3. Neoplasia

// Neoplasia

03.07.21 | 08:13 tags:


Neo - New Plasia - Growth

  • Even when there is no stimulus ( such as growth factor), the cell continues replicating - distinct from hyperplasia and repair
  • Monoclonal Growth
    • Clonality determines number of cells involved in replication of a clone
    • Monoclonal: Cells are derived from a single progenitor cell
    • Polyclonal: Multiple cells produce daughter cells
    • Clonality was historically determined by G6PD enzyme isoforms, but androgen receptor isoforms can be used (Both are present on X-chromosome)
      • G6PD have multiple isoforms - A, B, C, D etcetra
      • In females, only one isoform is inherited from each parent - X-linked inheritance
      • One isoform is randolmly inactivated by lyonization which inactivates one X chromosome at random
      • Normal ratio of active isoforms in any cell of a tissue is 1:1
        • 50% of cells have G6PD-A and 50% have G6PDB
      • When hyperplasia occurs in these cells, 1:1 ratio is maintained in hyperplasia, as the derivative of hyperplasic cells is polyclonal
      • Only one isoform is present in neoplasia
        • As growth is monoclonal, thus only one isoform is present
  • Clonality of B-lymphocytes is determined by immunoglobulin light chain phenotype
    • Ig is comprised of heavy and light chains
      • B cells express light chain phenotypes that are: kappa or lambda
      • Normal kappa to lambda ratio is 3:1 to 3:2
        • This ratio is maintained in hyperplasia, such as during infection, which again is polyclonal
        • When neoplasic growth such as lymphoma occurs, ratio is pushed to >6:1 or is inverted (Κ:γ - 1:3 or > 1:6) - due to monoclonal growth
BenignMalignant
Remain LocalizedInvade locally
Do not metastasizeHave the potential to metastasize
Slow growthRapid growth
Capsule is present except in HemangiomaCapsule is absent
Well differentiatedPoorly differentiated
Good prognosisPoor Prognosis
-OMA suffixSeminoma, Lymphona, Carcinoma (epithelial cells) Sarcoma (Connective tissues)

Nomenclature

Lineage of differentiationBenignMalignant
EpitheliumAdenoma - produces glandsAdenocarcinoma
Papilloma - produces papillary finger like structuresPapillary carcinoma
MesenchymeLipomaLiposarcoma
LymphocyteNon-existentLymphoma/Leukemia
MelanocyteNevus (mole)Melanoma
Husain Sattar’s brainNever benign - always proactivePathoma
  • Choristoma

    • Normal tissue at an abnormal site [Ectopic rest of normal tissue]
  • Hamartoma

    • Abnormal tissue at normal sites
      • Most common site -> Lungs
    • Considered as preneoplastic lesions
  • Teratoma ->

    • Growth in Totipotent cells
    • Arises from 1 germ cell layer
      • Most common site: Gonads > Mediatinum MRS

[[Pasted image 20210703133008.png]]

Components of Neoplasm

  • Parenchyma
    • Refers to the proliferating neoplastic cells
  • Stroma
    • Refers to the connective tissue material present in the neoplasm
  • When there is more stroma -> Firm appearance -Desmoplasia

    • Linitis plastica - adenocarcinoma of stomach wall - leather-bottle appearance
    • Colon cancer
    • Breast cancer
  • When Parenchyma -> Medullary appearance

Features of Neoplasia

1. Anaplasia

  • There’s a total absence of differentiation

  • Nucleo:Cytoplasmic ratio can show this - Normal N:C ratio - 1:4 - Anaplastic N:C ratio - 1:1 - Histology shows highly basophilic

    [[Pasted image 20210703183310.png]]

  • Anaplastic cells show high pleomorphism

    • Different morphologies - high variability
  • Anaplastic cells undergo abnormal mitosis

