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BASIC RADIATION PATHOLOGY
CHIRAAG D. PATEL, MD
PGY-2
STONYBROOK UNIVERSITY MEDICAL CENTER
DEPARTMENT OF PATHOLOGY
CONFLICT OF INTEREST
Neither I nor my family have any financial or conflicts of interest to disclose.
OUTLINE• Basic radiation physics
• Radiation changes
• biology• changes in prostate• changes in breast
• Acute radiation syndrome
RADIATION PHYSICSEXPOSURE
Ionization
Ionization is the process of removing an electron from an electrically neutral atom to produce an ion pair. An ion is an atom or subatomic particle with a positive or negative charge.
Ionization negative ion (electron)
positive ion: atom with 3 protons, 2 electrons
X-ray enters atom and strikes electron, knocking it out of its orbit and creating two ions (ion pair). The ejected electron is the negative ion and the atom with a net positive charge is the positive ion.
+++
PENATRATING ABILITY OF DIFFERENT FORMS OF RADIATION
Average effective dose to the human population in the US:
Dominated by radon exposure which is natural
NCRP, July 2006
Direct: Interaction directly with critical targets in the cell (DNA)
High LET is usually direct in action
(alpha particle, neutron, proton)
Indirect: Free radicals are produced which diffuse and cause damage
Low LET (x ray, gamma ray)
Linear energy transfer =measure of the energy transferred to material as an ionizing particle travels through it.
ACTION
Biomolecular Action of Ionizing Radiation; Editor:Shirley Lehnert, 2007
NEUTRON (USUALLY DIRECT)
Biomolecular Action of Ionizing Radiation; Editor:Shirley Lehnert, 2007
The principle chemical alteration induced in cells by IONIZING RADIATION that most closely correlates with cell death is?
A. Lipid peroxidation
B. Oxidative damage to proteins
C. Protein-protein cross-links
D. Damage to mitochondria
E. Damage to nuclear DNA
RADIATION CHANGES
Acute tissue injury
Chronic tissue injury
Seen in both early and late responding tissues.
Degree of change evident is different
TIMELINE
http://www.cs.unm.edu/~compmed/seminars/LT_MedPhys3.pdf
Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology, Bentzen S, NRC, 9/2006
RADIATION CHANGES PROSTATE
In the non-neoplastic irradiated prostate, nuclear enlargement and smudged chromatin are the most notable changes.
THE PRESERVATION OF AT LEAST A FOCAL BASAL CELL LAYER IS A COMMON FINDING
Basal cellsNormal - single layer (left), Abnormal - nuclear enlargement, irregular, potato-shaped nuclei are pathognomonic for basal cells.
Normal Basal cell post radiation
Identification of irradiated cancer is a problematic area in pathology, now that increased numbers of post-treatment biopsies are being performed. Early changes include cytomegaly, vacuoles, and nucleomegaly with persistent single and occasionally double nucleoli in each nucleus (left). Later changes include atrophy and sometimes cytoplasmic vacuolation, with the nucleoli now being inconspicuous.
Early radiation change Late radiation change
In this matched set of photomicrographs from the same patient, compared with pre-treatment grade 3 cancer (RIGHT), the main post-treatment change is atrophy (LEFT). Note, however, the maintenance of infiltrative pattern, angulated acini, absence of basal cells, and inspissated luminal blue mucin characteristic of cancer. Depending on the duration of irradiation, one may see all atrophic cancer acini, unchanged acini, or a combination of atrophic and unchanged acini.
Pretreatment Gleason grade 3Post treatment radiation changes
This biopsy was performed due to rising PSA several years after radioactive seed implantation (brachytherapy) for prostate cancer. The cytologic and architectural atypia seen here is within the spectrum of radiation-induced changes.
cytokeratin 34bE12 (CK903)
In cases in which the history of irradiation is not given or is uncertain, stromal and vascular changes can cue the pathologist to recognize radiation effect. The stroma becomes fibrotic, and the cellularity of normal vessel walls (normal: left) increases because of smooth muscle proliferation (right).
