Chapter 5 Cell and Vascular Response 5 to Infection and Injury

Activation of the defense systems gives rise to inflam- small numbers (1–6%). Their life span is somewhat mation which, if microbes are involved, is called in- longer than that of the . Under normal fection. The reactions may be acute or chronic and condition they migrate into the tissues and are found involve different types of inflammatory cells together scattered everywhere, but especially in the mucosa with lymphatics and vessels. of the gastrointestinal tract. In hypersensitivity reac- tions a high number of may be present in tissues as well as in the circulating blood. Mostly 5.1 the nucleus has no more than two segments and the Inflammatory Cells cytoplasm carries large, bright, eosinophilic granules, The types, number and proportion of inflammatory which differentiate them from old neutrophils with cells taking part in an inflammatory reaction depend eosinophilic cytoplasm. Eosinophilic granules contain on the type of /infection. cationic (positively charged) proteins, three of which are major basic protein (MBP), eosinophilic cationic protein (ECP), and eosinophilic derived neurotoxin 5.1.1 (EDN) (Peters et al. 1986). These positively charged Neutrophils proteins make eosinophils able to bind to negatively Neutrophils or (i.e., white blood cells charged molecules on other cells and make them toxic with discreet granules in the cytoplasm) are continu- for worms and other large parasites. ously produced in the and make up the main part of the white blood cells that normally circu- late in the blood (40–75%). At need more neutrophils 5.1.3 are recruited, which is followed by an increased num- ber in the circulation. Neutrophils are end cells and As already mentioned, B cells originate in the bone thus cannot divide. Their life span is short (3–4 days). marrow and T cells in the thymus. Together they make The nucleus of the cell is divided into two to five seg- up 20–45% of the white cells circulating in the periph- ments depending on the age of the cell (Fig. 12.1b). eral blood. Mature lymphocytes are small and have a The cytoplasm carries two types of fine, inconspicuous, round, compact and dark nucleus, and sparse cyto- and enzyme-containing granules. Neutrophils engulf plasm (Fig. 15.1). In routinely stained sections, B and (phagocytose) microbes and kill them by means of the T cells look alike. However, it is possible to differenti- enzymes stored in the cytoplasm. When released into ate between them and also between their subgroups by the tissue these enzymes also have the ability to de- means of immunohistochemical staining techniques grade dead cells and tissue fragments. Neutrophils do using monoclonal antibodies directed against their not reside in the tissues under normal condition, but surface antigens. are called upon at need, and thus are the dominating Stimulated lymphocytes are larger than mature lym- cells in acute inflammation. In old multisegmented phocytes. In routinely prepared sections stimulated B neutrophils the cytoplasm becomes eosinophilic and cells are easily identified in the fully developed germi- the cells may be mistaken for eosinophils. nal center of a lymphocytoma. They have large, light, and somewhat irregular nuclei, which contain one or two nucleoli (Fig. 18.2c). However, stimulated T cells, 5.1.2 usually components of a mixed lymphocytic infiltrate, Eosinophils stand out because they have a slightly irregular form Like neutrophils, eosinophils are end cells, produced and are larger and seem more compact than the sur- in the bone marrow. They circulate in the blood in rounding normal lymphocytes (Fig. 20.5c). The latter 22 5 Cell and Vascular Response to Infection and Injury

Fig. 5.1 Mast cells. a ACA. Between three dilated venules there ter (arrow); H&E, ×1000. c ACA. A small with hazy are two large mast cells (large arrows) and two small heav- cytoplasm (arrow). The vessel is an arteriole; H&E, ×1000. ily charged with granules (small arrows); toluidine blue, ×400. d Mastocytoma. Arrows binuclear cells; H&E, ×400 b ACA. A large mast cell stuffed with large granules in the cen-

