Learning Unit 7

Benign Reactive Changes: Inflammatory, Degenerative & Regenerative,

Proliferative & Iatrogenic
General Activity

 These will be presented under:

 Normal activity (Euplasia)
 Decreased activity (Retroplasia) - degeneration, cell death
 Increased activity (Proplasia) - regeneration, repair, hyperplasia
 Activity of cancer (Malignant neoplasia)
 General Activity

Examination of the cell:

 In general, the nucleus gives us the information about the state of activity of
the cell- provides info regarding the health of the cell:
 Normal – cells are not stressed and are healthy
 Inflamed – changes in tissue, in response to injury
 Hyperplastic – increase in the number of cells in tissue
 Neoplastic – progressive uncontrolled cell proliferation
General Activity

 Nuclear features tell us whether the cell is transforming as a result of

inflammation or on a path of carcinogenesis.
 If there is carcinogenic transformation nuclear features include:
 Changes in nuclear size
 Changes in nuclear shape
 Nuclear membrane
 Changes in chromatin – hyperchromatic, coarsening and irregular distribution
 Presence of nucleoli – abnormal number, size, shape
 Changes in nuclear cytoplasmic ratio
General Activity

 The cytoplasm about the origin and functional differentiation of the cell.
 Cytoplasmic features are used to determine the degree of differentiation and
for squamous cells these are:
 Distinct cell boundaries
 Accumulation of dense cytoplasm

 Interpretation of the state of activity and the functional differentiation is

based on the information obtained from both compartments of the cell and
their relation to each other.
General Activity

Normal (Euplasia) Activity: (Eu – well, typical or good)

 Growth activity that is only sufficient for continued existence in a healthy non-
stressed environment.
 -plasia – growth, formation, development
 In normal tissue, there is uniformity among the cells.
 The shape and size of the cells is uniform.
 The nuclei are rounded and uniform.
 The chromatin is usually very fine and evenly distributed throughout the nucleus.
 The nuclear membrane is smooth, thin and even in thickness.
 As cells mature, the cytoplasm increasingly reflects functional differentiation e.g.
cilia, mucous, keratin or microvilli
General Activity
General Activity

Decreased (Retroplasia) Activity: (back, reverse)

 Decreased activity below euplasia and retrogressive biologic and chemical changes such as
injury, aging, degeneration and death.
 Cellular structures that are normally crisp and clear are frequently blurry.
 Events such as ageing, injury, degeneration and necrosis causes include external agents (trauma,
heat, radiation, toxins ) and living organisms (viruses)
General Activity

 Nuclear:
 Size = may shrink, becoming small and dark (pyknosis/karyopyknosis) with a wrinkled
contour, or swell (fluid intake) and become large and pale.
 Shrinkage of the nucleus may result in a peri nuclear halo (space the nucleus occupied
previously)
 Chromatin and nuclear membrane = loss or alteration of normal chromatinic texture,
blurred appearance of chromatin, clumped chromatin with interrupted nuclear
membrane rim (karyorrhexis)
 Enlarged nuclei with blurred, pale, or clear areas (parachromatin clearing) may
occur. These findings may mimic the nuclear changes of malignancy.
 Cytoplasmic:
 Intracytoplasmic vacuoles
 Partial or complete loss of cytoplasm – often due to water intake, the cytoplasm swells
and ruptures, resulting naked nuclei and cytoplasmic fragments (“moth eaten”
appearance)
General Activity

Increased (Proplasia) Activity: (ahead, forward)

 Increased general activity occurs due to cell division stimulation, regeneration,
repair from degeneration or pre-invasive neoplasia
 Cellular features include:
 Chromatin becomes more hyperchromatic
 Chromatin rim becomes granular and thicker but maintains a uniform thickness
 Nucleus – nuclear membrane may appear wavy but not wrinkled or irregular
 Nuclei retain overall round shape, but may enlarge moderately and become multiple
 Nucleoli can enlarge, multiply and become prominent due to heightened protein
synthesis
 Increased number of mitotic figures
 Amount of cytoplasm and differentiation decreases with increased activity
General Activity