Gaudin PB, Zelefsky MJ, Leibel SA, et al. Histopathologic effects of three- dimensional conformal external beam radiation therapy on benign and malignant prostate tissues. Am J Surg Pathol. 1999;23:1021–1031.
Gaudin PB, Zelefsky MJ, Leibel SA, et al. Histopathologic effects of three- dimensional conformal external beam radiation therapy on benign and malignant prostate tissues. Am J Surg Pathol. 1999;23:1021–1031.
RADIATION CHANGES BREAST
Low magnification of a lobule shows several acini (ductules) with hyperchromatic nuclei.
Low magnification of another area displays thickening of periacinar basement mem- branes and epithelial cells with enlarged, hyper- chromatic nuclei.
Essentials of Diagnostic Breast Pathology: A Practical Approach By Farid Moinfar
Higher magnification displays a ductule with enlarged, hyperchromatic nuclei of luminal epithelial cells. Note the thickening of basement membrane and the presence of a few myoepithelial cells with enlarged nuclei. Luminal microcalcification is evident.
At higher magnification, several acinar structures (ductules) exhibit marked degenerative epithelial cell changes, including smudge chromatin pattern and large, vacuolated cytoplasm.
Essentials of Diagnostic Breast Pathology: A Practical Approach, Farid Moinfar
Note the intralobular sclerosis and thickening of the basement membranes.
Essentials of Diagnostic Breast Pathology: A Practical Approach, Farid Moinfar
Digital Atlas of Breast Pathology, M Singh, Department of Pathology, Stony Brook University Medical Center
Ductal carcinoma in situ with radiation effect, high power.Note the extreme nuclear atypia.
High magnification of sever- al blood vessels and capillaries shows radiation-induced changes characterized by atypical endothelial cells with enlarged and hyperchromatic nuclei. The chromatin pattern is, however, blurred.
Essentials of Diagnostic Breast Pathology: A Practical Approach, Farid Moinfar
High magnification of sever- al blood vessels and capillaries shows radiation-induced changes characterized by atypical endothelial cells with enlarged and hyperchromatic nuclei. The chromatin pattern is, however, blurred.
MOST COMMON FINDINGS?
Radiation-induced Histopathologic Changes of the BreastThe Effects of Time, Moore, GK, Am J Surg Pathol, Jan 2004
Matched pretreatment and Post RT biopsy or mastectomy specimen from 117 patients with a range of 1-229 months post RT.
Findings:Pre vs post RT- significant
However, changes over time (1 year,3year, 6 year post RT) were not significant
ACUTE RADIATION SYNDROME
Short-Term and Long-Term Health Risks of Nuclear-Power-Plant Accidents, NEJM, Glatstein, E et al 2011
NEOPLASTIC
NEOPLASTICSEQUELA OF IONIZINGRADIATION
INCREASING DOSE
SUBCLINICAL
BONE MARROW
(SOF)Reversible if
heterogenous irradiation
NEUROVASCULAR
(SOF)
GASTROINTESTINAL
(SOF)
( MOF)
1 Gy
50 Gy
30 Gy
6-8 Gy
4 Gy
The Classical Paradigm of the ARS
Acute radiation syndromes
1 rad = 0.01 gray2-8 gray
Acute radiation syndromes
1 rad = 0.01 gray10-20 gray
Loss of GI Epithelial Cells:
Loss of mature cells (villus) because of a lack of stem cells to repopulate.
