents an aberrant differentiation, not a true neoplasia.
    • Choristoma – normal mature tissue located at an ectopic site
    • Polyp – grossly visible nodule or mass projecting from a
    • mucosal or epidermal surface. It is a hyperplastic response to chronic inflammation or irritation. Also it is used to indicate a benign neoplasm in some cases.
      • – Nasal polyp, endometrial polyp, vaginal polyp, and fibroepithelial cutaneous polyp (acrochordon, skin tag) are considered a hyperplastic response to chronic irritation
      • – Intestinal polyps are benign neoplasm of mucosal epithelium
  • 40. Colon Polyp
  • 41. Pathogenesis of Neoplasia Normal Cell Neoplastic Cell DNA Damage Chemical or physical agents
  • 42.
    • Normal  Hyperplasia  Metaplasia  (DNA damage)  Dysplasia  (DNA damage)  (DNA damage) Anaplasia  (DNA damage) Infiltration  (DNA damage)  Metastasis….
    • Progressive DNA Damage – features of neoplasia.
    Pathogenesis of Neoplasia:
  • 43. Pathogenesis of Neoplasia: Late Adenoma Normal Crypt Early Adenoma Adenocarcinoma
  • 44. Pathogenesis of Neoplasia (Colon Cancer) Normal Epithelium “ Proliferative ” Epithelium “ Early ” Adenoma “ Intermediate ” Adenoma “ Late ” Adenoma Invasive Carcinoma Metastases APC gene (5q loss or mutation) Abnormalities Methylation k-Ras gene (12p mutation) DCC/SMAD (18q loss) p53 gene (17p loss) Additional mutations
  • 45. Development of squmous cell carcinoma in the mouse skin, UV radiation (Animal Experiments) A B C D 2 weeks 1 months 3 months
  • 46. Conventional Diagnosis of Tumor
    • Signs and symptoms
      • Palpable lump, pain
      • Fever, Fatigue, Weight gain or loss
      • Altered metabolism
    • Medical imaging: X-ray, CT, ECT,MRI
    • Gold standard : Surgical biopsy/ pathological diagnosis
      • direct microscopic examination
  • 47. Pathological Diagnosis of Neoplasia
    • Recognize: roles of pathological diagnosis applied in clinical oncology
    • Understand: definition, morphology, nomenclature, differentiation, differences between benign and malignant neoplasm, Grading and staging, Precancerous lesions
    • Familiar with: principles and technologies of diagnostic pathology
  • 48. Methodologies of Diagnostic Pathology
    • Classical Methodologies
        • Histological diagnosis: Biopsy, Intraoperative consultation
        • Cytological diagnosis: Fine-needle aspiration; Abrasive cytology; Exfoliative cytology
        • Autopsy
    • Modern Technologies
        • Histochemistry
        • Immunohistochemistry
        • Molecular biological methods
        • Electronic microscopy
        • Digital pathology and telepathology
  • 49. Histopathological Diagnosis
    • Biopsy: paraffin-embedded tissue section
      • Incisional biopsy
      • Excisional biopsy
    • Surgical excision: paraffin-embedded tissue section
      • Organs or tissues with the tumors
      • Regional lymph nodes
    • I ntraoperative consultation
      • Frozen section
  • 50. Paraffin-embedded tissue vs Frozen section Paraffin-embedded tissue section Frozen section Specimens Fixed tissues Fresh tissues Making time 24-48 hours 10-20 minutes Saving time Permanent Months Morphology under microscopy Clarity Opacity Application Pathological Diagnosis Intraoperative consultation
  • 51. Procedure of Paraffin-embedded Section and Pathologic Examination
    • Specimen of tissues or organs by excision (biopsy or operation)
      • Cutting
      • Tissue Treatment Procedure (Dehydration -> Paraffin embedding -> Section -> Staining -> Sealing)
      • Microscopic examination -> Reports signed out
      • Application of modern technologies (IHC, PCR, FISH, EM, etc.) for specific requirement -> Reports signed out
      • Placing on files (Blocks; Slides; Documents, etc.)