    • Normal cells form 2 mitotic spindles -> 2 daughter cells are produced

    • Anaplastic cells have more than 2 spindles

      • 3 spindles: Tripolar spindles

      • 4 spindles: Quadripolar spindles

        [[Pasted image 20210703183532.png]]

    • Abnormal giant cells

      • Reed sternberg cells

      [[Pasted image 20210703184107.png]]

    • Totally irreversible Condition

  • AN - Abnormal Nucleocytoplasmic ratio - very high
  • A - Abnormal mitosis
  • PL - Pleomorphism, loss of polarity
  • ASIA - IRREVERSIBLE

[[Pasted image 20210703184253.png]]

2. Rapid Rate of Growth

  • Minimum mass of tumor cells to be detected clinically is -> Billion (10^9) cells (1g of tumor cells)
  • Maximum number of cells compaitable with life -> Trillion (10^12) cells

Warburg effect

  • Even in the presence of sufficient oxygen, cancer/tumor cells undergo Glycolysis
  • Pyurvate -> Intermediates -> Growth Factors synthesis -> Tumor cell proliferation
  • This is basically Aerobic Glycolysis but no EMP
  • Physiologically seen in embryonic tissues, lymphoid cells where M2 isoform of pyurvate kinase is present
18 FDG - radioactive glucose sub-type that is non-metabolized is given to the patient
- As tumor cells leadto angiogenesis and thus are more vascularized, this 18-FDG is concentrated in the tumor. Normal cells have diffuse distribution of 18-FDG
- PET scan is done to localize tumors

3. Invasion

  • Tumor cells secrete VEGF and FGF
    • They are responsible for angiogenesis
    • Thus they are playing facilitatory role in the growth and spread of tumors
  • Without angiogenesis, tumor cells can grow only upto 1-2 mm

^b55de7

Anti-angiogenetics such as Angiostatin, endostatin [NATURAL] and drugs like Bevacizumab inhibit angiogenesis

CarcinomaCarcinoma In Situ
Basement Membrane is affectedBasement membrane is not affected
Carcinoma is found only in the place where it first formed in the body
It is also known as preinvasive/non-invasive tumor - Stage 0 Cancer

4. Metastasis

  • It is the most reliable feature of Malignancy

    • Pheochromocytoma
    • Follicular thyroid tumor
      • Follicular adenoma - benign
      • Follicular carcinoma - malignant -metasasis
  • Eventual accumulation of mutations results in invasion and spread Characteristics

  • Downregulation of E-cadherin

    • Cadherin keep cells attached with one another
    • For tumor cells to spread, downregulation of E-cadherin
    • The cell is attached to basement membrane - collagen IV and laminin
      • Cell that detaches from neighbouring cells attach to the basement membrane by laminin
      • Then they proceed to secrete collagenase and breakdown the collagen IV
      • In the extracellular matrix, cells attach to fibronectin 1 and spreads locally
      • It may gain access to vascular (hematogenous spread) or lymphatic spaces
  • Epithelial -> Mesenchymal Transition:

    • For spread of tumor, properties are up regulated and mesenchymal property is down regulated

    [[Pasted image 20210707104535.png]]

Malignancy maybe present without metastasis in:

  • Basal cell carcinoma - Skin
  • Glioma - CNS tumor

Metastasis are spread through:

  • Lymphatic spread - Property of Carcinomas

    • Tumor cells are generally spread first to ==Sentinel lymph-nodes ==
      • Sentinel lymph node (SLN) is defined as the first lymph node (or nodes) on a direct lymphatic drainage pathway from a primary tumor site, and as such, is hypothesized as the most likely location to harbor occult metastasis.

      • These sentinel lymph nodes are used for assessing prognosis [the likely course of a medical condition.]