The Gastro-intestinal Syndrome
Control 16 Gy Day 5
Disrupt Crypts Denudation of villi
Fluid and Electrolyte Loss
Endotoxemia, Bacteremia
DEATH
Acute radiation syndromes
1 rad = 0.01 gray> 30 gray
ACUTE RADIATION SYNDROME (ARS)
Cardiovascular/Neurologic• Mixed picture• Burning of skin within minutes• Pyrexia• Ataxia• Decreased higher cortical and motor function• Hypotension, increased intracranial pressures within minutes
to hours of exposure• Autopsy findings: Microvascular & endothelial damage, focal
brain hemorrhage & necrosis, white matter edema, demyelination
THE END
Pathways to Contamination following Chernobyl
American Scientist, 2005
Process of Reoxygenation
Experiments of Warren Sinclair: Survival curves during cell cycle
M>G2>G1>early S>late S for sensitivity
RESULT
2 Proton + 2 Neutron
1 Electron
Surplus energy
Main components of natural background radiation:
Building materials—U, Th
Solar flares, outer space
Ingested is 40-potassium from foodInhaled is Rn
Locations with high backgrounds: Brazil, France, India, Egypt, Nine Island (Pacific)
Cosmic ray exposure varies with altitude: avg in US is 26mrems or .26mSv at sea level. Increase this 2x for each 2000m increase in altitude.
Radiation-induced Effects in Relation to timing of effects:
RADIOBIOLOGY
FOUR RS OF RADIOBIOLOGY
Repair
Tumor and normal cells, benefits normal cells
Repopulation
Affects mostly tumor cells, negative consequence of fractionation
Reassortment
Redistribution of cells within the cell cycle—tumor and normal cells, benefits killing of tumor cells
Reoxygenation
Affects tumor cells, enhances therapy
Diffusion of Oxygen through Tumor Tissue
Oxygen can generally diffuse 70um at the arterial end of the capillary and lessat the venous end.
4RSTissue type Repair Redistribution Repopulation Reoxygenation
Time course 1-4h 4-8h Early: 2-4wLate: 6w
1-4d
NON-NEOPLASTIC SEQUELA OF IONIZING RADIATION
NEOPLASTIC
NEOPLASTICSEQUELA OF IONIZINGRADIATION
CASE REPORT: BELGIUM 200648 year old male, worked in radiation facility, presented with vomiting for 4d and possible gastroenteritis
Decrease in lymphocytes that continued with BM aplasia
Discovered that the shutter had not been working in radiation facility and his exposure was 4.5Gy
Gave cytokine therapy at day 29, responded with increased lymphocytes at day 30
Evidence for subclinical liver and cardiac damage (oxysterol levels elevated)
Alive and asymptomatic now
DAKAR ACCIDENT 2008Lost Ir192 source, accidentally stored near workplace, estimated 63 potentially exposed individuals
4 presented with burns, 2 had vomiting and decreased lymphocyte counts
Dose estimates: 2.6Gy for one, 1.2Gy for the other
Treated both with cytokine therapy and they responded
The Experimental ARS in PrimatesKidney Liver
lungs Jejunum
Liver, CD31 Lungs, vWf
» Late death of two animals, on day 23 and 30
• Despite the presence of circulating platelets and WBC
• Macroscopic lesions: necrosis, haemorrhages
• Biochemical modifications: gGT, creatinin, …
From
Bert
ho, 2
00
5
Creatinin
Days after irradiation
0 20 40 60 80m
ol/
l
0
50
100
150
200
250
300
350
After
After
Before
Manip VIII : 29-30-31 janv. 02
AA208,AA470 = mo prélevéé après irradAA870 = mo prélevée avant irrad
Multiple Organ Failure (MOF) or Multiple Organ Dysfunction Syndrome ?? A general picture of a multiple organ dysfunction
Provided by Dr. Patrick Gourmelon
1 2 3 4 5 6 7 8 9 10 11
DeathTime after irradiation (weeks)
Haematopoieticsyndrome
Gastrointestinaldisease
Cutaneoussyndrome
Lungdisease
Renal Failure
Liverdysfunction
PBSCT
Lung oedema
GI bleedingDiarrhoea
Aplasia Hemophagocytosis
Massive exudateErythema, Blister
Clinical Picture Tokaï-Mura Accident ( Japan 1999)
Provided by Dr. Patrick Gourmelon
Radiation-Induced MOFRadiation-Induced MOFIR
Induction of Genes for Cytokines
Release of Tissue Factor
Tumor necrosis factor-AlphaIL-1, -6, -8
Tumor growth factor-beta IL-4, -10, 12
Pro-Inflammation Anti-Inflammation
Clottingcascadeactivation
DICSIRS CARS
MOF SIRS-Systemic inflammatory response syndromeCARS-Compensatory anti-inflammatory response syndrome
Activation of Endothelium
Trauma
Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries
[HTML] from thelancet.com
AB de Gonzalez, RE Curtis, SF Kry, E Gilbert… - The Lancet …, 2011 - Elsevier
ACUTE TISSUE CHANGES
Acute changes are typically inflammatory
• Erythema• Edema• Dry > moist desquamation• Hemmorhage • Necrosis
Changes are the result of cells dying in the tissues within the radiation field.
