1. Nasal Polyps - Pathogenesis and Treatment Implications
Bastaninejad, Shahin, MD, Assistant Professor of ORL-HNS, TUMS, Amir’Alam Hospital

2. Importance
NPs have been shown to have a significant detrimental effect on the quality of life, which is similar in severity to COPD

3. Introduction
Nasal polyps appear as grape-like structures in the upper nasal cavity, originating from within the ostiomeatal complex
They consist of: loose connective tissue, oedema, inflammatory cells and some glands and capillaries, and are covered with varying types of epithelium, mostly respiratory pseudostratified columnar epithelium…

4. Eosinophils are the most common inflammatory cells in nasal polyps (80%), but Neutrophils, mast cells, plasma cells, lymphocytes and monocytes are also present, as well as fibroblasts
IL-5 is the predominant cytokine in nasal polyposis, reflecting activation and prolonged survival of eosinophils

5. In the general population, the prevalence of nasal polyps is 4% (2
In the general population, the prevalence of nasal polyps is 4% (2.2/1 MF Ratio)
The average age of onset is approximately 42 years
In patients with asthma, a prevalence of 7 to 15% has been noted whereas, in NSAID sensitivity, nasal polyps are found in 36 to 96% of patients

6. Factors associated with NP
Allergy  Only Kern state inhalant allergy as a risk factor for NP, but food allergy is significantly higher in NP patients (80%)
Asthma  NPs are present in 13% in non-atopic asthma (skin prick test and total and specific IgE negative) and 5% in atopic asthma
Aspirin sensitivity  In patients with aspirin sensitivity 36-96% have nasal polyps

7. Factors associated with NP
Genetics  NP are frequently found to run in families… HLA-A74 , HLA-DR7
Environmental factors  The role of environmental factors in the development of NP is Unclear

8. Hypotheses regarding the underlying mechanisms
Chronic infection (Fungal/Bacterial)
Aspirin intolerance (Samter)
Aerodynamics alteration with trapping of polutions
Epithelial cell defects / Epithelial disruptions
Gene deletions (CFTR genes in CF)
Inhalant or food allergens (discussed in previous page)

9. Chronic rhinosinusitis with and without nasal polyps
The spectrum of sinus disease
20-33% of CRS
Is NP and CRS in a continum or NP is a separate entity? This is not clear yet… but they seems to be separate entities…
Rhinosinusitis
PMN EOS
TH TH TH2
(INF-gama, IL-8) (IL-4, IL-5)

10. Histopathology
Frequent epithelial damage, a thickened basement membrane, and Edematous to sometimes fibrotic stromal tissue, with a reduced number of vessels and glands but virtually no neural structure
Among the inflammatory cells, Eosinophils are a prominent and characteristic feature in about 80% of polyps

11. . Immunoperoxidase staining
H&E staining
Photomicrographs of human nasal polyp (A and C) and adjacent nasal mucosa (B and D). The polyp (A) is characterized by extensive submucosal infiltration by eosinophils (arrowheads) and attenuation of the overlying respiratory epithelium. Immunoperoxidase staining of step sections of the polyp (C) with antieotaxin mAb 6H9 revealed intense immunoreactivity to epithelium, endothelium lining venules (v), eosinophils (arrows), mononuclear cells (arrowheads), and spindle cells. In contrast, the adjacent respiratory tissue is characterized by normal pseudostratified columnar epithelium and no eosinophil infiltration (B), and immunostaining for eotaxin shows only light constitutive immunoreactivity to epithelium and submucosal mesenchymal cells (D). (A and B) Hematoxylin and eosin, ×1,450; (C and D) ABC-peroxidase technique with Mayer's hematoxylin, ×1,450.
Ponath P. D. et al. J. Clin. Invest. Volume 97, Number 3, February 1996,
. Immunoperoxidase staining

12. The medium-power microscopic appearance of this lesion is characteristic of a nasal inflammatory polyp. Note the edemetous connective tissue filled with numerous eosinophils (bright pink granules) and plasma cells (blue cells with eccentric round nuclei and perinuclear pink zone in the cytoplasm). The overlying respiratory-type epithelium shows some reactive expansion (hyperplasia) of the basal cell layer but the overlying ciliated epithelial cells are still present.