        • If on biopsy, tumor cells are negative, it usually means that the cancer is localized -> Good prognosis as spread is limited
        • If biopsy is positive, then the prognosis is poor and the spread is more extensive
      • SLNs are prognostic and can tell the extent of surgery

        • Useful for
        • Breast cancer
        • Vulval cancer
        • Melanoma
      • These spread through Hematogenous route

    • Sarcomas with lymphatic spread
      • S: Synovial
      • C: Cell Clear Sarcoma
      • A: Angiosarcoma
      • R: Rhabdomyosarcoma
      • E: Epithelial Cell Sarcoma

    [[Pasted image 20210706174513.png]]

  • Hematogenous Spread

  • Tumor cells penetrate venous walls better than artery due to thickness of the wall being higher in the latter
  • Sarcomas generally spread through hematogenous spread
  • Any part that receives more blood have higher metastatic spread
    • Lungs >> Liver >> Kidneys(?)
  • Lymphatic spread does not occur in the following carcinomas: RCHF - Red Chilli Hot Feppers
    • R: Renal Cell Carcinoma
    • C Choriocarcioma (plancental tissue)
    • H Hepatocellular Carcinoma
    • F Follicular Carcinoma of Thyroid
  • SCARE sarcomas have lymphatic spread
  • Direct Seeding

    • Body cavities are involved directly
      • Pleural cavity: Lung Cancer, Mesothelioma
      • Pericardial Cavity: Cardiac cancer, Lung cancer
      • Peritoneal Cavity:
        • Most commonly affected in direct seeding

        • Responsible for

          • Omental Caking - thickened omentum

          [[Pasted image 20210706175130.png]]

          • Malignant Ascites - accumulation of fluid
            • Tumor markers such as Ca125 can assess the prognosis
        • Commonly seen in ovarian tumors, esp. at older age

  • Cerebrospinal Fluid - very rare

    • Drop metastasis - drop by drop CSF fa
    • Seen in brain tumor: Medulloblastoma

Screening

  • Approximately 30 divisions (1,073,741,824) occur before the earliest clinical symptoms arise ^a2faae
  • Each division -> Increased chances of Increased mutation
    • Cancers such as pancreatic, ovarian, lung carcinoma - cancers that are detected late are due to large growth area
      • These do not produce symptoms until late in the disease and would have undergone beyond >30 divisions thus are very mutated cells
      • Thus these cancers have poor prognosis
  • Screening seeks to lead to Detection of Dysplasia; Or detect carcinoma before clinical symptoms are manifested
    • e.g: Pap Smear: detects cervical dysplasia
    • Mammography - detects in situ breast cancer before invasion -> or detect before clinically palpable
    • Prostate specific antigen (PSA) and Digital Rectal Exam (DRE): detection before carcinoma spreads
      • Prostate carcinoma grows in the periphery thus doesn’t supress the urethra like in BPH
      • Thus it is silent
  • Hemoccult (blood in stool) test and colonoscopy: detect colonic adenoma before it becomes colonic carcinoma / before it spreads

Carcinogenesis

Hallmarks of Cancer

  • Self sufficiency of Growth Factors
  • Insensitivity to growth inhibitors
  • Altered Metabolism
  • Uncontrolled Replication
  • Evasion of Metabolism
  • Invasion and Metastasis
  • Sustained Angiogenesis
  • Evasion of host-immune response
  • Tumor promoting inflammation
  • Genomic instability
  • Warburg effect
  • Mutations result in cancer formation
  • Carcinogens include chemicals, oncogenic viruses and radiation

[[Pasted image 20210704095022.png]]