Activity of cancer (Neoplasia)- (new) invasive cancer:

 Progressive uncontrolled cell proliferation under conditions that would not
elicit multiplication of normal cells
 Nuclear membrane becomes sharp, angled, unpredictable and irregular
 Chromatin thickness varies markedly – massively thickened to extremely thinned
segments
 Irregular chromatin patterns, with chromatin clumping and clearing
 Nucleolus is frequently enlarged, irregular and sharply angled
 Nuclear shapes are pleomorphic ,and an increased N/C ratio is frequently noted
Injury & Cellular Response

 External agents and internal agents can cause injury.

 External agents include physical things like heat, cold, drugs, radiation,
cytotoxic chemical agents.
 External infectious agents are bacteria, fungi, viruses and parasites.
 Internal agents are hereditary defects like faulty metabolism and other
hereditary diseases, like immune diseases, such as autoimmune diseases,
inborn immune deficiencies and acquired immune deficiencies.
 The diagram illustrates the stages cells undergo after being injured:
Process Of Cell Injury & Cellular
Response
Normal cells

Stimulus Or Injurious Agent

Cell Injury

Inflammation Or Inflamed Cells

Degeneration Repair Dysplasia

Cell Death Normal cell Cancer Metastasis Or Spread

Inflammation & Inflammatory Changes

 After contact with an injurious agent, the epithelial tissue around the area of
injury undergoes inflammation.
 Inflammation is the change that occurs in a living tissue after an injury, provided
that the injury has not killed the tissue outright.
 Inflammation may be described as mild, moderate or severe and 4 types are
recognized:
- acute
- sub-acute
- chronic
- granulomatous
 Depending on the intensity and persistence.
 Inflammation does not necessarily mean that an infection/pathogen is present.
Acute Inflammation

 Acute inflammation, mostly due to trauma or bacteria, the smear is

dominated by neutrophils or polymorph nuclear leukocytes and histiocytes.
 In addition to neutrophils, necrosis and breakdown of tissues is seen, as well
as intercellular fluid, with or without fibrin.
 This forms a purulent exudate or pus that is easily recognized on cytology.
 Sometimes erythrocytes or haemosiderin is seen when haemorrhage is
present.
Sub-Acute Inflammation

 When the transitional phase between acute and chronic inflammation is

prolonged, there is a mixture of inflammatory elements.
 Sub-acute inflammation causes less tissue breakdown and less reaction to
injury.
 The duration of the inflammation is longer.
 The neutrophils die with age and thus decrease in number.
 Lymphocytes and plasma cells now appear.
 Eosinophils and basophils can also be seen, especially in
inflammation in hypersensitivity reactions.
Chronic Inflammation

 If the agent causing acute inflammatory response persists, neutrophils are replaced with large
and small lymphocytes and plasma cells.

 Lesser numbers of macrophages are also seen.

 Only a slight and slow tissue breakdown is seen, counterbalanced by repair.

Chronic Inflammation

Follicilar Lymphocytic cervicitis

 This is a form of chronic cervicitis - benign lymphoid follicles with germinal
centres may be formed in the stroma next to the basement membrane of
cervical epithelium.
 During smear taking, the fragile epithelial surface may be scraped off and a
mixture of mature and immature lymphocytes are released together with
plasma cells and histiocytes often seen as tangible body macrophages.
Granulomatous Inflammation

 Type of chronic inflammation, where there is formation of granulomas.

 Granulomas form in response to specific causative agents, which the body has
difficulty in handling in the usual manner e.g. Tb, Syphilis, Amoebiasis or in
response to inorganic substances like silica, starch and foreign material such as
talc, surgical sutures and asbestos.