  • 52. Tissue Treatment Procedure
  • 53. Parameters used in histological diagnosis of neoplasm
    • Gross appearance
    • Microscopic appearance
      • histological pattern
      • tumor cell cytology
    • Immunohistochemistry
    • Histochemistry
    • Cytogenetics /molecular pathology
    • Electron microscopy
  • 54.
    • Observe, descript and record gross appearance of tissues or organs by excision, specially lesions or tumors in the specimen
    Gross appearance
  • 55. Gross Appearance of Tumors
  • 56. Appearance of Tumors ---Gross and histological pattern Benign tumor --- adenoma of thyroid gland
  • 57. Appearance of Tumors ---Gross and histological pattern Benign tumor ---Fibroma Benign tumor ---Lipoma
  • 58. Microscopic Appearance of Tumors ---Histological pattern Carcinoma ---squamous carcinoma Carcinoma --- Papillary carcinoma
  • 59. Microscopic Appearance of Tumors ---Histological pattern
    • Fibrosarcoma
    • Liposarcoma
  • 60. Microscopic Appearance of Tumors ---Tumor Cell Cytology Normal squamous cells Squamous cell carcinoma
  • 61. Microscopic Appearance of Tumors ---Tumor Cell Cytology Abnormal mitotic figures often seen in malignant tumor
  • 62. Microscopic Appearance of Tumors ---Tumor Cell Cytology Reed-Sternberg cell
  • 63. Immunohistochemistry (IHC) in Tumor Diagnosis
    • Diagnosis confirmed in 40%
    • Important diagnostic information gained in 50%:narrowing of possibilities, or special diagnosis
    • Tumor phenotypes identified
    • IHC needed in 10-25% malignant tumors for reclassification, e.g., lymphoma
    • New entities and classifications established
  • 64.
    • Epithelium: Keratins
    • — pan-keratin and antibodies to keratins of different molecular weights
    • Supporting connective tissues:
    • — Vimentin, vWF, CD31 (PECAM)
    • Hematopoeitic tissues :
    • — CD45, B220, CD3, F480, Mac-1, Gr-1, CD41
    • Muscle :
    • — desmin, smooth muscle actin
    • Neural :
    • — GFAP, NeuN, F480/Mac-1, MBP, NSE, S100
    • Hormones :
    • — specific antibodies--insulin, casein, etc.
    • Germ cells :
    • — alpha-feto protein (teratomas)
    • Proliferation markers
    • — Ki-67
    Classification of Immunophenotype
  • 65. Immunohistochemistry (IHC) in Tumor Diagnosis Cytokeratin Vimitin Adenocarcinoma Sarcoma
  • 66. Immunohistochemistry (IHC) in Tumor Diagnosis Immunophenotypes of major groups of malignant tumors Tumor type CK VIM S-100 CD45 Carcinoma + - - - Sarcoma - + - - Lymphoma - - - + Melanoma - - + -
  • 67. Immunohistochemistry (IHC) in Tumor Diagnosis Estrogen Receptor (ER) Her-2 (Cerb B2) Breast Cancer
  • 68. Molecular Pathology in Tumor Diagnosis
    • Genetic abnormalities of Tumors
      • Changes in chromosome number and structure
      • Changes in genes (proto-oncogenes, tumor suppressive genes, DNA repair genes)
    • Diagnosis
      • Cytogenetic investigations
      • Molecular genetic investigations
  • 69. Specific Cytogenetic Abnormalities Determined in Tumors Tumor type Chromosomal changes Genes involved or fusion genes Follicular lymphoma t(14;18)(q32;q21) JH/Bcl-2 Mantle cell lymphoma t(11;14)(q13;q32) JH/Bcl-1 Synovial sarcoma t(X;18)(p11;q11) SYT-SSX1 Ewing ’ s sarcoma t(11,22)(q24;12) EWS-FL11 Follicular carcinoma t(2;3)(q13;p25) PAX 8 -PPAR γ
  • 70. Cytogenetic investigations - Fluorescent in situ hybridization (FISH) - Identify chromosome rearrangement detecting specific DNA sequences with fluorescently labeled probe
  • 71. Cytogenetic Changes of Lymphoma Determined by FISH FL diagnosed by FISH: IGH/BCL2 t(14;18)(q32;q21) MCL diagnosed by FISH: IGH/CCND1 t(11;14)(q13;q32)
  • 72. Diagnostic Cytology
    • Introduction
    • Advantages and disadvantages
    • Cytopathologic methods and samplings
  • 73.
