Keywords

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Core Messages

  • The pathogenesis of nasal polyps explains how the polyps start and grow.

  • The pathophysiology of nasal polyps explains the events and processes taking place in the outgrowth of nasal polyps.

  • Histopathological studies at various stages of polyp formation, using whole-mount methods, the glands of the uncut polyps and the ordinary histological sections, allow our statements on pathogenesis of nasal polyps.

  • Origin and incidence of nasal polyps on autopsies, studies on the changing epithelium and quantitative studies of the inflammatory cells of the nasal polyps, removed from the patients, allow us some statements on pathophysiology of the nasal polyps.

  • In fact, only the age of the nasal polyps separates the term pathogenesis from the pathophysiology.

7.1 Introduction

Several pathogenetic theories on the formation of nasal polyps have been published during the last 150 years that have been summarised previously [23]. These theories are based on oedema, an increase in tubulo-alveolar glands, the presence of the cysts of mucous glands and on mucous glands of NP.

7.2 Adenoma and Fibroma theory

Billroth [3] found increased number of long tubulous glands in the polyps. He interpreted them as new formations within the nasal mucosa. The NP were interpreted as adenomas that began by growing under the nasal mucosa, pushing the epithelium and the original nasal glands outwards (Fig. 7.1). Hopmann [10] did not find any glands in the NP from his study and interpreted NP as soft fibromas, protruding towards the nasal mucosa. Both the adenoma theory and the fibroma theory have been refuted in the past century.

Fig. 7.1
figure 1

Adenoma theory on polyp formation. (a) New formation of glands in nasal mucosa (arrows). (b) Newly formed glands are growing and pushing the original epithelium outwards as a polyp (E epithelium; G original tubulo-alveolar mucosal glands)

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7.3 Necrotizing Ethmoiditis Theory

This theory supposes that ethmoiditis leads to periostitis and osteitis of the ethmoid bone and causes bone necrosis (Fig. 7.2). The necrotic bone becomes surrounded by the myxomatous tissue, which projects towards the nasal mucosa, which is pressed caudally as a polyp. Hayek [9] argued strongly against this theory, based on the fact that he could not found bone necrosis in the ethmoid sinus.

Fig. 7.2
figure 2

Necrosing-ethmoiditis theory. [29]. (a) Bone necrosis within the ethmoid bone, with myxomatous tissue protrusion toward the nasal mucosa (arrows). (b) Growth of the myxomatous tissue pressing the nasal tubulo-alveolar glands (G) downward as a polyp (arrows)

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7.4 Glandular-Cyst Theory

This theory is based upon the presence of cystic glands and mucus-filled cysts in NP [8]. This is the oldest of several theories involving the mucous glands directly. It is hypothesised that oedema of the nasal mucosa causes obstruction of the ducts of basal glands, leading to the formation of cysts in the nasal mucosa (Fig. 7.3a). The cysts expand and push the nasal mucosa downwards, forming a polyp (Fig. 7.3a, b). However, Taylor [21] and our studies [22, 24, 28] have shown that cystic dilatation of the glands occurs after the polyp has been formed.

Fig. 7.3
figure 3

Glandular-cyst theory. (a) A cyst (C) is formed within the nasal tubulo-alveolar gland (G). (b) The cyst (C) is expanding, pressing the nasal epithelium outwards. (c) Further expanding of the cyst (C) results in the nasal polyp

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7.5 Mucosal Exudate Theory

Hayek [9] believed that the formation of NP started via an exudate localised deep in the nasal mucosa, which pressed outwards caudally (Fig. 7.4a). A vascular stalk then forms and vascular congestion increases the volume of the polyp (Fig. 7.4b). According to this theory, both layers of the tubulo-alveolar sero-mucous nasal glands should be displaced outwards and be found in the distal part of the polyp. Our studies have not found such glands in the NP [22, 24, 28]. Glands in NP develop after the polyp has been formed and attained a certain size.