ACUTE TISSUE CHANGES
Cellular death attracts inflammatory cells
• Radiation injury of these cells further exacerbates the inflammation.
Severity proportional to the dose received
Inversely proportional to time span of dose
Other sources of trauma such as abrasion and infection will increase severity
ACUTE TISSUE CHANGESFollowing the acute changes there are two possible outcomes.
• Regeneration - Replacement of the cells lost by cells of the same type.
• May be complete or partial and is comonly seen in rapidly dividing cell lines and those arising from blast cells
• Generally is a low dose phenomenon but may occur in some tissues at relatively high doses.
• Influenced by the response of other cells in the area (critical cells)
ACUTE TISSUE CHANGES
Following acute tissue injury the tissue may also undergo replacement.
• Original cell population replaced by different population – usually fribroblasts
• Results in permanent loss of the original cell population and its function.
• Occurs in tissues with long cell cycle times• Tends to occur more commonly at high doses
CHRONIC TISSUE CHANGES
Changes manifest after healing process
• May be minimal if regeneration is dominant • Depigmentation • Hair loss and thinning• Atrophy• Scar formantion and strictures• Non-healing ulcers or necrosis
CHRONIC TISSUE CHANGES
Chronic changes may supersede apparent healing.
• Occurs when a slowly dividing critical cell line dies off after early healing of rapidly dividing cell lines.
• Classic example is loss of vascular supply to a tissue such as the intestine after mucosal regeneration has occurred.
CHRONIC TISSUE CHANGES
• Or, if a subsequent insult (infection, trauma, etc) exceeds the repair tolerance of the tissue
• Classic example is a non-healing surgical incision made in a radiation field.
• Another example is bone necrosis is a radiation field months to years after soft tissues in the radiation field have healed.
LATE VRS. EARLY RESPONDING TISSUESAcute and chronic changes are both seen in either:
• Early (rapidly dividing cell lines)• Or late (slowly dividing cell lines) responding tissues• Generally speaking the changes are less evident in late
responding tissue unless necrosis occurs.
OTHER FACTORS IN RADIATION RESPONSEVolume of tissue irradiated
• Increased volume increases effectsOxygenation at the cellular level
• Normal cells are typically 100% oxygenated• Tumor tissues may contain hypoxic areas.
Presence of some chemicals
• Some chemotherapy agents increase effects• Some drugs such as Amophostine mitigate effects
OTHER FACTORS IN RADIATION RESPONSEDose Rate
• Decreased dose rate decreases effects
Cellular Kenetics
• Growth fraction - The percentage of cells actually moving through the cell cycle.
• Can blunt effects > repopulation • Can increase effects > more cells irradiated in Mitosis
OTHER FACTORS IN RADIATION RESPONSECellular Kinetics
• Cell loss fraction – number of cells naturally being lost from the cell population.
• Increased loss Fx. - Accelerates effects• Decreased loss Fx. – Blunts effects.
Cell type
• Non-cycling population blunts effects markedly.• Critical cell line may supersede and cause effects.