is an artifact probably due to too much stain and/or blood, but are present in connective tissue through- thick sections. The reason for this proposition is that out the body. Morphologically there are two variants in smears (Fig. 26.3c) and in sections, slightly faded of mast cells, a larger and a smaller. The large cells are after demonstration using a carbon arc lamp projec- also called connective tissue mast cells, and the small tor, these cells also reveal large nuclei containing one cells mucosal mast cells. In spite of this, both variants or two nucleoli and many mitotic figures (Fig. 26.3f). may be present together in the skin as well as in the In routinely stained sections, stimulated T cells are mucous membranes. The large mast cell is triangular, impossible to differentiate from T cell lymphoma cells has a round nucleus and a rich cytoplasm stuffed with (Sect. 26.3.4). large granules. The small mast cell is round or slightly oval. It has a round nucleus and because of densely packed small granules the cytoplasm is hazy. Among 5.1.4 other substances the granules contain . In Plasma Cells normal skin, mast cells are located around vessels in Plasma cells, the effector cells of B cells, are larger than the papillary dermis and close to nerves and append- lymphocytes. They are oval and have a round and ec- ages. centrically located nucleus. In the cytoplasm close to A greatly increased number of mast cells are found the nucleus there is a typical crescent-like light area. in urticaria pigmentosa, mastocytoma, and related In longstanding lesions binuclear plasma cells may be conditions. However, the number of mast cells is also present (Figs. 18.1 and 18.4b). Plasma cells are com- increased in lesions of common dermatoses such as mon in chronic inflammation and are often numer- chronic dermatitis, psoriasis, and lichen planus (Tharp ous in infections caused by spirochetes and Leishma- 2001). According to the experience of the author there nia protozoa. They develop and mature in the lymph is also an increase in mast cells in infectious diseases nodes and migrate to the skin. such as acrodermatitis chronica atrophicans (ACA), a kind of borreliosis, and secondary , and in amalgam tattoo. In acute inflammation/infection to- 5.1.5 gether with they release histamine (Sect. Mast Cells 5.2.1). Mast cells originate from the bone marrow and are Once recognized in H&E-stained sections, mast able to divide. They do not normally circulate in the cells are not difficult to identify, but they are better 5.2 Acute Inflammation 23

Fig. 5.2 . Smear from a subepidermal vesicle. with a newly engulfed . In the middle there is a group There are two old neutrophils with a multisegmented nucleus of which contain the remains of neutrophils in (arrowheads) and several macrophages. Arrow, top left macro- various stages of processing in the cytoplasm. In the macro- phage in close contact with a neutrophil containing a disinte- phage in the top right corner the remains of a nucleus are lying grating, swollen neutrophil; arrow, bottom right in a vacuole (arrow). Mayer staining, ×1000

displayed by means of special stains such as toluidine of phagocytosis are often, as in this book, called his- blue or Giemsa stains, which accentuate the granules tiocytes. Macrophages () are a common (Figs. 5.1 and 29.7b). In sections stained with tolu- component of inflammatory cell infiltrates in chronic idine and Giemsa, granules become blue and with infections and in the healing stage of acute infections May-Grünwald Giemsa metachromatically red. (Fig. 5.2).

5.1.6 5.2 Basophils Acute Inflammation Basophils are bone marrow-derived granulocytes The histologic hallmarks of acute inflammation are which circulate in the blood in small numbers (0–1%). exudation of plasma and migration of inflammatory They have a segmented nucleus and like mast cells cells, predominantly neutrophils, from postcapillary carry basophilic granules containing histamine in the venules into the perivascular tissue. cytoplasm. They are not precursors of mast cells.

5.2.1 5.1.7 Active Phase /Macrophages In response to injury or bacterial infection, histamine Monocytes have an abundant cytoplasm and a large and , short-lived vasoactive chemical media- bean-shaped nucleus. They originate from the bone tors stored in the tissue (histamine in mast cells and marrow and circulate in the blood (2–10%). However, basophils and serotonin in ) are released and after a short time in the circulation they migrate into start the inflammatory process. Histamine and sero- connective tissue where they become larger, acquire tonin cause dilatation of arterioles, which increases the capacity to phagocytose and when doing so be- the blood flow and capillary pressure. Closed capillar- come activated. Like neutrophils, macrophages rec- ies open up and become filled with blood. Due to the ognize bacteria by surface receptors that are specific increased capillary flow and pressure, postcapillary for bacterial products. On activation they become venules become distended and gaps appear between even larger, and their ability to phagocytose and kill the endothelial cells, through which plasma leaks out bacteria increases. Tissue macrophages without signs into the surrounding tissue. The gaps are the result of 24 5 Cell and Vascular Response to Infection and Injury