14. Pathomechanism Eosinophilic inflammation
IL-5 was found to be significantly increased in nasal polyps
Cytokine IL-5  Eos  ECP (E. cationic protein)  progression in pathology

15. Pathomechanism Extracellular matrix regulation
Eos  TGF-β1&2  Fibroblast activity  progression in pathology (increase in extra cellular matrix formation)

16. Pathomechanism Role of Staphylococcus aureus enterotoxins (SAE)
Multiclonal IgE antibody formation to SAE can be seen in nasal polyp tissue, but rarely in CRS
It is positive in about 30-50% of the patients with NP and in about 60-80% of nasal polyp subjects with asthma

17. Nasal polyposis: aetiology and pathogenesis
Epithelial damage (barrier dysfunction)
chronic microbial trigger
Chemokines T B
Cytokines 
Hyper IgE 
Eosinophils 
( apoptosis)
Superantigens
IL-5
ECP
Albumin
Eotaxin
Polyclonal IgE
S. Aureus enterotoxins: disease modifiers

18. Demo for Pathogenesis Y Y Y Y Y Y Y polyps B cell Mast cell eosinophil
Arachydonic acid
cytokines Y Y Y
Cycloxygenase
5 lipoxygenase
Leukotrienes
Prostaglandin
Histamine
Interleukin
Thanks from Dr. R. Cathcart for this demo

19. Differentials Encephalocoeles Gliomas Dermoid tumours Haemangiomas
Papillomas / transitional cell papillomas
Nasopharyngeal angiofibromas
Rhabdomyosarcomas
Lymphomas
Neuroblastomas
Sarcomas
Chordomas
Nasopharyngeal carcinomas

20. Medical Treatments Corticosteroids
reduce airway eosinophil infiltration by preventing their increased viability and activation
Directily
Or via reducing the secretion of chemotactic cytokines by nasal mucosa and polyp epithelial cells
Topical Cort.: effect on poly size and also on symptoms associated with NP such as nasal blockage, secretion and sneezing but the effect on the sense of smell is not high

21. Postoperative treatment with topical corticoidsteriods
Postoperative effect on recurrence rate of NP after polypectomy with intranasal steroids is well documented and the evidence level is Ib
But in patients who undergone FESS operation did not show a positive effect of local corticostoroids over placebo (3mo-1yr-2yr)

22. Systemic steroids :
Is effective in polyp reduction and nasal symptoms associated with NP, even on sense of smell
Oral corticosteroids for 10 days (20-40mg)  there are reports with 21 days and also higher doses (up to 50mg) of prednisolone
The benefit of oral steroids, however, remains less definitive with little randomized data available and the risk of systemic effect from oral steroids  use in severe cases

23. Antibiotics:
There is also increasing evidence in vitro of the anti-inflammatory effects of macrolides
The exact mechanism of action is not known, but it probably involves down regulation of the local host immune response as well as a downgrading of the virulence of the colonizing bacteria

24. Regimens (12wk also you can try 6wk):
Erythromycin Ethylsuccinate: 400 q6h up to 2wk, then 400 q12h up to 10wk
Clarithromycin: 500 q12h up to 2wk, then 500 daily up to 10wk
AZM  2011  lack of efficacy in treatment of CRS with or without NP

25. Antihistamines:
Cetirizine in a dose of 20 mg/day for three months, significantly reduced sneezing, rhinorrhoea and obstruction compared to placebo but with no effect on polyp size
So it is recommended in allergic patients with NP

26. Antileukotrienes:
There are a few case controlled trials indicate that antileukotriene treatment may have beneficial effect on nasal symptoms in patients with chronic/persistent rhinosinusitis and nasal polyposis