Fig. 7.4
figure 4

Mucosal exudate or/and mucosal oedema theories on nasal polyp formation. (a) Nasal mucosa with an expanding exudate localised between the bone and the deeper layer of the tubulo-alveolar glands. (b) The expanding exudate has displaced both layers of the glands outwards in a nasal polyp (arrows). As a consequence of this theory, the tubulo-alveolar glands should be found in the distal part of the polyp, which is not the case. (c) In this situation exudates or oedema is predominantly between the deep and superficial glandular layers. Expansion of the oedema pushes the superficial layer outwards as a nasal polyp. As a consequence of this theory, the superficial layer of the tubulo-alveolar glands should be in the distal part of the polyp, which is not the case. (d) In predominantly sub-epithelial oedema

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7.6 Theory on Cystic Dilatation of the Excretory Duct of Nasal Glands and Vessel Obstruction

In chronic inflammation of the nasal mucosa, excretory ducts of nasal tubulo-alveolar glands are obstructed, distended and dilatated into cystic structures [31]. The capillaries and veins (which are arranged around the excretory ducts and the gland mass) become stretched and obstructed, resulting in increased permeability, transudation and oedema. Our comment to this pathogenesis is that cystic dilatation of glands occurs among the newly formed glands only after the polyp is formed. The dilatation of tubulo-alveolar glands is seen in the nasal mucosa as a result of the hereditary gene defect of mucus transport through the duct system. This theory has been used to explain polyp formation in cystic fibrosis. We found in the NP exactly the same newly formed, long, tubulous glands in patients with and without CF [24, 28].

7.7 Blockade Theory

The theory of Jenkins [11] is based on the premise that the polyp formation is always preceded by the same degree of chronic inflammation, either infectious or allergic. The polyp itself is an accumulation of intercellular fluid dammed up in a localised tissue. The dam is usually caused by an infiltration of round cells, producing blockade of intercellular spaces and local lymph oedema. If the blockade persists, a typical polyp forms, and if the blockade covers a large area, multiple polyps may form. If the blockade of the same round cells is lifted, accumulated fluid in the polyps will be absorbed, and the polyps will disappear. This is one of the many theories of polyp formation based on oedema, but in our opinion, it does not explain why and how polyps can arise in one particular place but not in another.

7.8 Peri-Phlebitis and Peri-Lymphangitis Theory

The theory of Eggston and Wolff [6] is based upon the recurrent infections that lead to the blocking of intercellular fluid transport in the mucosa and oedema of the lamina propria. If the oedema involves major areas, the result is the prolapse of the mucosa and formation of polyps. This theory is based upon the demonstration of chronic vascular changes in the nasal mucosa, but these changes are diffuse, and the theory cannot explain how the polyp is formed in a particular place. The theory is an explanation for oedema formation rather than polyp formation.

If the oedema forms predominantly deep in the lamina propria and beneath the deepest glandular layer (Fig. 7.4a, b), this would lead to a situation already discussed by the theory of Hayek [9]. We should find displaced and prolapsed tubulo-alveolar mucous glands in the most distal part (top) of the nasal polyp, but we did not find such glands in the polyps. If the oedema arises predominantly between the deeper and the superficial layers of glands (Fig. 7.4c), the superficial layer of the tubulo-alveolar glands should be found in the distal parts of the NP, but this was not the case in our studies [24]. Furthermore, the elongated ducts of the deeper layer of the tubulo-alveoral glands should be found in the stalk of the polyp. If the oedema is localised predominantly sub-epithelially in the nasal mucosa between the epithelium and the superficial layer of glands, the epithelium will bulge out in the form of a polyp and pull out the ducts of the nasal glands (Fig. 7.4d). In such case, the stalks of the polyps would contain mainly long ducts, which we did not found.

7.9 Glandular Hyperplasia Theory

Krajina [13] found in cases of chronic infection or allergy localised infiltrates in the nasal mucosa and localised hyperplasia of nasal glands. The glands will increase in size and cause bulging of the mucosa (Fig. 7.5). Apart from the gland hyperplasia, the change of the blood vessels and the oedema in the region of the middle nasal meatus will lead to mucosal prolapses in the form of polyps. We did not find tubular-alveolar glands in polyps. In the chronic hypertrophic rhinitis, there is very little gland hyperplasia in the nasal mucosa and we did not observe localised bulging of the nasal mucosa on the inferior turbinate caused by hyperplasia of the nasal glands [22, 24, 28]. The number and density of glands were the same in patients with chronic hypertrophic rhinitis and in normal subjects [22, 25, 26].