contraction of two adjacent endothelial cells brought but then they suddenly stop and stick to the intima about by the influence of the vasoactive mediators. before they sneak through the wall using the gaps be- Contracted cells bulge into the vascular lumen and tween the epithelial cells. This phenomenon is called the vessels become so-called high endothelial (epithe- diapedesis. lioid) venules. The two events, rolling and sticking, are generated The leakage of plasma leaves closely packed eryth- by means of receptor–ligand interactions between rocytes with only a small amount of fluid in the dis- endothelial cells and neutrophils (Sect. 4.5). Rolling tended venules. This means increased resistance, and is dependent on adhesion molecules present on the the blood flow now becomes slower. During this phase membrane of platelets and endothelial cells, which neutrophils migrate through the wall of the venules bind to receptors (ligands) on the neutrophils. Stick- into the perivascular tissue. This is made possible by a ing takes place when two related adhesion molecules series of events and interactions at the molecular level. on the surface of the neutrophil become activated and In vessels with a normal blood flow, neutrophils oc- bind to receptors (ligands) on the endothelium. The cupy the center of the stream and the red corpuscles mechanism is principally the same as that for lym- the periphery. When the flow slows down the red phocyte homing in the skin and lymphocytes recircu- blood cells aggregate and form rolls. These structures lating from blood to lymph nodes, but the adhesion are larger than neutrophils, which consequently are molecules/ligands used are different. Outside the ves- transposed to the periphery and get closer to the en- sel, neutrophils phagocytose bacteria. Plasma that has dothelial surface. leaked into the tissue provides antibodies and comple- Neutrophils are attracted to the site of damage by ment, which facilitate the phagocytosis, and even neu- chemotaxins which are molecular products released tralize noxious agents. from injured tissue, extravasated blood and bacteria. An acute inflammatory process may heal without Neutrophils, like other cells capable of phagocytosis, residue, give rise to an abscess, heal with fibrosis and have membrane receptors for different kinds of che- scar formation, or change into a chronic inflamma- motaxins. They also have a huge reserve of receptors tion. stored in their cytoplasmic granules. When chemotac- tic molecules bind to appropriate receptors on the sur- face membrane of a neutrophil, the receptors 5.2.2 fuse with the membrane and are then expressed on Healing Without Residue the cell surface, and in that way enhance the chemo- If the inflammation/infection has been slight and/or tactic response of the cell. Chemotaxin bound to neu- effectively controlled, the process starts to decline. The trophils activates or turns on the neutrophils, which influx of neutrophils stops in favor of immigration of thereby make contact with the endothelium. At first macrophages. The short-lived neutrophils die on the the neutrophils are only loosely attached to the endo- spot. When disintegrated they release the enzyme fi- thelium, which allows them to roll along the intima, brinolysin which makes deposited fibrin soluble. In

Fig. 5.3 Angiogenesis. a Bacillary epithelioid angiomatosis and formed vessel (arrows). c Close-up of another area shows prolif- AIDS. Close to a deep-seated hair follicle is a rather large area erating endothelial cells containing a large light nucleus with a with proliferating vessels. b Granulation tissue at the margin distinct nucleolus (arrow mitotic figure). H&E of an abscess. In the middle there is a longitudinally cut newly 5.2 Acute Inflammation 25

Fig. 5.4 Scar formation. a White scar on the back. In the mid- nodules composed of sclerotic collagen bundles arranged in dermis there is a band of sclerotic collagen bundles arranged whirls. c Between some whirls there are strings of connective parallel to the epidermis; vG. b A small clinically keloid-like tissue and newly formed vessels; H&E scar on the back. In the middle and deep dermis there are large