  • Chemicals:
    • Aflatoxins -> Hepatocellular carcinoma: Common in Africa
    • Alkylating agents -> due to chemotherapy: side efect Antineoplastics ^f85b3c
    • Alcohol -> SCC of OP, Upper Esophagus, pancreatitis -> pancreatic carcinoma, Cirrhosis -> Hepatocellular carcinoma
    • Arsenic -> SCC of skin, lung cancer (smoking)
      • Woman in england applied Arsenic onto the skin to prevent tan coz they secretly had orgy parties in the sun. Yes. (no they worked in fields lol. maybe they didn’t)
    • Asbestos -> Lung carcinoma >> mesothelioma (pleural)
    • Cigarette smoke Most common carcinogen-> Lung cancer, OP, Esophagus, and Kidney and bladder (due to concentration of carcinogen while excretion)
    • Nitrosamines -> Intestinal Stomach Carcinoma -
      • Waifus in japan eat smoked meat ( ͡❛ ͜ʖ ͡❛) then get stomach cancer. sed. 2
    • Napthylamine -> derivative of cigarette smoke: Urothelial carcinoma of bladder
    • Vinyl chloride -> Angiosarcoma of liver ~> Used in PVC pipe industry - occupational exposure
    • Si, Be, Ni, Cr -> Lung cancer, occupational again
  • Oncogenic:
    • EBV: Nasopharyngeal carcinoma
      • Chinese and African descent more susceptible (like how china debt trapped them lmao)
      • Neck mass presentation
    • HHV-8: Kaposi carcinoma (endothelial cells)
      • E. Eu males @ skin
      • AIDS patients as secondary infection
      • Transplants due to immunosupression
    • H-BV and H-CV: -> HPC
    • HTLV-1: Adult T-Cell Leukemia/Lymphoma
    • High-risk HPV (Subtypes)
  • Radiation
    • Ionizing: Papillary carcinoma of thyroid
      • Nuclear reactor accidents and radiothyroid
      • Occurs due to hydroxyl free radicals (ionizing)
    • Non-ionizing: Skin -> Basal>Squamous>Melanoma
      • UVB sunlight radiations
      • Xeroderma pigmenotosum

Disrupted

  • Proto-oncogenes
  • Tumor supressor genes

Protooncogenes

  • These are genes essential for cell growth and differentiation
    • Mutations in these genes lead to unregulated cellular growth
      • These mutations are gain of function mutation
      • This leads tumor cells to become self-sufficient

[[Pasted image 20210705173150.png]]

  • Categories of proto-oncogenes that produce:
    • Growth Factors
    • Growth factor receptors
    • Signal Transducers
    • Cell Cycle regulators

[[Pasted image 20210705151649.png]]

  • Growth Factors

    • PDGF usually divides the astrocyte
      • Mutation of SIS gene leads to astrocyte production of PDGFB (autocrine)
      • This autocrine overexpression leads to a loop of overgrowth -> Astrocytoma a type of glioma
    • HGF: Hepatocyte Growth Factor
      • Liver cancer
  • Growth Factor Receptors

    • When excess growth factor receptors are expressed, a simple stimulus by a single GF -> overstimulation of growth signals
    • These are associated with tyrosine kinase
    • ERBB2 [HER2/neu] -> amplified in subset of breast cancer
      • Trastuzumab is a MAB against HER2/neu
    • RET -> medullary carcinoma of thyroid: associated with MEN2A MEN2B
      • MEN2A and 2B are types of Multiple Endocrine Neoplasia, a syndrome in which tumors are developed in endocrine organs
      • 2A and 2B cause medularry carcinoma of thyroid
      • If Pheocromocytoma or mucosal neuromas (feature of MEN2B) is present, then RET mutation studies can be done and if positive, thyroid can be removed Endocrine
    • KIT -> GIT stromal tumor
    • ERB-B1 - lung cancer
  • Signal Transducers

    • Normally 1 receptor molecule has only 1 signal transducer

    • If however multiple signal transducers are produced due to mutation, excess transduction occurs

    • RAS gene family

      • 70-80% of cancers are due to this mutation
      • GTP-binding protein function
      • RAS usually sits in off state - GDP with growth factor receptors
        • When activated, GTP is bound, and RAS-GTP complex acts as a messenger
      • RAS has the ability to dephosphorylate
        • Augmented by GTPase Associated Protein - Neurofibromin (an example of tumor suppressor gene)
      • RAS mutations lead to loss of this ability leading to prolonged activated RAS
      • This causes excess transduction