Fig. 7.5
figure 5

Glandular hyperplasia theory of Krajina (1963) on nasal polyp formation. (a) Normal nasal tubulo-alveolar glands (G) arranged in two layers. (b) Hyperplasia of nasal glands causing protrusion of nasal mucosa, especially the nasal epithelium (E)

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7.10 Epithelial Rupture Theory

We studied the shape, distribution, density and histologic profiles of the glands by staining NP using the whole-mount method, implicating that the polyp is not sectioned, but stained and studied in total. Based on these studies, we described a new theory for the pathogenesis of NP [27]. We postulated that in the initial stage of polyp formation, an epithelial rupture or necrosis caused by inflammation and tissue pressure from the oedematous and infiltrated lamina propria takes place (Fig. 7.6a). Lamina propria protrudes through the epithelial defect, and the adjacent epithelium tends to cover the defect by migrating from the surroundings (Fig. 7.6b). If the epithelial defect is not covered soon enough or if it is insufficiently covered, the prolapsed lamina propria continues to grow and the polyp, with its vascular stalk, is established (Fig. 7.6c). After epithelialization of the polyp, the characteristic new, long tubulous glands are formed (Fig. 7.6d, e).

Fig. 7.6
figure 6

Epithelial rupture or glandular new formation theory on nasal polyp formation. (a) An epithelial defect with prolapse of the underlying lamina propria. (b) Epithelialization of the lamina propria prolapse. (c) Formation of a vascular stalk. (d) Formation of the glands from newly formed epithelium. (e) A fully developed and epithelialized polyp with long tubular glands has been formed

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Whole-mount studies elucidated the structure and density of glands in NP and showed that their shape and distribution were completely different from normal nasal mucosal sero-mucous glands.

Our studies strongly indicate that the glands of the polyps are newly formed structures and that the polyps are not a prolapse of the original nasal mucosa. We have been able to confirm the epithelial rupture theory in experimental otitis media in rats [4]. We illustrated the early stages of polyp formation (Fig. 7.7):

Fig. 7.7
figure 7

Experimental polyp formation in the rat middle ear. (a) Small polypoid prominence seen on the mucosal surface 16 days after pneumococcal inoculation of the middle ear. (b) Section of the polyp seen in a, illustrating epithelial rupture, incipient prolapse of the fibrous tissue of the lamina propria and re-epithelialization

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  1. 1.

    Localised rupture of the epithelium.

  2. 2.

    Luminal protrusion of the lamina propria through the epithelial defect.

  3. 3.

    Re-epithelialization of the protruded tissue and formation of a polyp.

  4. 4.

    Growth of the polyp.

During these processes, the glands are formed with further growth and stretching of the polyp and become elongated and stretched. Polyp formation, including initiation by rupture of the epithelium, prolapse of the lamina propria and re-epithelialization of the protruded tissue, was also demonstrated in chronic tubal occlusion in rats (Figs. 7.8 and 7.9) [15, 17]. Polyp formation initiated by epithelial defects was also documented by Norlander et al. in experimental sinusitis in a rabbit model [18].

Fig. 7.8
figure 8

Experimental middle ear polyp after long-term tubal occlusion in rat. (a) Initial, partially epithelialised polyp. Arrow; epithelium. (b) Fully epithelialised polyp

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Fig. 7.9
figure 9

Various types of mucous glands in nasal polyps. Long, simple tubular glands (a, f). Long tubular glands with some branches (b–e). Short, simple tubular glands (g). Short, branched tubular glands (h, i). Tubular glands with flask-shaped dilatation (j, k). Tubulo-alveolar glands, which are found extremely rarely (l)

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Histopathological examination of small, newly formed NP [14, 16] showed a low cubic or cylindrical epithelium with ciliary cells, but no or few goblet cells, compared to large (fully developed) NP, where the dominant type is the pseudostratified (respiratory) epithelium with goblet cells (Fig. 7.10a–c). A semi-quantitative analysis of epithelia in nine small polyps revealed pseudostratified in few areas, low cuboid in some more areas and low cylindric epithelium in most areas (Table 7.1).