this form fibrin as well as accumulated is re- predominate in the inflammatory cell infiltrate. The moved from the tissue by the lymphatics. Macrophages newly formed vessels are leaky, and allow plasma and phagocytose dead neutrophils (Fig. 5.2), necrotic tis- red blood cells to pass through the vessel wall, which sue fragments, extravasated red blood cells, pigment, makes the tissue edematous. Gradually the etc. They are also able to phagocytose and liquefy lay down collagen fibers, the vessels and edema dis- fibrin. Macrophages with engulfed material may be appear, and finally nonvascular fibrous tissue replaces found in the sinuses of the regional lymph nodes. The the lost tissue; a scar is formed. Repair by granulation result of these cleaning procedures is called resolution. tissue and fibrosis is called organization (Figs. 7.12b,c If there is only a minimum of dead tissue it is replaced and Fig. 10.1b). by regenerating new cells from the edge of the dam- Occasionally a scar becomes hypertrophic or devel- aged zone. Provided the resolution and regeneration ops into a keloid. Clinically a hypertrophic scar fades are complete, the pattern and function of the damaged and flattens with time, while a keloid remains reddish area will be the same as before the injury. and even becomes larger. Histologically it may be dif- ficult to differentiate between the two. A spared papil- lary dermis, bands or whirls of sclerotic collagen in the 5.2.3 reticular dermis are in favor of keloid (Lee et al. 2004). Abscess Formation Abscesses and pustules are local accumulations of pus (i.e., a large number of neutrophils, disintegrating 5.2.4.1 neutrophils, and inflammatory exudate). The abscess Examples is walled off by granulation tissue (Sect. 5.2.4). Boils, Case 1. Scar pimples and pustules caused by microbes such as bac- A 13-year-old girl over a period of 1.5 years had ob- teria and fungi are examples of abscesses (Figs. 12.1, served asymptomatic, white, papular lesions spread- 13.4c, 13.5, 14.1b and 29.2a and b). ing over the trunk. The clinical suggestion was guttate lichen sclerosus et atrophicus. A biopsy specimen from the back revealed scar tis- 5.2.4 sue with a band of sclerotic collagen in the mid-der- Healing with Fibrosis and Scar Formation mis (Fig. 5.4a). In all probability the lesions were scars If lost tissue cannot be replaced, or fibrin clots are not caused by varicella. cleared rapidly enough, healing takes place by means of granulation tissue. Proliferation of new vessels and Case 2. Keloid fibroblasts, promoted by macrophages, invade the A 22-year-old man had a small keloid-like lesion on damaged area (Fig. 5.3). Lymphocytes and plasma cells the back. It had developed without previous injury. 26 5 Cell and Vascular Response to Infection and Injury

Fig. 5.5 . a Epithelioid cell with a giant eration of giant cells (arrows); the infiltrate of lymphocytes is cell of Langhans type (arrow). There are only a few lymphocytes. more dense; H&E b Another granuloma in the same section contains a conglom-