27. Capsaicin:
It is a neurotoxin that depletes substance P with some other neurokinins and neuropeptides, leading to long-lasting damage to unmyelinated axons
Tested in Eosinophilic non allergic non asthmatic NP
capsaicin significantly increased NSAV (nose-sinuses air volume) and very significantly improved subjective and endoscopy scores, but did not significantly alter ECP

28. Method of Capsaicin delivery:
for 3 consecutive days patients received: 0.5 ml 30 mmol/L capsaicin solution sprayed into each nostril, and 100 mmol/L of capsaicin solution on days 4 and 5, respectively

29. Furosemide: It exhibited an anti-inflammatory effect
Also it acts on Na/Cl transporter and reduce tissue edema, too
Passali (2003) - RCT-n=177, post polypectomy furosemide vs. placebo vs. mometasone. Results after 5yr F/U:
17% recurrence with furosemide
30% recurrence with placebo
24% recurrence with mometasone

30. Method of furosemide delivery:
Furosemide diluted in physiological solution (2 ml of furosemide in 2 ml of saline) administered as nasal puffs (2 puffs per nostril a day, each puff corresponding to 50 micg) for 30 days.
Frist 2yrs: every other mounth (12/24mo)
Next 2yrs: 1mo on, 2mo off (8/24mo)
In 5th yr: 2mo in a year (2/12mo)

31. Strength of evidence for treatment of CRS vs. NP
Intervention Chronic rhinosinusitis Nasal polyps
Corticosteroids Topical A  A 
Systemic / C 
Antibiotics Oral short term < 2w C D
Oral long term (12w) C  C 
Antimycotics Topical / Systemic D D
Antihistamines D B
Anti-leukotrienes / C 
Nasal saline douche C  D 
Decongestants D D
Allergen avoidance D  D

32. Guideline in our country
INCS for undisclosed time  ?
Macrolide administration for 6 to 12wks
Oral corticosteroids for days (20-40mg)
Montelukast (10mg/day)
In allergic patients: Cetrizine 20mg/day for 3mo

33. Scheme for experimental polyp treatment
polyps
B cell
Mast cell
eosinophil 2 Y Y Y Y
Arachydonic acid
cytokines Y Y
Aspirin desensitisation (lysine aspirine)
5-lipoxygenase inhibitorsZileuton (hepatotoxic)
Leukotriene receptor antagonists  Montelukast, Zefirlukast
Antihistamines
Furosemide Y
Cycloxygenase
5 lipoxygenase 1 3
Leukotrienes
Prostaglandin
Histamine
Interleukin 4 5

34. Future therapies in nasal polyposis
Anti IgE
Anti-CCR3?
Anti-IgE?
Eotaxin
Anti IL-5
Tacrolimus?
IgE
Anti-IL-5?
IL-5
Corticosteroids?
Anti-LTs?
ECP
Antibiotics? Anti-fungal?

35. Surgical Treatments
Surgical treatments, including Polypectomy alone or in combination with FESS, rarely result in long term control of polyposis and are typically combined with medical treatment
When hyposmia is the primary symptom, no additional benefit seems to be gained from surgical treatment. If nasal obstruction is the main problem after steroid txy, surgical treatment is indicated

36. When to proceed with surgical therapy?
when medical therapy fails to control symptoms
when the patient is not suitable for oral steroids
when total nasal obstruction occurs
when there is persistent infection or complications

37. Simple polypectomy vs. FESS!? Dalziel (2003) - meta-analysis :
Symptom improvement Recurrence
FESS % %
Simple 43-84% %
7% difference!!

38. When is it logical to perform FESS instead of a simple polypectomy operation?
Severe and extensive disease
Underlying diseases (Asthma, Samter, Allergic fungal, CF,…)
Revision cases when pathology is not localized

40. Thank You!
Bastaninejad MD