Fig. 7.10
figure 10

(a) A small polyp found by endoscopic examination in an autopsy. The polyp originated from the mucosa of the edgy part of the frontal recess. (b) Cross-section of the small polyp with low, cubic two-layered epithelium with ciliary cells, but no goblet cells (H&E). (c) Cross-section of epithelium in a “fully developed” nasal polyp showing a higher, pseudostratified respiratory epithelium with ciliary cells and goblet cells (Pas–Alcian, H&E)

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Table 7.1 Different types of epithelia in longitudinal cross-sections from nine small polyps (spread of epithelia was evaluated semiquantitatively)
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7.11 Mucous Glands in Nasal Polyps

In most of the pathogenetic theories, the mucous glands have played a role. Therefore, our findings on these glands are presently reviewed. Billroth, in his thesis on the structure of NP, described NP glands as long tubular, new formations [3], while Zuckerkandl considered the glands as nasal glands. We [24, 28] have studied the mucous glands in NP and demonstrated that they play an important role in understanding the pathogenesis of the polyp [23, 24, 27, 28].

The glandular orifices are irregularly distributed, as there is no particular concentration of glands in the stalk or in the most distal end of the polyp. In some polyps, less than 10 glands can be found, whereas others demonstrate more than 100. In most polyps the density is between 0.1 and 0.5 glands/mm2 of polyp surface. The density of glands in NP is considerably lower than in the nasal mucosa [22]. In the nasal mucosa, the glands are regularly distributed throughout the mucosa and the density is around 7 glands/mm2. Thus, the pattern is completely different from the polyp.

The polyp glands are tubular, of different shapes and sizes and differ widely from those of the nasal glands [24, 28]. They are of various types (Fig. 7.9). The most striking glands are the long tubular glands, which may be 1–8 mm of length. These glands most often arise from the middle or distal part of the polyp and grow towards the stalk. They are orientated parallel to each other and to the longitudinal axis of the polyp. Some are very simple, narrow tubes (Fig. 7.10), other have prominences of small, round, alveolar bulges on their sides (Fig. 7.11). Some glands are small, simple tubuli, without dichotomous division (Fig. 7.12), whereas others do present with a dichotomous branching.

Fig. 7.11
figure 11

Long, simple tubular glands in a polyp. Whole-mount, PAS-Alcian blue staining

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Fig. 7.12
figure 12

Tubular glands with small bulges indicating dichotomous division (a) and a long, thin, simple gland branched at the end (b) Whole-mount, PAS-Alcian blue staining

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The epithelial lining of the tubules is extremely polymorphous. Some long glands are lined with pseudostratified, columnar, ciliated epithelium with goblet cells (Fig. 7.13). Distally, these glands become thinner (one- or two-layered). Others are lined with tall, simple columnar epithelium, in which all the cells are mucous-producing.

Fig. 7.13
figure 13

A relatively high density of small, simple tubular glands formed in the polyp after its formation

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7.12 Formation and Growth of Glands

The glands most often have their orifices in the lower halves, and the long tubules run up towards the stalk. The shape and architecture of the glands differ a great deal from those in the nasal mucosa and indicate that the glands are formed during the growth of the polyps and that none grow into the polyp from the original nasal mucosa. When the first glands form, the polyps have already attained a certain size. This is the only explanation for the shape and orientation of the long glands (Figs. 7.10 and 7.11). Presumably, the long glands are the first to form in the polyp, growing from the basal layer of the surface epithelium down towards the depth of the polyp and then becoming canalised. As the polyp continues its growth and elongates, the glands become long and stretched (Fig. 7.14). Passive stretching of the glandular ducts indicates that growth of the polyp is also passive, i.e. there is an increase in length.

Fig. 7.14
figure 14

Cross-section of a tubular gland covered with active, pseudostratified epithelium. H&E–PAS-Alcian blue staining

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7.13 Gland Degeneration

All the types of glands described above have been observed as active and as completely degenerated types. The most striking glands are the degenerated, long glands in which the entire long duct and the small lateral ducts are distended twofold or threefold and are filled with mucous (Fig. 7.15). The degeneration of glands starts with the stagnation of mucus within the tubulus and the duct, which then become distended. The secretory epithelium stretches, and the cells become cuboidal and flat, loose their secretory ability and gradually become entirely inactive. Such degenerated ducts in whole-mount preparations are seen as dilated; in section, they are seen as small cysts. Loss of secretory activity in the glands of NP has also been demonstrated using immunofluorescent techniques.