Histologic investigation showed the typical picture sels become thick-walled due to edema and/or fibrosis, of keloid (Fig. 5.4b,c). Keloid may be a complication which may cause narrowing and even occlusion of the in acne vulgaris. It is not known if this was the cause lumen (Figs. 7.17a–c and 7.18c). in this case. Granulomatous inflammation is a type of chronic inflammation that develops in response to antigens or particles which are difficult to eliminate because 5.3 they are poorly soluble or hard to disintegrate. The Chronic Inflammation inflammatory tissue contains more or less well-cir- As well as being the result of an acute process, chronic cumscribed aggregates of inflammatory cells called inflammation may start insidiously. The histologic . There are two main types of granuloma: hallmarks are infiltrates of macrophages, lymphocytes immune granulomas and foreign body granulomas. and plasma cells. Areas of tissue destruction alternate with areas of granulation tissue and fibrosis (healing). Histiocytes/macrophages play a major role. Cy- 5.3.1 tokines such as IFN-γ secreted by sensitized T cells, Immune Granulomas and bacterial endotoxins are examples of substances Immune granulomas (hypersensitivity granulomas) able to activate macrophages, which accumulate in are caused by antigenic particles or bacteria, which the tissue by proliferation (cell division) and contin- are difficult to eliminate, and are able to induce cell- ued recruitment of monocytes from the blood. Also mediated immunity. They are composed mainly of of the migration inhibitor factor macrophages, epithelioid cells, and multinucleated gi- by sensitized lymphocytes restrains the macrophages ant cells, and are mostly surrounded by a moderately from moving away from the area. In turn activated dense infiltrate of lymphocytes; older granulomas are macrophages produce a wide variety of biologically encircled by fibroblasts. These types of granulomas are active products, which are helpful in destroying per- generally called epithelioid cell granulomas. sistent bacteria, but if not balanced also destroy the Epithelioid cells are derived from macrophages. tissues. Promotion of new vessel formation, Transitional cell forms exist, which sometimes makes proliferation, and collagen deposition finally lead to it difficult to decide if an aggregate of cells is macro- fibrosis. In longstanding conditions newly formed ves- phages (histiocytes) or epithelioid cells. The latter have 5.3 Chronic Inflammation 27 abundant, pale, poorly defined cytoplasm and a pale, 5.3.1.1 rounded, oval or banana-like nucleus (Figs. 17.2d and The Tuberculous Granuloma 18.1). The primary tuberculous granuloma of the lung is the With respect to morphology, there are two types of prototype of infectious immune granulomas. Primary multinucleated giant cells: Langhans giant cells (LGC) infection with Mycobacterium is usually and foreign body giant cells (FBGC) (Figs. 5.5 and 5.6, contracted by inhalation of droplets dispersed in the 15.1b and 15.2b). LGCs have several nuclei (up to 30) air by an infected person coughing or sneezing. In the arranged at the cell membrane in a circular or horse- lungs the infected droplets give rise to usually only a shoe-like manner, and FBGCs contain numerous single 10–20 mm large subpleural inflammatory focus. (more than than 30) disorderly spread nuclei (van der The first inflammatory cells to arrive are neutrophils, Rhee et al. 1978). It is likely that giant cells are formed which engulf the mycobacteria and die without kill- by fusion of cells rather than by mitosis without cell ing them. Macrophages phagocytosee the released division (Sect. 5.3.3). bacteria and transport them to the regional lymph Granulomas contain no or very few vessels. The cen- nodes at the hilus of the lung. At the first encounter tral part may become necrotic. Occasionally a granu- with the mycobacteria, macrophages are not able to loma consists of a large area of surrounded destroy them. They die and the freed bacteria infect by a brim or ring of epithelioid cells with scattered other macrophages. In this way the regional lymph giant cells (Figs. 15.1c and 15.2). Microscopically, ne- nodes also get infected and the cell-mediated immune crotic areas are usually composed of non-eosinophilic, response becomes activated. In contact with the bac- amorphous and slightly granular material. Examples terial antigen, naive T4+ cells in the lymph nodes are of immune granulomas are tuberculous granulomas stimulated and give rise toT4+-1 cells. These produce (Sect. 15), syphilitic gummas (Sect. 17), and granulo- the cytokine INF-γ, which in turn activates macro- mas occurring in sarcoidosis (Sect. 5.3.1.2). phages to kill intracellular bacteria. Furthermore, T4+- 1 cells induce the development of macrophages into epithelioid cells. After a few weeks epithelioid cell granulomas occur both at the primary site of inoculation in the periph- eral lung parenchyma and in the infected lymph nodes. As already mentioned, granulomas may be necrotic in the center. The necrosis is thought to be due to the toxic effect of the mycobacteria on macrophages in combination with lysis of macrophages by toxic lym- phocytes; in the latter case living bacteria may be re- leased into the tissue. However, mycobacteria cannot grow in the acid oxygen-deprived necrotic tissue and finally, in most cases, the infection is controlled and the lesions heal. The Ghon complex (i.e., a fibrotic scar in the parenchyma and enlarged and calcified lymph nodes at the hilus) is all that remains to the naked eye. During the primary infection the patient becomes sensitized to tuberculin, a mycobacterial protein, and is said to be tuberculin positive. Intradermal injection of tuberculin leads to a local reaction with erythema and swelling which reaches its maximum after 48 h. This is a type IV hypersensitivity reaction, which, if moderate, is thought to be an indicator of a healed primary infection and a guarantee for at least some immunity to tuberculosis. Both the degree of sensitiv- ity and the degree of immunity may vary, but do not parallel each other. Fig. 5.6 Foreign body granuloma. A foreign body (arrow), If the mycobacteria are not eliminated, the disease probably a thorn, is surrounded by foreign body giant cells and becomes chronic and gives rise to so-called secondary lymphocytes; H&E lung tuberculosis. Also an infection that is not 100% 28 5 Cell and Vascular Response to Infection and Injury