      K-RAS - Colon Cancer***** H-RAS - Kidney and bladder cancer N-RAS - Melanoma

    • ABL

      • Non-receptor Tyrosine kinase (i.e, they are cytosolic rather than receptor bound)

      • 9:22 translocation

        • ABL:BCR 9:22 switch up
        • This leads to ABL-BCR fusion gene
          • Leads to overactivity of tyrosine kinase which causes cancer
      • Causes CML 3 and some ALL 3 types

        • ALL is usually associated with children
        • ALL with 9:22 translocation has poor prognosis
        • However CML with 9:22 translocation has good prognosis
      • Tyrosine-Kinase addiction by tumors is called oncogene addiction (dependency)

      • BRAF

        • Responsible for MAP kinase
        • Hairy cell leukemia - Associated 100%
        • Benign Nevi (mole) - Associated 80%
        • Melanoma - Associated 60%
      • Beta-catenin ^8c95e7

        • Responsible for increased MYC (nuclear transcription facor) activity
        • APC gene and E-Cadherin inhibit the activity
        • Colon cancer - high risk
  • Nuclear Regulators

    • These are transcription factors that lead to upregulation of growth promoting proteins
    • Also called as master regulator of the cell
    • These increase
      • Cyclin activity
      • Telomerase activity
      • Reprogram -> Stemness (de-differentiation)
    • Mutations in these lead to excess growth promoting proteins
    • c-MYC ^79b23f
      • Burkitt Lymphoma
        • translocation 8:14 ->
        • Immunoglobin H (IgH) is ON state in Chromosome 14
        • Chromosome 8 contains the MYC gene
        • This translocation leads to excess producion of c-MYC leading to high growth of cells (fastest rate of replication - highest mitotic activity)
          • The starry sky appearance is due to:
            • Tumor cells are sky - blue
            • White areas : eating cells that are dying
            • Macrophages consume dying cells leadng to starry sky
    • N-MYC
      • Neuroblastoma
    • L-MYC
      • Lung carcinoma (Small Cell)
  • Cell Cycle Regulators

    • Cell Cycle consists of G1->S [Most regulated step] -> G2 -> M
    • G1 -> S
      • In this it is made sure that S phase doesn’t contain mutations
    • Cyclins activate Cyclin-dependent kinase which phosphorylate
      • Cyclins have OFF/ON state
    • CCND1 [Cyclin D1]
      • 11:14 translocation

        • Cyclin D sits on Chromosome 11 and it gets translocated to Chromosome 14 (IgH - ON)
        • Leads to overexpression
      • Mantle cell Lymphoma

        • In a lymph node, the B area (cortex of lymph node), outside the region of the follicle there’s a Mantle and outside that there’s a Marginal zone

        [[Pasted image 20210705160906.png]]

      • Cyclin D1 is important for regulation of G1 -> S phase

: > DEA Bitch!

CyclinCDKCycle
D4, 6G0 phase to G1 checkpoint 1 (G1 -> S)
E2G1 phase (G1 -> S)
A2, 1S -> G2
B1Before (Checkpoint 2) and after M phase

[[Pasted image 20210705182159.png]]

: Mutations affecting other CDKs and cyclin E also occur in cancers, but they are infrequent, presumably because these factors are less important in control of the G1 -> S transition, which has a preeminent role in regulating tumor growth rates.

[[Pasted image 20210705182739.png]]

CDK InhibitorCDK Inhbited
p21 - p27 familyAll CDKS
p16,17, 18, 19CDK4,CDK 6 (Cyclin D)

Tumor Supressor Genes

  • These are genes that decrease/suppress (as the name says dimwit) the risk of tumor formation : e.g: p53 and Retinoblastoma (Rb)
  • Mutations here are loss of function mutation
CycleGene
G1 -> SRb, p53
S -> G2p53

[[Pasted image 20210707092822.png]]

p53

  • Most common genetic mutation seen in human cancers
  • G1 -> S phase traffic cop bitch
  • p53 “verifies” DNA integrity before it enter S phase
    • In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes

    • If DNA repair is not possible, (such as too many high fucks inside the car wayyy too much cocaine broo) due to excess mutations, then p53 nukes the entire cell via apoptosis

      • Calls in BAX which disrupts BCL2 -> Cyt C (cocaine stash caught rip) leaks from the cell -> apoptosis

    • Both copies of p53 must be knocked out - Knudson two-hit hypothesis cops take cocaine rip corrupt crack addicts

      • Loss is seen in >50% of cancers
      • Germline mutation results in knock out of one copy of p53 (1 corrupt fucker) - in Li-Fraumeni syndrome and the second hit is somatic
        • S - Sarcoma
        • L - Lymphoma
        • O - Osteosarcoma
        • C - CNS Tumor
        • A - Adrenal Cortex Tumor
        • B - Breast Cancer

Retinoblastoma (Rb)

Retinoblastoma is a cancer that starts in the retina

[[Pasted image 20210705164527.png]]

Retinoblastoma (Rb, RB, RB1) protein is a tumor suppressor protein. It is the most common tumor supressor gene associated with cancers

  • G1 -> S
    • E2F - a transcription factor is required for this transition
    • However Retinoblastoma is that old-ass overprotective parent who needs some phosphorylation (dowry) for release of E2F
      • Guess the dowry? Oh yeah Cyclin D activated CDK4 Complex
    • The release of E2F lets the G1 to phase into S phase (change of surname biatch)
  • However if there’s a mutation in Rb, the E2F is constituively free (rebellious daughter lmao no respect for parents these zoomers)
  • This results in tumor formation and uncontrolled cell growth
  • Both copies of Rb must be knocked out - Knudson’s Two-Hit hypothesis
    • Well, both parents are greedy.. both need dowry… how can you split :(
      • Sporadic mutation - Hits are somatic -> Unilateral retinoblastoma - During birth, no genes are mutated - Bilateral retinoblastoma sporadic mutation is very rare as in order for tumor to be develop, Both copies of Rb gene should be mutated of which the probability is extremely slim
      • Germline mutation - bilateral retinoblastoma and osteosarcoma
        • 1 gene of the allele is mutated (Autosomal dominant)
          • One more mutation in the normal gene leads to loss of this heterozygosity
        • In germline mutation, the chance is higher relatively as one gene is knocked out and mutation of the other normal gene
        • Thus Germline mutation has bilateral retinublastoma 4

BRCA

  • BRCA:BReast CAncer gene
    • BRCA-1: Breast/ovarian cancer
      • presence of BRCA1 mutation is an indication for prophylactic mastectomy and Oopherectomy: important in familiak variant of breast cancer
    • BRCA-2: Male breast/prostate cancer
  • Normal role: involved in DNA repair

APC

  • The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin
  • Mutations of APC leads to inactivation of APC thus allowing activating mutations in beta-catenin -> increased MYC activity -> cell proliferation

Cellular Metabolic Alterations

Regulators of Apoptosis

  • 1. Cell Injury

    • BCL2 stabilizes Mitochondrial Outer Membrane - making it impermeable to Cyt C
    • Yoinking (disruption) of BCL2 leads to Cyt. C to leave and activate apoptosis
  • In follicular Lymphoma overexpression of BCL2 is overexpressed

    • This is due to t(14;18)
      • Bcl2 is on chromosome 18
      • IgH is on Chromosome 14
      • BCL2 is now on the ON Chromosome 14 -> overexpression thus the mitochondrial membrane is suuuuuuuper stabilized
      • This is normally okay, coz no apoptosis is… nice
      • But in the follicle, B-cells are undergoing somatic hypermutation to increase diversity in antibodies
        • Basically Uyghurs getting experimented upon and the shit ones are killed off - except with this mutation they… don’t die….
        • i.e, naive B-cells that go to lymph node (the college) and then fail to produce antibody -> apoptosis
        • If no apoptosis occurs, then Follicular Lymphoma occurs
  • Altered Autophagy maybe present depending upon the need of cancer cells