Fig. 7.15
figure 15

Growth and passive stretching of long tubular glands in nasal polyps. The dichotomous divisions are numbered 1–5; only one side of each division stretches and grows, making the glands asymmetrical

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7.14 Cellular Infiltration in the Pathophysiology of Nasal Polyps

Eosinophilic inflammation is an important feature in the pathogenesis of chronic rhinosinositis (CRS) with nasal polyps with NP. The eosinophilic accumulation in the polyp stroma is basically caused by increased transendothelial migration and increased survival time in the tissue, where an increased concentration of interleukine 5 (IL-5) plays a major role [7], [12]. The increased amount of IL-5 is predominantly released from T-lymphocytes, independently of atopy, and the highest concentration has been found in polyps from patients with non-allergic asthma and acetylsalicylic acid (ASA) intolerance (refID 3458). These are the sub-groups of patients also known to exhibit the greatest accumulation of eosinophils [1, 2].

In the ASA intolerant patients, a lowered prostaglandin E2 (PGE2) production has been observed (refID 1115, refID 1023). PGE2 has a significant anti-inflammatory activity, including inhibition of eosinophils. A possible intrinsic defect in PGE2 production might, therefore, be responsible for a further increase of eosinophilic accumulation in ASA intolerant patients.

The Staphylococcus aureus enterotoxin (SAE)-induced T-lymphocyte production of IL-5, which activates eosinophils and prolongs their survival, is another possible factor in the inflammatory response in NP [20] (refID 70, refID 3457). The SAE IgE antibody is found in 80% of patients with asthma and ASA intolerance (B415) and 60–80% of asthmatics [19] (refID 3458, refID 904, refID 220, refID 356, refID 271, refID 289).

In the classic allergic fungal rhinosinusitis (AFRS), specific IgE against the causative micro-organism has been detected. A high number of T-lymphocytes (refID 10) and a depletion of B-lymphocytes have been observed in NP (refID 10, refID 286). Relating to T-cellular sub-types, a slight increase in CD4+ T-lymphocytes has been reported, while others have found that CD8+ dominated over CD4+ T-lymphocytes (refID 1173). In a study including 140 patients and using unbiased uniform random sample technique for quantification of cellular elements in NP, the cellular infiltration was correlated to clinical findings in order to evaluate pathophysiologic aspects of the cellular infiltration in relation to clinical activity, as well as to sub-groups of patients with NP. Quantification of all inflammatory cells was performed, including eosinophils, CD3+ and CD20+ T-lymphocytes. There was a strong relationship between clinical recurrence and eosinophilic accumulation (Fig. 7.16) [14]. The T- and B-lymphocytes, as well as the total number of inflammatory cells, did not show a similar correlation. The T-lymphocytes outnumbered the B-lymphocytes by a factor around 4, with the exception of unilateral polyps, in which equal numbers were observed. The T-lymphocytes were a little more predominant in patients with ASA intolerance and those with allergy.

Fig. 7.16
figure 16

Degeneration of glands. The lumen of a gland tubulus is completely filled with stagnated mucus. H&E–PAS-Alcian blue stained section

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Based on the above findings, a classification of NP with respect to both cellular pathophysiologic findings and clinical parameters can be proposed. The eosinophilic group constitutes the largest number of patients with NP, while the neutrophilic-dominated group is much smaller, but with an overlap between the two. Within the eosinophilic group, there is a large population with clinically overt asthma and they show an increased eosinophilic infiltration, which is even more pronounced in patients having ASA intolerance. SAEs induce severe eosinophilia and seem related to the group with asthma and ASA intolerance. Eosinophilic mucus rhinosinusitis (refID 48) is described as a systemic disease caused by a dysregulation of immunologic control and has a strong relation to asthma and ASA intolerance. Classical AFRS and Churg–Straus syndrome are other eosinophilic groups. CF is a separate group within the neutrophilic type polyp, like the antro-choanal polyp, the Young’s syndrome- and the Kartageners syndrome-associated polyp.