eliminated can be reactivated later in life depending cells with admixture of lymphocytes. Sometimes epi- on the state of immunity of the individual. Even an ex- thelioid cells are also present (Fig. 5.6). ogenous reinfection may occur. In secondary lung tu- berculosis the lesions are sometimes widespread and contain large areas of soft and yellowish-white necro- 5.3.3 sis, which macroscopically resembles curd cheese, and Relevant Investigations is therefore called caseation necrosis. Unfortunately Investigations performed on cultured human blood this designation is also widely accepted in modern lit- monocytes, to which were added different kinds of cy- erature for necrosis in cutaneous epithelioid cell gran- tokines, indicated that giant cells are formed by fusion ulomas observed under the microscope (Sect. 15.3). of differentiated monocytes (macrophages) and not di- rectly from monocytes. It was found that the cytokine -macrophage colony-stimulating factor 5.3.1.2 (GM-CSF) promoted differentiation into Sarcoidosis macrophages, and that the cytokine IL-4 provoked the Sarcoidosis is a systemic disease thought to be due to coalescence of histiocytes into large giant cells with some unknown poorly degradable antigen, and may many nuclei. If IL-4 is not added to the macrophage give rise to aggregates of epithelioid cell granulomas culture only a few giant cells, which rarely contained anywhere in the body. The organs most affected are more than three nuclei, were observed (Dugast et al. the lungs, lymph nodes, liver, bone marrow, and skin. 1997). Other investigations have shown that with the A typical granuloma consists of densely packed epithe- combination GM-CSF and IL-4 large giant cells with a lioid cells and a variable number of giant cells of both high number of nuclei (FBGCs) were formed, whereas types, and is surrounded by a sparse number of lym- the combination GM-CSF and INF-γ, under other- phocytes, and therefore is often called naked granu- wise identical conditions, gave rise to smaller giant loma (Fig. 5.5). Necroses are not common, but, if pres- cells with fewer than 30 nuclei (LGCs) (McNally and ent, are usually small and fibrinoid (i.e., have the same Anderson 1995). shiny eosinophilic appearance as fibrin deposited in the tissue). Plasma cells are sparse. Sometimes inclu- sions of laminated concretions (Schaumann bodies) or 5.4 stellate (asteroid) bodies are observed in giant cells. Angiogenesis Angiogenesis (neovascularization) implies formation of new blood vessels from already existing vessels 5.3.1.2.1 both in the embryo and in the adult. In adult females Example angiogenesis normally occurs in the cyclic variations in the reproductive organs. It also plays an important Case 3. Sarcoidosis role in wound healing and regeneration, and in many A 48-year-old woman had a 7-year history of histo- pathologic conditions such as chronic inflammation, logically verified lung sarcoidosis, later complicated organization of thrombi, and tumor growth (Figs. 5.3, with adenopathy and lacrimal gland enlargement. For 8.7c, and 22.5c,d). several years she also had had progressing skin lesions The mechanism of angiogenesis is complicated and suspected to be sarcoidosis. Biopsies were taken from not all the details are clearly understood. The process lesions on the face and the forearm. may be induced by several angiogenic stimuli (cyto- Both biopsies showed principally the same pattern. kines), of which the two most important are vascular The whole dermis was permeated with different-sized endothelial growth factor (VEGF) and TNF. It starts epithelioid cell granulomas with a sparse number of from small venules, which lack smooth muscle cells, lymphocytes and scattered LGC. A conglomeration of and possibly also from capillaries. In the stimulated giant cells, mainly FBGC was located close to a hair area endothelial cells and pericytes are activated. The follicle. Necrosis was not observed (Fig. 5.5). activated endothelial cells produce proteolytic en- zymes, which degrade the basal membrane of the par- ent vessel; this allows the endothelial cells to migrate 5.3.2 (by means of pseudopodia) into the surrounding tissue Foreign Body Granuloma and they then proliferate (by mitotic activity) towards Foreign body granulomas are caused by non-antigenic the angiogenic stimulus. Thus, in the perivascular tis- material such as silica and suture material. They con- sue, at first a sprout and then a cord of endothelial cells sist mainly of macrophages and foreign body giant are formed. In general it is accepted that the lumen of 5.5 Cell Division 29