Upregulation and Downregulation

  • Telomerase is necessary is required for cell immortality
    • Normally telomeres shorten with cell divisions eventually leading to cellular sensecence : Hay Flick limit - 60-70 times
    • Often, cancers have upregulated telomerase, an enzyme that preserves telomeres, normally present in stem and germ cells
  • Tumor cells also avoid immune surveillance for survival
    • They do this by downregulating MHC-I of the cells thus CD8+ T Cells cannot detect them
    • They grow antigen negative variant
    • Secretion of TgF-Beta, IL-10 : reduced inflammatory response
    • Secretion of PgE2, VEgF -> T-cell migration is reduced
    • Immune checkpoint bypass through
      • PD-L1 : inhibits T-cell Activation
      • CTLA-4 : removes B7 molecules on APCs (tumor itself here) preventing binding to CD28 4.1 Immunity
    • Immunodeficiency (primary or secondary) increases the risk for cancer

^c7c179

Oncometabolism

  • A few enzymes have been revealed to have shown a new mechanism of oncogenenesis
  • One such example is the Isocitrate Dehydrogenase - IDH, part of the Kreb’s cycle

[[Pasted image 20210707103728.png]]

  • 2-HG in turn acts as an inhibitor of several other enzymes that require a metabolite called α-ketoglutarate as a cofactor.
  • Among the proteins that are inhibited by 2-HG are several members of the TET family, including TET2, which are normally responsible for methylation of DNA
  • IDH mutation seen in glioma, AML, cholongiocarcinoma

Clinical Features

BenignMalignant
Slow growingRapid growing
Well circumscribed (restricted)Poorly Circumscribed
Distinct and mobileInfiltrative and fixed to surrounding tissues

Biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty

Histological Features

BenignMalignant
Well differentiatedUsually poorly differentiated
OrganizedDisorganized (loss of polarity)
UniformNuclear pleomorphism and hyperchromasia 5
Nucleo:Cytoplasmic ratio is lowHigh Nuclear:Cytoplasmic ratio
No invasionInvasion maybe seen through Basement membrane or local tissue
Minimal mitotic activityHigh mitotic activity with atypical mitosis (such as more than 2 spindles)
No metastatic potentialMetastatic potential is present - hallmark
[[Pasted image 20210706180243.png]][[Pasted image 20210706180256.png]]
Follicular adenoma of thryoidAnaplastic carcinoma of thyroid

Immunohistochemistry

  • Immunohistochemistry is used to characterize tumors that are difficult to classify on histology
    • An antibody against a particular target is labelled with a brown stain (IHC stain) which then binds to the specific antigen that may help to subclassify the cell type

[[Pasted image 20210706181750.png]]

The most well diff. carcinoid tumor <-> least differentiated small cell carcinoma - Differentiated by Chromogranin

[[Pasted image 20210706181849.png]]

Screening

Serum Tumor markers

A. Proteins released by tumor into serum (e.g., PSA) B. Useful for screening, monitoring response to treatment, and monitoring recurrence C. Elevated levels still requires tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA).

Grading

A. Microscopic assessment ofdifferentiation (i.e., howmuch a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features 1. Well differentiated (low grade)-resembles normal parent tissue 2. Poorly differentiated (high grade)-does not resemble parent tissue B. Important for determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers.

Staging

A. Assessment ofsize and spread ofa cancer B. Key prognostic factor; more important than grade C. Determined after final surgical resection ofthe tumor D. Utilizes TNM staging system

  • T - tumor (size and/or depth of invasion) e.g: size in breast, depth in bowel
  • N - spread to regional lymph nodes; second most important prognostic factor
  • M - metastasis; single most important prognostic factor

Paraneoplastic Syndromes

Syndrome non explicable par le caractéristiques du cancer:

  • Direct spread
  • Metastasis
  • Indigenous hormones

Pourquoi c’est important?