 A granuloma is a focus of inflammation that has the following elements:

- Lymphocytic infiltration.
- Epithelioid cells, that are elongated spindle shaped cells, or modified histiocytes.
- Giant multinucleated histiocytes.
- Necrosis with necrotic debris may be present in the background.
Inflammation & Inflammatory Change

 According to the region involved, an inflammation of the female genitalia is

called vulv-, vagin-, cervic-, endocervic-, endometr-, salping- itis
 The two most common symptoms of genital inflammation include:
- Pruritus (itching)
- Leukorrhoea (vaginal discharge)
Inflammation & Inflammatory Change

 Infection is an inflammation produced by a living organism(virus, parasites,

bacteria or fungi)
 Almost all inflammation produce some changes in the composition and
features of exfoliated cells.
 Inflammation may cause a localized/partial loss (erosion) or complete loss
(ulcer) of the epithelium by the enzymatic degradation of the injured cell and
it’s organelles (necrosis).
 This destruction results in cluttering the background of a smear with debris.
 Followed by a healing stage in which various reactive/reparative cells
exfoliate.
Inflammation & Inflammatory Change

Clinical Symptoms of Acute Inflammation:

 Oedema: swelling due to accumulation of fluid in the interstitial tissue
 Fever: Localized increase in temperature of the affected area as a result of
dilated blood vessels and increase in rate of blood circulation
 Redness of the mucosa due to dilation of the small blood vessels
 Pain and itching are the result of swelling
 Due to various serous or purulent discharges, resulting from destruction of
some cells and proliferation of the invading organism
 Destruction or change of function: e.g. Endocx may overproduce secretions
Cytology Of Inflammation

Degenerative changes in the nuclei

 Nuclear enlargement – karyomegaly, due to early response to cytoplasmic injury.
 Chromatin clumping – round and regular clumps, variable in size, with fuzzy
contours.
 Karyopyknosis – nuclei shrink, staining darker, with sharp edges.
 Nuclear oedema – cloudy swelling, giving the impression of hypochromatism.
 Karyorrhexis – chromatin breaks up in round masses, sign of rapid degeneration
 Karyolysis – due to swelling, nucleus disappears, anucleated or ghost cell results.
 Nuclear vacuolisation – Occasional small, round single/multiple vacuoles are seen
in rapid death of the cell, e.g. irradiation.
 Stripped nuclei – delicate cytoplasm may be lost in mild injuries e.g. smearing
Cytology of Inflammation

Degenerative Changes in the Cytoplasm

 Vacuolisation – usually multiple and vary in size, can contain neutrophils.

 Cloudy swelling – accumulation of excess fluid in the cell, cell size increases 2 -3x, cytoplasm
fuzzy, granular or cloudy.
 Perinuclear halo – clear area around shrunken nucleus often produced artificially during
fixation.
 Loss of cellular organelles – non-vital organelles like cilia may disappear- ciliocytophtoria
 Irregular shape – cytoplasm shows pseudopod like projections, attempt at healing itself.
 Polychromasia – degenerate cells can show variation in staining in individual cells.
 Hyperkeratosis – accumulation of keratin in the cytoplasm during degeneration
 Cytolysis – loss of cytoplasm, leaving stripped nuclei as in Döderlein bacilli.
Cytology of Inflammation

Background features
 When severe inflammation – a protein rich exudate, with fibrin and a finely
granular precipitate may be seen in background
 Also mucus, bacteria, inflammatory cells and lysed cells may cause a ‘dirty’
background
 Cytoplasmic
Karyorhhexis Vacoulization

Inflammatory Change
 Hyperkeratosis

Cytolysis

Chromatin Clumping
Summary of Inflammatory Change

Background “dirty”
Inflammatory
Mimics tumour diathesis
Cytoplasm
Vacuolisation
Perinuclear halo
Pale stain
Polychromatic
Eosinophilia – pseudo-keratinised
Frayed ragged edges – moth eaten
Engulfed PMN’s
Enlarged irregular shape
Nucleus Enlargement – usually <2x intermediate cell nucleus
Vacuolisation
Chromatin – either hypochromatic, bland (chromatolysis) or
hyperchromatic, clumped (degeneration)
Karyopyknosis, -rhexis, -lysis
Bi- or multinucleated