    • Cytopathology refers to diagnostic techniques that are used to examine cells from various body sites to determine the cause or nature of disease
  • 74. Advantages vs Disadvantages
    • Advantages
      • Samples can be collected quickly and easily
      • Inexpensive
      • Little or no risk to the patient
      • Examine the cause or nature of disease
        • Specific vs nonspecific inflammation
        • Inflammation vs neoplasia
      • Direct therapy
      • Determinate next diagnostic procedures
  • 75.
    • Disadvantages
      • It is not always possible to
      • Localize neoplastic lesion
      • Distinguish preinvasive of invasive cancer
      • Distinguish reactive of dysplastic and neoplastic changes
      • Determine tumor type
    Advantages vs Disadvantages
  • 76. Cytopathology Methods
    • Exfoliative cytology
    • — spontaneously shed cells in body fluids
    • Abrasive cytology
    • — dislodge cells from body surfaces
    • Fine needle aspiration cytology (FNA)
    • — Superficial nodules and organs – easily targeted
    • — Deep organs – guidance of CT, US
  • 77.
    • Exfoliative cytology
    • — spontaneously shed cells in body fluids
      • Urine
      • CSF (cerebrospinal fluid)
      • Sputum
      • Effusion in body cavities (pleura, pericardium, peritoneum)
    Cytopathology Methods
  • 78.
    • Abrasive cytology
    • — dislodge cells from body surfaces
      • Imprint
      • Scraping and swabbing
      • Endoscropic brushing of mucosal surfaces
      • Washing of mucosal or serosal surfaces
    Cytopathology Methods
  • 79. Fine needle aspiration cytology (FNA)
  • 80. Diagnostic Cytology
    • The first important decision for suspicious case is:
    • inflammation vs neoplasia
    • Second important decision is
    • Benign vs malignant
  • 81. Tumor Cell Types in Diagnostic Cytology
    • Round to caudate large cells — epithelial tumors
    Round large cells Caudate large cells
  • 82. Diagnostic Cytology
    • Summary
      • Cytology is diagnostic method to determine cause or nature of disease
      • Cytology is quick, inexpensive and accurate method, with a little risk to patient
      • Cytology has disadvantage in tumor diagnosis
  • 83. Case Presentation
    • History : xxx, M/37y, enlarging painless preauricular mass in the left for more than 6 years.
    • Physical examination : preauricular mass in the left :2x3cm, no tenderness, little movable, No other abnormalities.
    • Initial diagnosis : The unknown nature of the left parotid gland tumor
    • Therapy : Surgery
  • 84. Gross appearance
  • 85. Microscopic appearance
  • 86.  
  • 87.  
  • 88. CK
  • 89. p63
  • 90. p53
  • 91. Pathological Diagnosis
    • Nature : benign tumor
    • Name : keratocystoma of the left parotid gland
    • Differential diagnosis :
    • Tumor-like disease : c horistoma
    • Benign tumor : l ymphatic cystadenoma
    • Malignant tumor : squamous carcinoma
  • 92. Pathological Diagnosis Report
    • Gross appearance : 2x3x1cm, enveloped olive-shaped mass, little soft, aspect gray
    • Microscopic morphology : consisted of a cystic structure lined with keratinized stratified squamous epithelium and solid nests of parenchymal squamous cells, no mitotic figures, a dense lymphoid element with follicles in the stroma.
    • Immunohistochemistry : CK (+), CK5/6(+), p63(+), p53(+)
    • Pathological diagnosis : keratocystoma of parotid gland.
    XXX, M/37y,Pathological No: xxxxxx, the left parotid gland mass
  • 93. Learning without thinking leads to confusion, thinking without learning ends in danger. 学而不思则罔 , 思而不学则殆 -Kong Zi Learning is like rowing upstream: not to advance is to drop back 学如逆水行舟 , 不进则退