Fig. 5.7 Mitotic figures:a prophase; b metaphase; c anaphase; d anaphase; e telophase; f telophase, the cell to the left of the mi- totic figure is in interphase; g atypical metaphase. H&E, ×1000

the vessel sprout is formed between two adjacent en- sis is called interphase. The chromatin, the carrier of dothelial processes budding off the wall of the parent the genes, is enclosed in the nucleus and is diffusely vessel, and thus is an elongation of the lumen of the spread as a network of fine threads; individual chro- parent vessel. When the angiogenic stimuli cease most mosomes are not distinguishable under the light mi- of the newly formed vessels involute. Some capillar- croscope. ies may differentiate into arterioles and venules (Diaz- Prophase: In prophase the cell is ready for mitosis Flores et al. 1994). and the chromatin is arranged in a long pleated thread, divided into chromosomes, the number of which is specific for each species. The chromosomes are lon- 5.5 gitudinally split up into two halves, which are made Cell Division complete by building-stones (nucleic acids) already Cells multiply, proliferate, by division in a process synthesized in the cell. There are now two identical termed mitosis. This is a complicated process in which sets of chromosomes in the cell and the nuclear mem- the cell and its chromosomes pass through four con- brane has dissolved (Fig. 5.7a). secutive phases called prophase, anaphase, metaphase Metaphase: In metaphase the two sets of chromo- and telophase. In each phase the chromosomes form a somes are situated close to each other at the equator of different mitotic figure. Mitotic figures are rather com- the cell and in routinely processed sections are seen as mon in inflammatory tissue and can be identified in a single black band (Fig. 5.7b). routinely stained sections. Anaphase: In anaphase the two sets slowly move Interphase: The period when the cell is not in mito- away from each other towards the poles of the cell. At 30 5 Cell and Vascular Response to Infection and Injury

least at high magnification parts of individual chro- References mosomes may be discerned (Figs. 5.7c,d). 1. Diaz-Flores L, Gutiérrez R, Varela H (1994) Angiogenesis. Telophase: In telophase the cytoplasm starts to di- An update. Histol Histopathol 9:807–843 vide. At each pole the set of chromosomes becomes 2. Dugast C, Gaudin A, Toujas L (1997) Generation of multi- surrounded by a nuclear membrane and once more nucleated giant cells by culture of monocyte-derived mac- becomes dispersed as chromatin. Telophase com- rophages with IL-4. J Leukoc Biol 61:517–521 pleted, the dividing cell has become two cells with ex- 3. Lee JY-Y, Yang C-C, Chao S-C, Wong T-W (2004) Histo- actly the same set of chromosomes (Fig. 5.7e,f). pathologic differential diagnosis of keloid and hypertrophic In routinely processed specimens it is rare to find scar. Am J Dermatopathol 26:379–384 cells in prophase and telophase, but mitotic figures 4. McNally AK, Anderson JM (1995) Interleukin-4 induces of the metaphase and anaphase are often observed foreign body giant cells from human monocytes/macro- phages. Differential lymphokine regulation of macrophage (Figs. 7.5a, 7.17c, 18.2c, 21.3a and 26.3f). Atypical mi- fusion leads to morphological variants of multinucleated totic figures contain either too many or too few chro- giant cells. Am J Pathol 147:1487–1499 mosomes, and may be seen in malignant tumors and 5. Peters MS, Rodriguez M, Gleich GJ (1986) Localization of sometimes even in benign conditions. The mitotic human granule major basic protein, eosinophil figures in Fig. 5.7a–f were observed in a carcinoma in cationic protein, and eosinophil-derived neurotoxin by im- situ of the preputium penis. It is not possible to de- munoelectron microscopy. Lab Invest 54:656–662 cide if they or some of them are atypical. In tissue, the 6. Tharp MD (2001) Skin mast cells. In: Freinkel RK, Woodley only reliable signs indicating atypia are the presence of DT (eds) The biology of the skin. Parthenon, New York, pp tri- or multipolar mitotic figures. The figure shown in 265–279 Fig. 5.7g is quadripolar and occurred in a dermal cell 7. van der Rhee HJ, Hillebrands W, Daems WT (1978) Are infiltrate in a lesion of lymphomatoid papulosis (Sect. Langhans giant cells precursors of foreign-body giant cells? 26.3.4). Arch Dermatol Res 263:13–21