  • Can be an initial manifestation
  • May mimic metastasis
  • May indicate worsening condition

Endocrinopathies

1. Hypercalcemia

  • Most common paraneoplastic syndrome
  • Presence is due to prostaglandins or parathyroid hormone related peptide
  • Seen in:
    • Squamous cell carcinoma of lung
    • Kidney cancer
    • Breast cancer

2. Cushing syndrome

  • A condition that occurs from exposure to high cortisol levels for a long time
  • It is seen in carcinoid tumor
  • Seen in Small Cell lung cancer
  • Most common endrocrinological PNS

3. SIADH

Initialism of Syndrome of inappropriate antidiuretic hormone secretion

  • Seen in lung cancer [Small Cell Cancer]
  • CNS tumors
  • Clinical manifestation: Hyponatriemia

4. Hypoglycemia

  • Seen mostly in tumors with mesenchymal origin/connective tissue
  • Seen in Fibrosarcoma (connective tissue)
  • Hepatocellular carcinoma
  • Ovarian cancer

5. Polycthemia

  • Erythropoeitin
  • HCC
  • Kidney
  • Fibromyoma (uterine muscles)
  • Cerebellar hemangoblastoma

Vascular and Hematological

1. Venous Thrombophlebitis

Thrombophlebitis (throm-boe-fluh-BY-tis) is an inflammatory process that causes a blood clot to form and block one or more veins

  • Mucin is secreted by the tumor

    • This secretion slowly migrates causing migratory venous throbophlebitis
      • This is the Trousseau sign of malignancy/ Trousseau syndrome [Different from trossaeu sign seen in latent tetany] [[Pasted image 20210707145427.png]]
      • a.k.a Thrombophlebitis Migrans
  • Seen in AML-M3

  • Pancreatic cancer

  • Bronchogenic cancer/adenocarcinoma

2. Marantic Endocarditis

3. Anemia

  • Seen in thyoma

Dermatological

Acanthosis nigricans

  • Thickened and **hyperpigmented ** skin Seen in:
  • Stomach cancer
  • Lung cancer
  • Uterine malignancy

Dermatomyositis

  • Involvement of skin and muscle tissue

  • Involves Antip140Ab Antip155Ab

  • Seen in

    • Breast cancer
    • Lung cancer

Seberrheic keratosis

  • Sign of leser trelat

[[Pasted image 20210707151409.png]]

  • Seen in Stomach (most common)

Neurological

Myasthenia Gravis

  • Antibodies against: ACh receptor [Post-synaptic]
    • Antibodies against calcium channel may also be [See Labort-Eaton]
    • Both are responsible for decreased contractility
  • Seen in Thymoma

Lambert-Eaton Syndrome

  • Anti-bodes against Pre-synaptic calcium channel of the nerves
  • Causes late entry of calcium
  • Seen in small cell carcinoma of lung

L-E-S

Late - Entry - SmallCell

Opsoclonus

  • Random eye moments
  • Seen in neuroblastoma and adrenal

Limbic encephalitis

  • Limbic encephalitis represents a group of autoimmune conditions characterized by inflammation of the limbic system and other parts of the brain
  • Anti-HU antibodies
  • Strongly associated with small cell lung carcinoma

Subacute cerebellar degeneration

  • Anti-YO antibodies
  • seen in
    • Endometrial
    • Ovarian cancer
    • Breast cancer
    • Thus wahmen are susceptible to this Paraneoplastic Syndrome

Osseus Soft Tissue

  • Hypertrophic pulmonary osteoarthopathy
  • causes clubbing of fingers
Footnotes
1.
high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin - Wikipedia
2.
It’s a joke sorry
3.
CML: Chronic Myeloid Leukemia Lymphoma | ALL: Acute Lymphoblastic Leukemia
5.
Some nuclei are big and some are small. Hyperchromasia : The nucleus is really blue (hyperchromatic)